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Cell to Cell Signaling through Light in Artificial Cell Communities: Glowing Predator Lures Prey
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  • Taniya Chakraborty
    Taniya Chakraborty
    Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
    Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
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  • Seraphine V. Wegner*
    Seraphine V. Wegner
    Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstr. 15, 48149 Münster, Germany
    Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-9072-0858
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ACS Nano

Cite this: ACS Nano 2021, 15, 6, 9434–9444
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https://doi.org/10.1021/acsnano.1c01600
Published June 21, 2021

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Abstract

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Cells commonly communicate with each other through diffusible molecules but nonchemical communication remains elusive. While bioluminescent organisms communicate through light to find prey or attract mates, it is still under debate if signaling through light is possible at the cellular level. Here, we demonstrate that cell to cell signaling through light is possible in artificial cell communities derived from biomimetic vesicles. In our design, artificial sender cells produce an intracellular light signal, which triggers the adhesion to receiver cells. Unlike soluble molecules, the light signal propagates fast, independent of diffusion and without the need for a transporter across membranes. To obtain a predator–prey relationship, the luminescence predator cells is loaded with a secondary diffusible poison, which is transferred to the prey cell upon adhesion and leads to its lysis. This design provides a blueprint for light based intercellular communication, which can be used for programing artificial and natural cell communities.

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Diffusible signaling molecules are the main basis of intercellular communication. (1,2) This cell-to-cell communication allows cells to adapt functions to their neighbors and can lead to the emergence of collective responses. (3,4) A recent focus in artificial cells is to implement concepts of chemical communication into nonliving systems in order to produce synthetic communities that signal to each other and possess sophisticated behavior. (5−9) Diverse examples of synthetic sender-receiver cells, (6,10,11) bidirectional communication, (12) engineered signaling circuits, (13,14) prey-predator communities, (15−17) communication networks, (18) phagocytosis, (8) and quorum sensing behavior (19−21) demonstrate the versatility of functions that are possible in consortia of synthetic cells using diffusible singling molecules. Building on similar principles, synthetic cells can also be interfaced with living cells and brought together in hybrid communities with enhanced capabilities. (22,23)
Bioluminescence is a widespread signal for the communication between organism at the macroscopic scale, although it is still controversial if plausible at the cellular level. (24,25) From fireflies to deep sea fish, many organisms communicate with others through the light they produce for attracting mates, luring prey, the defense against predators and so on. (26) Light as a specialized mode of communication works particularly well in darkness at night, underground, and in the deep sea and comes with distinct advantages. (27) First, light does not interfere with soluble signaling molecules. (28) Unlike some of the chemical signals such as pH, (29) oxidative species, and metal ions, (30) which alter the activity of many biomolecules, the response to light is rare and highly specific in molecules. Second, visible light passes across optically transparent barriers, such as membranes, and eliminates the need for transporters or pores. (31) In addition, light as a signal is fast in its delivery as it does not require diffusion to propagate. Light is also an information rich signal (24) since different characteristics such as wavelength, brightness, and frequency can code different information. These distinct features of light as a signal make this mode of communication conceptually very attractive.
Here, we present how cell-to-cell communication through light in artificial cell communities is possible. Inspired by deep-sea fish that attract prey through their glow, we implemented this light based mode of communication in synthetic prey–predator communities. We demonstrate that the bioluminescent signal from an artificial predator cell leads to the adhesion to an artificial prey cell. Upon adhesion, the predator injects its poison into the prey and causes its lysis. This example of communication through light between two synthetic cells demonstrates its plausibility and can serve as a blueprint for the future implementation into living cells and the communication in hybrid systems.

Results and Discussion

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Design of Cell to Cell Communication through Light in a Predator–Prey Community

The generation of an intrinsic light signal and its translation into a response in another cell are the two essential elements for light based communication between cells. The conversion of the intracellular luminescence into an intercellular response requires at least one light responsive element, which is part of a response cascade. In our design, we used luciferase activity to generate the light signal in the sender cell and the photoswitchable protein–protein interaction between iLID and Nano (32−34) as the light responsive element to convey the signal from the sender to the receiver cell. These and many other photoswitchable proteins have been employed in the field of optogenetics for the regulation of diverse functions in cells (35) and synthetic systems (33,34,36,37) with external light sources. More recently, it was shown that bioluminescence can also stimulate some light responsive proteins, which has been used to activate neurons, (38,39) regulate intracellular protein localization (40−42) and trigger bacterial aggregation. (43) In this study, we built on photoactivation with bioluminescence and employed an intrinsically generated light signal in synthetic cells as the basis of intercellular communication.
In particular, we used the bioluminescent signal from one synthetic cell, the sender (the later predator), to activate its adhesion to another cell, the receiver (the later prey) (Figure 1). These cell–cell adhesions were coupled to the exchange of a secondary chemical signal, which in the case predator–prey community functions as a poison and activates the lysis of the prey cell. Throughout the study, we worked with giant unilamellar vesicles (GUVs) as a biomimetic artificial cell model. The predator GUVs contained renilla luciferase (RLuc) inside, such that they generated an intracellular blue light signal in the presence of the substrate, coelenterazine. (44) Coelenterazine is a membrane permeable small molecule and was added externally to initiate the bioluminescence inside the sender GUV. As light responsive elements, the outer membranes of the predator and prey GUVs were decorated with the proteins iLID and Nano, respectively. The two proteins, iLID and Nano, bind to each other under blue light and dissociate in the dark, such that they can mediate adhesions between the GUVs. (34) In this design, we hypothesized that the blue bioluminescence of the luciferase can trigger the adhesion between the two types of GUVs. As part of the response cascade, we implemented adhesion dependent transfer of a secondary soluble molecule from the predator to the prey GUV. For this purpose, the membranes of both the predator and the prey GUVs had incorporated α-hemolysin (α-HL) pores (pore diameter 1.4 nm, MW cutoff = 2000 Da). These pores were blocked with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB), which noncovalently binds into the lumen of the α-HL pores and prevents the leakage of intracellular content. (11,45) Upon GUV–GUV adhesion, the blocker molecules were excluded from the adhesion sites, as TRIMEB is larger than the intermembrane distance. As a result, otherwise membrane impermeable soluble molecules could pass through the α-HL pores from one GUV to the other. Here in particular, the secondary signal was chosen to be a poison for the receiver GUV so that a predator–prey relationship was established between the two GUV populations. The predator GUVs were loaded with membrane impermeable Ca2+ ions, which upon transfer through the α-HL pores to the prey GUV activate the phospholipase A2 (PLA2) (46,47) and lead to a fluorescent signal coming from the calcium sensitive dye, Rhod2. Finally, the calcium activated PLA2 cleaved the fatty acid tail of the phospholipid in the prey GUVs and caused to their collapse. Toward the realization of this design, we demonstrated step by step each element and finally their integration.

Figure 1

Figure 1. Design of cell to cell communication through light between synthetic predator and prey cells. Predator GUVs are loaded with renilla luciferase and generate an intrinsic light signal upon addition of the substrate coelenterazine. (1) The bioluminescence of the predator GUV, activates the light dependent adhesion of predator (functionalized with iLID, membrane labeled in green) and prey (functionalized with Nano, membrane labeled in red) GUVs, due to the photoswitchable binding of iLID and Nano. (2) The blocker of the α-HL pores is displaced at the adhesion site of the predator and prey GUV and (3) allows for the contact dependent transfer of Ca2+, as a secondary soluble signal, from the predator to the prey GUV. (4) Ca2+ binds and activates apo-PLA2 and the Ca2+ sensitive fluorescent dye Rhod2. (5) PLA2 cleaves the phospholipid membrane of the prey GUV and results in its lysis.

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Generation of an Intracellular Light Signal

The first step for the realization of the above envisioned design was the generation of an intracellular light signal and the photoactivation of the iLID protein on the sender GUV though the intracellular bioluminescence. For this purpose, we prepared renilla luciferase (100 nM, RLuc-TEV-His6) loaded GUVs (lipid composition: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) with 10 mol % 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (POPG) + 0.1 mol % DGS-NTA-Ni2+) and immobilized iLID protein at their outer surface through the interaction between the His6-tag on the protein and headgroup of the DGS-NTA-Ni2+ lipid. We chose renilla luciferase due to its blue bioluminescence (emission maximum at 482 nm), which has significant spectral overlap with the absorption spectrum of the blue light responsive protein, iLID, around 480 nm (Figure S1a). To generate a bioluminescent signal inside the luciferase loaded GUVs, we added to the external buffer the substrate, coelenterazine (10 μM), which can freely pass across the lipid bilayer without needing a transporter. Indeed, we observed bright bioluminescence from a sample with these GUVs but not in a control sample, which only contained the buffer surrounding the GUVs (Figure 2a). The bioluminescence inside the GUVs had a half-life of 15 min following pseudo first order kinetics and decreased as the substrate was consumed. Moreover, the luminescence could be triggered multiple times upon repeated addition of substrate (Figure S1b). This result showed that an intracellular light signal can be generated in the GUVs upon addition of the substrate, sustained for a considerable duration and even triggered repeatedly.

Figure 2

Figure 2. Photoactivation of extracellular iLID and Nano through intracellular bioluminescence. (a) Luminescent of renilla luciferase (100 nM) loaded GUVs(orange) and the external GUV buffer after washing the GUVs (gray, negative control) upon addition of external substrate, coelenterazine (10 μM, orange). The luminescence of the GUVs has a half-life of 15.4 min based on first order kinetic kinetics. (b) Schematic representation of mOrange-Nano protein recruitment due to the bioluminescence of iLID-functionalized GUVs. As the bioluminescence decreases over time mOrange-Nano dissociates from the GUV. (c) Confocal images of an iLID functionalized GUV loaded with renilla luciferase (DiD dye on membrane, shown in red) in the presence of mOrange-Nano (2.5 μM, shown in green) upon addition of coelenterazine (10 μM). Scale bar is 10 μm. (d) Change in mOrange-Nano fluorescence intensity at the GUV membrane over time for the GUV in c. mOrange-Nano was recruited over the first 15 min, remained stable for 50 min and declined to the baseline after 60 min.

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Intrinsic Luminescence Photoactivates iLID on GUV’s Membrane

Next, we investigated if the bioluminescence generated inside the GUVs could activate an extracellular response, i.e., photoactivate iLID and result in the binding to Nano. (48) To address this question, we investigated the recruitment of fluorescently labeled Nano protein without a His-tag, mOrange-Nano (2.5 μM, shown in green), to the above-described luminescent GUVs (100 nM RLuc, iLID protein at the surface, DiD dye in the membrane shown in red) (Figure 2b). We detected a gradual increase in mOrange fluorescence on the GUV membrane upon addition of coelenterazine over the course of 15 min using confocal microscopy (Figure 2c). The quantification of the mOrange fluorescence intensity on the membrane over time showed that the mOrange signal increased for the first 15 min, was stable up to 25 min and later decreased over the course of 60 min to background levels (Figures 2d and S2a). In a negative control without the addition of coelenterazine, no such mOrange-Nano recruitment was observed (Figure S2a). These results demonstrated that the bioluminescence generated inside the GUV activated the iLID protein at the surface, which subsequently lead to the binding of mOrange-Nano. The decrease in iLID-Nano binding was expected at later time points as this binding is reversible in the dark within minutes. (32) As the bioluminescence intensity decreased less iLID protein was photoactivated and the reversion become the dominant reaction.

Cell to Cell Communication through Light Results in Adhesions between Synthetic Cells

Next, we investigated if the intracellular bioluminescence can lead to intercellular communication in the form of adhesions between a sender and a receiver cell. (34)
In this experiment, the sender GUVs were loaded with renilla luciferase (100 nM) and functionalized with iLID at their surfaces and their membranes were labeled with the membrane dye, DiL (shown in green). The receiver GUVs had Nano at their surface (immobilized thought His6-tag on Nano) and were labeled with the membrane dye, DiD (shown in red) (Figure 3a). These two GUV populations were mixed in equivalent ratios in a glass chamber for 30 min with gentle agitation. In one sample, where bioluminescence was triggered through the addition of coelenterazine, the iLID (shown in green) and Nano (shown in red) decorated GUVs adhered to each other as observable with confocal microscopy (Figures 3b and S3a). In comparison, nonluminescent GUVs (i.e., in the absence of coelenterazine) adhered to each other similarly well under blue light (positive control) but didn’t adhere to each other in the dark (negative control). The lack of GUV–GUV adhesions in the absence of coelenterazine in dark and the formation of multi-GUV clusters upon addition of the substrate confirmed that the intracellular bioluminescence induced the GUV-GUV adhesions.

Figure 3

Figure 3. Intrinsic luminescence signal induced adhesion between sender and receiver GUVs. (a) Schematic representation of cell to cell communication through intracellular light. The sender GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM), and the receiver GUV (shown in red) is functionalized with Nano. Upon addition of coelenterazine, the sender GUV generates intracellular light, activates iLID on the membrane, which results in the adhesion to the receiver GUV. (b) Confocal images of sender (Dil membrane dye, shown in green) and receiver (DiD membrane dye, shown in red) GUVs in the presence of coelenterazine (10 μM) (luminescence) and in the absence of coelenterazine either in dark (negative control) or under blue light (positive control) after 30 min. Scale bars are 30 μm. (c) Average area of objects (single and clustered GUVs, see Methods for details) described in (b). Sender and receiver GUVs cluster under luminescence as efficiently as under blue light illumination. (d) Average area of objects over time after the addition of coelenterazine to luminescence and dark sample in (b). Luminescence triggered GUV clustering increased over the first 60 min and decreased after 120 min as the luminescence decreased. The average of three technical replicates was reported and statistical significance was evaluated with one-way ANOVA, ***p < 0.001.

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The clustering of GUVs upon photoactivation was quantified using automated image analysis and scanning large areas (0.5 mm2 with ca. 300 GUVs) of each sample. In this analysis, the area of each object, including single GUVs and clusters of GUVs, was measured and the average area of all detected objects was used as a metric for clustering: the more the GUVs cluster, the higher was the average area of the detected objects. In this analysis, it was apparent that the average area for GUVs that produced luminescence and that were illumined with blue light was the same and higher than for GUVs kept in the dark (Figure 3c). In parallel, objects with large areas, representing clusters of multiple GUVs, were only observed in the luminescent and the blue light sample but not in the dark (Figure S3b). It should be noted that the total number of sender and receiver GUVs was kept constant between samples to avoid artifacts in clustering arising from overcrowding and difference in confluency (Figure S3c).
The luminescence induced clustering of GUVs was reversible over time as the luminescence decreased (Figures 3d and S4a). More precisely, the GUV clustering was maximal 1 h after inducing the luminescence and decreased significantly after 2 h. In fact, the reversion of the GUV clusters was almost complete after 2 h but still higher than the negative control sample kept in the dark (Figures 3d and S4b,c). As previously shown, not all adhesions between iLID and Nano decorated GUVs were completely reversible as adhesions that strongly deform the GUVs are not reversible. (34)

Coupling Cell to Cell Communication through Light with Contact Dependent Chemicals Communication

In many bioluminescent organisms, the light signal acts as an attractant and once the partner is in close proximity subsequent actions are triggered such as in the mating of fireflies or the luring of a prey in the case of deep sea fish. (25) Inspired by this concept, we designed a predator–prey pair, where the luminescence of the predator GUV first leads to the proximity of the prey GUV followed by the injection of a secondary soluble signal into the prey, which leads to its lysis. This adhesion triggered cell-to-cell communication through secondary soluble signals at the adhesion interphase increases the efficiency of this signal transduction and prevents its loss into the environment through excessive dilution. For this reason, also in biology cell-to-cell communication based on direct contacts are critical in coordinating various processes, from tissue development to immune cell regulation (49) and to the injection of poisons by predator into their prey.
Here, we demonstrated how the luminescence induced adhesions between two populations of GUVs lead to the transfer of a secondary diffusible signaling molecule (Figure 4a). In this case, the above-described sender GUV (loaded with 100 nM RLuc, iLID protein at the surface, DiL dye in the membrane shown in green) were additionally loaded with 2 mM CaCl2 as a secondary signaling molecule. Likewise, the receiver GUVs (Nano protein at the surface, DiD dye in the membrane shown in red) were loaded with the Ca2+ sensitive dye, Rhod2 (2 μM, shown in green). Thus, in the here envisioned setup, the transfer of Ca2+ from sender to receiver GUVs would be visible as an increase in green Rhod2 fluorescence inside the red labeled receiver GUVs. Unlike the intracellular light signal, Ca2+ requires a pore for its transport across the GUV membranes due to its charge, for which we used the transmembrane protein pore α-hemolysin (α-HL, 25 ng/μL). To make the transport of Ca2+ adhesion dependent, the α-HL pores were blocked with TRIMEB (4 mM). TRIMEB acts as a blocker of the pores and is removed when two GUV membranes come into proximity such that the transport from one GUV to the next becomes possible at the adhesion interphase through the α-HL pores.

Figure 4

Figure 4. Coupling cell to cell communication through light to contact dependent chemical communication. (a) Schematic representation of contact dependent transfer of a secondary soluble signal following light triggered adhesion. The sender GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM) and Ca2+ (2 mM) and the receiver GUV (shown in red) is functionalized with Nano and loaded with Rhod2. Both types of GUVs contained α-HL (25 ng/μL), which were blocked by TRIMEB (4 mM). Upon addition of coelenterazine (10 μM), the sender GUV generates intracellular light and activates the adhesion to the receiver GUV. The blocker is displaced at the adhesion interphase and the secondary Ca2+ signal is transferred from the sender to the receiver GUV, visible as an increase in fluorescence of Rhod2. (b) Confocal images of sender (Dil membrane dye, shown in green) and receiver (DiD membrane dye, shown in red and intracellular Rhod2, shown in green) GUVs in the presence of coelenterazine (luminescence) and in the absence of coelenterazine either in the dark (negative control) or under blue light (positive control) after 40 min. The intracellular Rhod2 fluorescence increases in the luminescence and the blue light sample, where the sender GUVs adhere to receiver GUVs. Scale bars are 30 μm. (c) Mean Rhod2 fluorescence intensity inside receiver GUVs (n = 30) in (b). In the luminescent and blue light sample, two populations of receiver GUVs were defined as proximal if in close contact with a sender GUV and as distal if not. Statistical significance was evaluated with the one-way ANOVA test, ***p < 0.001.

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Indeed, when equal numbers of sender and receiver GUVs were mixed an increase of Rhod2 fluorescence was visible in the receiver GUVs upon addition of the coelenterazine using confocal microscopy (Figure 4b). In comparison, a similar increase in Rhod2 fluorescence was also observed in the positive control, where the GUVs adhesions were induced with blue light illumination but not in the negative control, which was kept in the dark and where the GUVs did not adhere to each other. The quantification of the mean fluorescence intensity of Rhod2 inside randomly picked receiver GUVs (n = 30) further supported this observation (Figure 4c). Moreover, both with the bioluminescence and under blue light, the Rhod2 fluorescence only increased in receiver GUVs which were in direct contact with sender GUVs (proximal) but not in receiver GUVs which were far away from sender GUVs (distal). This is further evidence for that the transfer of the Ca2+ signal requires the adhesion between sender and receiver GUVs. These results showed that first the luminescence signal from sender GUVs lead to the adhesion of receiver GUVs and subsequently, the transfer of a second soluble Ca2+ signal from the sender to the receiver GUVs through the α-HL pore.

Luminescence Induced Prey–Predator Behavior in an Artificial Cell Community

In a population of two different types of artificial cells the transfer of a soluble signaling molecule from one to another can lead to diverse reactions (6,9,22) In particular, we designed a predator–prey couple such that the predator would lure the prey through its bioluminescence and cause its lysis. For this purpose, we employed the above-described Ca2+ loaded luminescent sender GUVs as the predator and loaded phospholipase A2 (PLA2, 100 nM) enzyme in its apo-form into the receiver GUVs above, which were the prey. The rationale behind this set up was that when the cofactor Ca2+ activates apo-PLA2, it cleaves the fatty acid tail in position two of phospholipids. Thus, the Ca2+ transferred from predator to the prey GUVs would act as a poison and initiate the digestions of the phospholipid bilayer of prey GUV from inside. Finally, this would result in the lysis of the prey GUV and the formation of micelles (Figure 5a).

Figure 5

Figure 5. Lysis of prey GUVs by luminescent predator GUVs in a synthetic cell community. (a) Schematic representation of a luminescent predator GUV lysing the prey GUV. The predator GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM), Ca2+ (2 mM), and the prey GUV (shown in red) is functionalized with Nano and loaded with apo-PLA2 enzyme and Rhod2. Both types of GUVs contained α-HL (25 ng/μL), which were blocked by TRIMEB (4 mM). Upon addition of coelenterazine (10 μM), the predator GUV generates intracellular light, adheres to the prey GUV, and transfers Ca2+ to the prey GUV. Ca2+ activates PLA2, which cleaves the phospholipid bilayer of the prey GUV and results in its lysis. (b) Confocal images of a predator GUV (Dil membrane dye, shown in green), which first adhered to a prey GUV (DiD membrane dye, shown in red) in the presence of coelenterazine and subsequently lysis. See Movie 2. Scale bars are 20 μm. (c) Confocal images of predator and prey GUVs in the absence and presence of coelenterazine after 40 min. Predator GUVs not loaded with Ca2+ and prey GUVs not loaded with PLA2 were used as negative controls. Prey GUVs only lysed when the predator GUV generated intracellular luminescence, contained the secondary Ca2+ signal and the prey GUV was loaded with PLA2. Scale bars are 20 μm. (d) Number of predator or prey GUVs present in (c). The number of prey and predator GUVs was similar in all samples except for the prey GUVs in the presence of coelenterazine, PLA2 and Ca2+, which was reduced due to their lysis.

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In an initial experiment using only prey GUVs, we monitored the lysis of GUVs upon activation of intracellular PLA2 (100 nM) with externally added Ca2+ (1 mM). In this case, the calcium selective ionophore, ionomycin (34) was added to the GUVs to initiate the transfer of the external Ca2+ into the GUVs. Indeed, the GUVs lysed a few minutes after the addition of ionomycin, indicating that the Ca2+ ions active the PLA2 enzyme and cleave the phospholipids in the GUV membrane (Figure S5a, Movie 1).
Next, the predator GUVs (100 nM RLuc, 1 mM CaCl2, 25 ng/μL α-HL, iLID protein at the surface, DiL dye in the membrane shown in green) and prey GUVs (100 nM PLA2, 2 μM Rhod2, 30 μM EDTA, 25 ng/μL α-HL, Nano protein at the surface, DiD dye in the membrane shown in red) were mixed (external buffer: 100 μM EDTA, 4 mM TRIMEB blocker). Then, the bioluminescence inside the predator GUV was triggered through the addition of coelenterazine. In this mixture of prey and predator GUVs, the prey GUVs selectively lysed when the predator GUVs produced light as observed by confocal microscopy (Figures 5b and S5b, Movies S2 and S3). The prey GUV first adhered to predator GUVs within 30 min and then lysed a few minutes later. The lysis of the prey GUV resulted in the formation of small red fluorescent micelles, which were visible in the bulk. In some cases, the prey GUVs lysed, being partially observable as vesicles inside the prey GUVs (Figure S5c,d). On the other hand, prey GUVs did not lyse when no stable contacts formed between prey and predator GUV (Figure S5e, Movie 4). The adhesion dependent transfer of Ca2+ ions from the predator to the prey GUV was further supported with similar results when the adhesions were triggered with blue light illumination rather than luminescence (Figure S5f,g, Movies S5 and S6).
In this predator–prey community, each molecular component in the reaction cascade between the luminescent predator and the prey played an essential role for the final behavior (Figure 5c). The lysis of the prey GUVs was only observed upon triggering the luminescence inside the predator GUVs. On the other hand, the prey and predator GUVs coexisted when the predator GUV was not luminescent. When one of the elements, the primary light signal or the secondary Ca2+ signal from the predator or the effector in the prey, PLA2, was not included in the system, the prey–-predator relationship between the GUVs was impaired. The exclusion of different components stopped the reaction cascade at different stages: the luminescence triggered adhesion between the GUVs in all cases, the exclusion of Ca2+ impaired the transfer of the secondary signal and subsequent PLA2 activation, and the omission of PLA2 only stopped the lysis of the prey GUVs but the secondary Ca2+ was still transferred (visible as an increase in Rhod2 fluorescence in prey GUVs, Figure 5c).
The selective lysis of the prey GUVs was also apparent in the count of the predator (shown in green) and prey (shown in red) GUVs at the population level from the microscopy images (Figure 5d). When the predator GUVs produced light, the number of prey GUVs was reduced by 50% after 40 min. In contrast, without the luminescence of the predator or if the Ca2+ in the predator or PLA2 in the prey GUV were missing, the number of prey GUVs was as high as the predator GUVs, which reflects the initial mixing in equal proportions. This quantification further demonstrated that the activated PLA2 did not attack the predator GUVs after the lysis of the prey GUVs. There were two reasons behind the predator GUV survival. First, the extracellular EDTA (100 μM) removed the Ca2+ ions from PLA2 once released from the prey GUVs and protects the GUVs from extracellular digestion as GUVs were stable even in the presence of 100 nM PLA2 with EDTA in the external buffer (Figure 6a). Second, the excessive dilution of PLA2 in the medium after GUV lysis significantly lowered its activity. Control experiments showed that already a 2-fold dilution of PLA2 no longer resulted in GUV lysis (Figure S6b). It is noteworthy that it is possible to selectively lyse the prey GUV although the predator and the prey GUVs have the same chemical lipid composition.

Conclusions

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Here, we presented that cell-to-cell communication through light is possible with artificial cells. We have successfully demonstrated that an intrinsic light signal produced in one cell leads to the communication through a molecularly designed reaction cascade. Elements of this reaction cascade are the intracellular bioluminescence of the sender cell, the light triggered adhesion between sender and receiver cells, the adhesion dependent transfer of a coupled secondary signal and response of the receiver cell, which in this case is its lysis. This design is a blue print for the cell-to-cell communication through light and contact dependent exchange of soluble signals as the choice of secondary soluble signals is flexible and can be chosen such that any other desired function is activated.
The communication through light and the coupled downstream activation of follow-up processes is widely spread in biology at the macroscopic scale and should not be underestimated as a mode of communication. Many organisms across the evolutionary tree use bioluminescence to transmit messages and bioluminescence has evolved independently about 40 times, which speaks for its importance. For instance, it is estimated that 90% of deep-sea animals’ luminesce (25,26) is used for diverse purposes from mating or prey attraction, protection from predators, to camouflaging. This diversity of functions that built on light based communication calls for translation into synthetic life like systems and speaks for its potential to achieve diverse behavior in consortia of cells.
Whether communication through light is possible between single cells is still controversial. (24) Such communication requires the cells to generate light with some specific property (wavelength, intensity, etc.) and another cell to have the ability to sense it. Strong luminescence in the visible range is produced by single cell luminescent bacteria, (19,20) but there is no report that links it to communication with other bacteria. On the other hand, cells emit very weak autoluminescence but it is uncertain if such low photocounts can lead to a cellular reaction. The here presented bioluminescent based signaling between artificial cells shows that indeed communication through light is possible at the cellular level, and this simplified system provides a design model for it. Considering that cells in the human body are not known to bioluminescence, this mode of intercellular communication has the potential to be an orthogonal way to address artificial cells in vivo.
The cell-to-cell communication through light has distinct features compared to signaling with diffusible molecules (50,51) in terms of transport across cell boundaries, propagation, and specificity. The transport of soluble signals across a lipid bilayer requires transporters or semipermeable membrane structures, (31) which differ depending on the chemical identity. In contrast, visible light passes through the optically transparent bilayer without the need of further modifications. (52) This difference is also obvious in the here presented example, where the light signal was directly transmitted to the exterior but the secondary Ca2+ signal required the presence of α-HL pores. Second, the propagation speed of the signal is limited by diffusion and dilution in the case of chemical signals. (6,10,14,18,34) On the other hand, light signals propagate at the speed of light and are constantly produced at the source as long as the underlying the bioluminescent reaction continues. In the here presented prototype, it was possible to adjust the bioluminescent output and reactivate it as desired, yet for the secondary Ca2+ signal it is not possible to replenish it in the sender GUVs once it is released. (11,34) Finally, it should be noted that light as a signal is highly specific as the response of a molecule to visible light is a rather unusual feature and hence undesired cross reactivity is very unlikely. On the other hand, a depending on its chemical identity (acids/bases, metal ions, reactive oxygen species), such a diffusible signal can cause multiple changes in the system. For example, the here used Ca2+ signal both activated the PLA2 and the fluorescence of the dye and in a more complex environment can bind to other proteins and alter their activity. (53)
Opto-chemogenetics, which uses bioluminescence for the activation of optogenetic proteins, (40−42) is a fast-growing part of the optogenetic toolkit as it allows for photoactivation in places that are not accessible to physical light sources. (39) The intrinsic generation of light in the place of interest overcomes limitations in deep tissue penetration of light and its delivery through implanted optical fibers. (54) For instance, opto-chemogenetic systems have made it possible to regulate neuronal activity using light sensitive ion channels with bioluminescence. (38,55) As these approaches gain in importance in vivo, communication through light provides is an orthogonal communication interphase to chemical communication and an opportunity to guide artificial cells in the body.

Methods

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Materials

The Ni2+-NTA functionalized polystyrene beads with a 2 μm diameter were purchased from Micromod Partikeltechnologie GmbH as a water suspension (50 mg/mL, 1.2 × 1010 beads/ml). All lipids, 1-palmitoyl-2-oleoylphosphatidylcholine (16:0–18:1 PC) (catalog number 850457), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (16:0–18:1 PG) (catalog number 840457), and 1,2-dioleoyl-sn-glycero-3-{(N-(5-amino-1-carboxypentyl)iminodiacetic acid) succinyl} Ni2+-salt (18:1 DGS-NTA(Ni)) (catalog number 790404) were purchased from Avanti Polar Lipids in chloroform. The membrane dyes 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiL) (catalog number D282-100 mg) and 1,1′-dioctadecyl-3,3,3′,3′-Tetramethylindodicarbocyanine (DiD) (catalog number D7757-10 mg) and the calcium sensitive dye Rhod2 (catalogue number R12220) were purchased from Thermo-Fisher Scientific. Coelenterazine native (catalog number 10110) was purchased from Biotium. All others chemicals including α-HL from Staphylococcus aureus (catalog number H9395) and TRIMEB (catalog number H4645) were purchased from Sigma-Aldrich. All microscopy experiments for GUV were performed in μ-slide 24-well glass bottom chambers from ibidi (catalogue number 81817).

Plasmids and Proteins

The sequence coding for renilla luciferase was synthesized by the GeneScript and inserted into a pET21b plasmid between the Ndel and Sac1 restriction sites such that it has a TEV cleavable C-terminal His6-tag (RLuc-TEV-His6, Figure S8). pQE-80L iLID (C530M) and pQE-80L MBP-SspB Nano were gifts from Brian Kuhlman (Addgene plasmid # 60408 and 60409, respectively). pQE-80L iLID expresses iLID with an N-terminal His6-tag (His6-iLID), and pQE-80L MBP-SspB Nano expresses Nano with a TEV cleavable N-terminal His6-MBP-tag (His6-MBP-TEV-Nano). The previously described mOrange-Nano plasmid includes an N-terminal TEV cleavable His6-MBP-tag and a mOrange protein fused to the N-terminus of Nano (His6-MBP-TEV-mOrange-Nano). All proteins were expressed and purified as previously described, (48) and details are provided in the Supporting Information.

GUV Preparation, Protein Functionalization, and Washing

GUVs were prepared by the poly(vinyl alcohol) (PVA)-gel assisted formation method and as previously described. (34) In detail, a PVA solution was prepared by mixing 5% (w/v) PVA (MW: 145 000 g/mol) in Milli-Q water with 100 mM sucrose overnight at 400 rpm at 80 °C. A volume of 40 μL of the PVA solution was dried as a thin film on a glass slide (60 mm × 24 mm) at 50 °C for 30 min. Then, 5 μL of a lipid mixture in chloroform containing 10 mol % POPG, 0.1 mol % DGS-NTA-Ni2+ and either 0.2 mol % Dil dye or 0.2 mol % DiD dye in 10 mg/mL POPC was spread into the PVA layer and dried for 1 h at 30 °C. Using a Teflon chamber (ca. 40 mm × 24 mm) as a spacer and a second glass slide, a chamber was built on top of the slide with PVA and lipid layers. Then, the lipids were hydrated with 1 mL of 100 mM sucrose in Buffer B (10 mM Tris, 100 mM NaCl, pH 7.4) containing all the components to be loaded into the GUV depending on the experiment (100 nM RLuc, 100 nM PLA2, 30 μM EDTA, 25 ng/μL of α-HL, 1–2 mM CaCl2, 1–2 μM Rhod2) for 1 h at room temperature allowing GUV formation. After that, the chamber was inverted for 5 min, gently taped twice using a pipet tip and the GUVs were harvested into a 1.5 mL LoBind Eppendorf tube.
To functionalize the outer membrane of the GUVs with His-tagged proteins, 400 μL of GUVs was mixed with 1 μM of either His6-tagged iLID or His6-tagged Nano in the dark for 30 min. Next, to wash away excess protein and loaded components, 1 mL of Buffer B supplemented with 100 mM glucose was added to the GUVs and the GUVs were allowed to settle overnight at 4 °C in the dark. The next day morning, the top 1 mL of the buffer was removed without disturbing the bottom layer. The GUVs were washed a second time as before but the GUVs were only allowed to settle for 2 h. In the third washing step, 500 μL of 100 mM glucose containing Buffer B was added and the GUVs were allowed to settle for 1h at room temperature in dark. The bottom 40 μL of each GUV preparation was used in further experiments. In most experiments, 40 μL of iLID and Nano functionalized GUVs were mixed. The three-step washing protocol and the 1:1 mixing of the two GUV types results in a 55-fold dilution (1.8% background) of the GUV loaded components in the exterior buffer, which was used as a negative control in experiments.
For GUVs loaded with α-HL, the buffer contained 4 mM TRIMEB blocker during protein functionalization and all washing steps. For GUVs loaded with PLA2 the buffer also contained 30 μM EDTA for all steps. For communication and lysis experiments, the GUVs were prepared on the day of the experiment and were allowed to settle for only 2 h in the dark during each washing step.
The partial quenching of mOrange fluorescence by coelenterazine was assessed with GUVs that were functionalized with Histag-mOrange-Nano (Figure S2b).

Luminescence Measurements Inside the GUVs

All luminescence measurements were performed on a multimode plate reader (Spark, Tecan Life Science). GUVs loaded with 100 nM renilla luciferase without membrane dye were prepared and washed as described above. A volume 200 μL of GUVs from the bottom of the tube and exterior buffer from the top of the tube (negative control) were added into 96-well white bottom plate. External coelenterazine (5–20 μM) was added into the solutions just before initiating the luminescence measurements.

mOrange-Nano Recruitment to iLID-GUVs with Bioluminescence

iLID functionalized GUVs loaded with 100 nM RLuc were mixed in a 1:1 ratio with 2.5 μM mOrange-Nano without His-tag in Buffer B in a BSA treated 24-well glass bottom chamber. The GUVs were located under the confocal microscope using the DiD membrane dye (λex = 644 nm; λem = 665 nm) and the recruitment of mOrange-Nano (λex = 557 nm; λem = 576 nm) was triggered through the addition of 10 μM coelenterazine. The mean fluorescence intensity of a whole GUV was quantified using ImageJ and corrected for the background signal.

Luminescence Triggered GUV-GUV Adhesions

The GUV containing tubes were left open for ca. 20 min at RT in dark to partially deflate the GUVs. Subsequently, sender GUVs (iLID protein at the surface, DiI membrane dye, loaded with 100 nM RLuc) and receiver GUVs (Nano protein at the surface, DiD membrane dye) were mixed in 1:1 ratio in a BSA coated imaging chamber in the dark. The GUVs mixtures were kept in the dark (negative control) or under blue light (positive control) or in the dark in the presence of 10 μM coelenterazine (luminescent sample). The samples were gently agitated at 30 rpm on an orbital shaker for up to 120 min. Then, a total area of 0.5 mm2 (737 × 737 μm) was imaged through a 63× water objective in the DiD and DiI channels and analyzed using ImageJ. The images in the DiD and DiI channels were analyzed separately to quantify the number of GUVs of each type and the images in the DiD and DiI channels were merged for the GUV clustering analysis. For both analyses, the images were converted into binary images setting the threshold such that all GUVs were detected, the GUVs were filled with the fill holes function and the number and area of objects larger than 10 μm2 were detected using the particle analyzer tool. All experiments were performed in triplicate.

Secondary Ca2+ Signaling between Sender and Receiver GUVs

Sender GUVs (iLID protein at the surface, DiI membrane dye, loaded with 100 nM RLuc, 2 mM CaCl2 and 25 ng/μL α-HL) and receiver GUVs (Nano protein at the surface, DiD membrane dye, loaded with 2 μM Rhod2 and 25 ng/μL α-HL) were mixed in equal volume in the presence of 4 mM TRIMEB and 30 μM EDTA in a BSA coated imaging chamber and incubated on an orbital shaker at 30 rpm for 40 min. Samples were kept in the dark, under blue light or in the dark in the presence of 10 μM coelenterazine. Images of the GUVs were acquired in the DiI/Rhod2 and DiD channels using confocal microscopy. The mean Rhod2 fluorescence intensity inside randomly picked (n = 30, for each type) receiver GUVs (DiD labeled) proximal and distal to a sender GUV (DiI labeled) was measured using ImageJ.

Lysis of Prey GUVs by Luminescent Predator GUVs

Predator GUVs (iLID protein at the surface, DiI membrane dye, loaded with 100 nM RLuc, 1 mM CaCl2 and 25 ng/μL α-HL) and prey GUVs (Nano protein at the surface, DiD membrane dye, loaded with 100 nM PLA2, 2 μM Rhod2, 30 μM EDTA and 25 ng/μL α-HL) were mixed in equal volumes in the presence of 4 mM TRIMEB and 100 μM EDTA in a BSA coated imaging chamber and incubated on an orbital shaker at 30 rpm for 40 min in the presence or absence of 10 μM coelenterazine. Similarly, predator GUVs without CaCl2 and prey GUVs without PLA2 were prepared and mixed with the corresponding prey or predator GUVs in the presence of absence of coelenterazine. Then, images of the GUVs were acquired in the DiD and DiI channels (total area = 0.4 mm2, 737 μm × 552 μm) and the number of each GUV type as quantified as described above.

Confocal Fluorescence Microscopy

All images were acquired on a Leica SP8 confocal laser scanning microscope through a 63× water objective. The Dil dye and Rhod2 dye were excited with a 552 nm laser, and the emission was detected 560–630 nm (DiI: λex = 557 nm; λem = 576 nm, Rhod2: λex = 552 nm; λem = 581 nm); the DiD dye was excited with a 638 nm laser, and the emission was detected 650–700 nm (DiD: λex = 644 nm; λem = 665 nm). All images were analyzed using ImageJ 1.52b.

Statistical Analysis

The data was presented with the mean ± SEM from three independent samples. The statistical significance was determined by one-way ANOVA using OriginPro9.1. p values: ns > 0.1, *p < 0.1, **p < 0 .01, ***p < 0.001

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.1c01600.

  • Details of protein purification, absorbance spectrum of iLID and luminescence spectrum of RLuc, additional examples of mOrange-Nano recruitment to luminescent GUVs decorated with iLID, detailed analysis of luminescence induced adhesion and its reversion between iLID and Nano functionalized GUVs, additional examples of predator GUVs lysing prey GUVs including negative controls, SDS-PAGE of proteins, RLuc plasmid map and sequence (PDF)

  • Receiver GUVs lysis with presence of ionomycin and calcium (AVI)

  • Prey GUVs lysing after forming adhesions with luminescent predator (AVI)

  • Prey GUVs lysing after forming adhesions with luminescent predator (AVI)

  • Prey GUVs not lysing when luminescent predator GUVs pass by without forming adhesions (AVI)

  • Prey GUVs lysing after forming adhesions with predator GUVs under blue light (AVI)

  • Prey GUVs lysing after forming adhesions with predator GUVs under blue light (AVI)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
    • Seraphine V. Wegner - Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstr. 15, 48149 Münster, Germany;  Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany;  Orcidhttps://orcid.org/0000-0002-9072-0858;  Email: [email protected]
  • Author
    • Taniya Chakraborty - Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstr. 15, 48149 Münster, Germany;  Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
  • Author Contributions

    T.C. and S.V.W. designed the experiments, T.C. conducted the experiments. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work is funded by the MaxSynBio consortium, which is jointly funded by the Federal Ministry of Education and Research (BMBF) (FKZ 031A359L) of Germany and the Max Planck Society as well as the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 433682494 – SFB 1459. We would like to thank Prof. Brian Kuhlman for the plasmids coding iLID and Nano (Addgene # 60408 and 60409) and Ms. Nina Knubel for technical support with graphic design.

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    In nature, cells self-assemble into spatially coded tissular configurations to execute higher-order biol. functions as a collective. This mechanism has stimulated the recent trend in synthetic biol. to construct tissue-like assemblies from protocell entities, with the aim to understand the evolution mechanism of multicellular mechanisms, create smart materials or devices, and engineer tissue-like biomedical implant. However, the formation of spatially coded and communicating micro-architectures from large quantity of protocell entities, esp. for lipid vesicle-based systems that mostly resemble cells, is still challenging. Herein, we magnetically assemble giant unilamellar vesicles (GUVs) or cells into various microstructures with spatially coded configurations and spatialized cascade biochem. reactions using a stainless steel mesh. GUVs in these tissue-like aggregates exhibit uncustomary osmotic stability that cannot be achieved by individual GUVs suspensions. This work provides a versatile and cost-effective strategy to form robust tissue-mimics and indicates a possible superiority of protocell colonies to individual protocells.
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  10. 10
    Tang, T. D.; Cecchi, D.; Fracasso, G.; Accardi, D.; Coutable-Pennarun, A.; Mansy, S. S.; Perriman, A. W.; Anderson, J. R.; Mann, S. Gene-Mediated Chemical Communication in Synthetic Protocell Communities. ACS Synth. Biol. 2018, 7, 339– 346,  DOI: 10.1021/acssynbio.7b00306
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    10
    Gene-mediated chemical communication in synthetic protocell communities
    Tang, T-Y. Dora; Cecchi, Dario; Fracasso, Giorgio; Accardi, Davide; Coutable-Pennarun, Angelique; Mansy, Sheref S.; Perriman, Adam W.; Anderson, J. L. Ross; Mann, Stephen
    ACS Synthetic Biology (2018), 7 (2), 339-346CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    A gene-directed chem. communication pathway between synthetic protocell signaling transmitters (lipid vesicles) and receivers (proteinosomes) was designed, built and tested using a bottom-up modular approach comprising small mol. transcriptional control, cell-free gene expression, porin-directed efflux, substrate signaling, and enzyme cascade-mediated processing.
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  11. 11
    Bolognesi, G.; Friddin, M. S.; Salehi-Reyhani, A.; Barlow, N. E.; Brooks, N. J.; Ces, O.; Elani, Y. Sculpting and Fusing Biomimetic Vesicle Networks Using Optical Tweezers. Nat. Commun. 2018, 9, 1882– 1892,  DOI: 10.1038/s41467-018-04282-w
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    11
    Sculpting and fusing biomimetic vesicle networks using optical tweezers
    Bolognesi Guido; Friddin Mark S; Salehi-Reyhani Ali; Barlow Nathan E; Brooks Nicholas J; Ces Oscar; Elani Yuval; Salehi-Reyhani Ali; Brooks Nicholas J; Ces Oscar; Elani Yuval; Salehi-Reyhani Ali; Ces Oscar; Elani Yuval
    Nature communications (2018), 9 (1), 1882 ISSN:.
    Constructing higher-order vesicle assemblies has discipline-spanning potential from responsive soft-matter materials to artificial cell networks in synthetic biology. This potential is ultimately derived from the ability to compartmentalise and order chemical species in space. To unlock such applications, spatial organisation of vesicles in relation to one another must be controlled, and techniques to deliver cargo to compartments developed. Herein, we use optical tweezers to assemble, reconfigure and dismantle networks of cell-sized vesicles that, in different experimental scenarios, we engineer to exhibit several interesting properties. Vesicles are connected through double-bilayer junctions formed via electrostatically controlled adhesion. Chemically distinct vesicles are linked across length scales, from several nanometres to hundreds of micrometres, by axon-like tethers. In the former regime, patterning membranes with proteins and nanoparticles facilitates material exchange between compartments and enables laser-triggered vesicle merging. This allows us to mix and dilute content, and to initiate protein expression by delivering biomolecular reaction components.
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  12. 12
    Joesaar, A.; Yang, S.; Bögels, B.; van der Linden, A.; Pieters, P.; Kumar, B. P.; Dalchau, N.; Phillips, A.; Mann, S.; de Greef, T. F. DNA-Based Communication in Populations of Synthetic Protocells. Nat. Nanotechnol. 2019, 14, 369– 378,  DOI: 10.1038/s41565-019-0399-9
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    12
    DNA-based communication in populations of synthetic protocells
    Joesaar, Alex; Yang, Shuo; Boegels, Bas; van der Linden, Ardjan; Pieters, Pascal; Kumar, B. V. V. S. Pavan; Dalchau, Neil; Phillips, Andrew; Mann, Stephen; de Greef, Tom F. A.
    Nature Nanotechnology (2019), 14 (4), 369-378CODEN: NNAABX; ISSN:1748-3387. (Nature Research)
    Developing mol. communication platforms based on orthogonal communication channels is a crucial step towards engineering artificial multicellular systems. Here, we present a general and scalable platform entitled 'biomol. implementation of protocellular communication' (BIO-PC) to engineer distributed multichannel mol. communication between populations of non-lipid semipermeable microcapsules. Our method leverages the modularity and scalability of enzyme-free DNA strand-displacement circuits to develop protocellular consortia that can sense, process and respond to DNA-based messages. We engineer a rich variety of biochem. communication devices capable of cascaded amplification, bidirectional communication and distributed computational operations. Encapsulating DNA strand-displacement circuits further allows their use in concd. serum where non-compartmentalized DNA circuits cannot operate. BIO-PC enables reliable execution of distributed DNA-based mol. programs in biol. relevant environments and opens new directions in DNA computing and minimal cell technol.
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  13. 13
    Adamala, K. P.; Martin-Alarcon, D. A.; Guthrie-Honea, K. R.; Boyden, E. S. Engineering Genetic Circuit Interactions within and between Synthetic Minimal Cells. Nat. Chem. 2017, 9, 431– 439,  DOI: 10.1038/nchem.2644
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    13
    Engineering genetic circuit interactions within and between synthetic minimal cells
    Adamala, Katarzyna P.; Martin-Alarcon, Daniel A.; Guthrie-Honea, Katriona R.; Boyden, Edward S.
    Nature Chemistry (2017), 9 (5), 431-439CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    Genetic circuits and reaction cascades are of great importance for synthetic biol., biochem. and bioengineering. An open question is how to maximize the modularity of their design to enable the integration of different reaction networks and to optimize their scalability and flexibility. One option is encapsulation within liposomes, which enables chem. reactions to proceed in well-isolated environments. Here we adapt liposome encapsulation to enable the modular, controlled compartmentalization of genetic circuits and cascades. We demonstrate that it is possible to engineer genetic circuit-contg. synthetic minimal cells (synells) to contain multiple-part genetic cascades, and that these cascades can be controlled by external signals as well as inter-liposomal communication without crosstalk. We also show that liposomes that contain different cascades can be fused in a controlled way so that the products of incompatible reactions can be brought together. Synells thus enable a more modular creation of synthetic biol. cascades, an essential step towards their ultimate programmability.
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  14. 14
    Dupin, A.; Simmel, F. C. Signalling and Differentiation in Emulsion-Based Multi-Compartmentalized in vitro Gene Circuits. Nat. Chem. 2019, 11, 32– 39,  DOI: 10.1038/s41557-018-0174-9
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    Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits
    Dupin, Aurore; Simmel, Friedrich C.
    Nature Chemistry (2019), 11 (1), 32-39CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Multicellularity enables the growth of complex life forms as it allows for the specialization of cell types, differentiation and large-scale spatial organization. In a similar way, modular construction of synthetic multicellular systems will lead to dynamic biomimetic materials that can respond to their environment in complex ways. To achieve this goal, artificial cellular communication and developmental programs still have to be established. Here, we create geometrically controlled spatial arrangements of emulsion-based artificial cellular compartments contg. synthetic in vitro gene circuitry, sepd. by lipid bilayer membranes. We quant. det. the membrane pore-dependent response of the circuits to artificial morphogen gradients, which are established via diffusion from dedicated organizer cells. Utilizing different types of feedforward and feedback in vitro gene circuits, we then implement artificial signalling and differentiation processes, demonstrating the potential for the realization of complex spatiotemporal dynamics in artificial multicellular systems.
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  15. 15
    Qiao, Y.; Li, M.; Booth, R.; Mann, S. Predatory Behaviour in Synthetic Protocell Communities. Nat. Chem. 2017, 9, 110– 119,  DOI: 10.1038/nchem.2617
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    15
    Predatory behaviour in synthetic protocell communities
    Qiao, Yan; Li, Mei; Booth, Richard; Mann, Stephen
    Nature Chemistry (2017), 9 (2), 110-119CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    Recent progress in the chem. construction of colloidal objects comprising integrated biomimetic functions is paving the way towards rudimentary forms of artificial cell-like entities (protocells). Although several new types of protocells are currently available, the design of synthetic protocell communities and investigation of their collective behavior has received little attention. Here we demonstrate an artificial form of predatory behavior in a community of protease-contg. coacervate microdroplets and protein-polymer microcapsules (proteinosomes) that interact via electrostatic binding. The coacervate microdroplets act as killer protocells for the obliteration of the target proteinosome population by protease-induced lysis of the protein-polymer membrane. As a consequence, the proteinosome payload (dextran, single-stranded DNA, platinum nanoparticles) is trafficked into the attached coacervate microdroplets, which are then released as functionally modified killer protocells capable of rekilling. Our results highlight opportunities for the development of interacting artificial protocell communities, and provide a strategy for inducing collective behavior in soft matter microcompartmentalized systems and synthetic protocell consortia.
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  16. 16
    Balagaddé, F. K.; Song, H.; Ozaki, J.; Collins, C. H.; Barnet, M.; Arnold, F. H.; Quake, S. R.; You, L. A Synthetic Escherichia coli Predator-Prey Ecosystem. Mol. Syst. Biol. 2008, 4, 187– 194,  DOI: 10.1038/msb.2008.24
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    16
    A synthetic Escherichia coli predator-prey ecosystem
    Balagadde Frederick K; Song Hao; Ozaki Jun; Collins Cynthia H; Barnet Matthew; Arnold Frances H; Quake Stephen R; You Lingchong
    Molecular systems biology (2008), 4 (), 187 ISSN:.
    We have constructed a synthetic ecosystem consisting of two Escherichia coli populations, which communicate bi-directionally through quorum sensing and regulate each other's gene expression and survival via engineered gene circuits. Our synthetic ecosystem resembles canonical predator-prey systems in terms of logic and dynamics. The predator cells kill the prey by inducing expression of a killer protein in the prey, while the prey rescue the predators by eliciting expression of an antidote protein in the predator. Extinction, coexistence and oscillatory dynamics of the predator and prey populations are possible depending on the operating conditions as experimentally validated by long-term culturing of the system in microchemostats. A simple mathematical model is developed to capture these system dynamics. Coherent interplay between experiments and mathematical analysis enables exploration of the dynamics of interacting populations in a predictable manner.
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  17. 17
    Liu, F.; Mao, J.; Lu, T.; Hua, Q. Synthetic, Context-Dependent Microbial Consortium of Predator and Prey. ACS Synth. Biol. 2019, 8, 1713– 1722,  DOI: 10.1021/acssynbio.9b00110
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    17
    Synthetic, Context-Dependent Microbial Consortium of Predator and Prey
    Liu, Feng; Mao, Junwen; Lu, Ting; Hua, Qiang
    ACS Synthetic Biology (2019), 8 (8), 1713-1722CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    Synthetic microbial consortia are a rapidly growing area of synthetic biol. So far, most consortia are designed without considering their environments; however, in nature, microbial interactions are constantly modulated by cellular contexts, which, in principle, can dramatically alter community behaviors. We present the construction, validation, and characterization of an engineered bacterial predator-prey consortium that involves a chloramphenicol (CM)-mediated, context-dependent cellular interaction. Varying the CM level in the environment can induce success in the ecosystem with distinct patterns from predator dominance to prey-predator crossover to ecosystem collapse. A math. model successfully captures the essential dynamics of the exptl. obsd. patterns. We also illustrate that such a dependence enriches community dynamics under different initial conditions and further test the resistance of the consortium to invasion with engineered bacterial strains. This work exemplifies the role of the context dependence of microbial interactions in modulating ecosystem dynamics, underscoring the importance of including contexts into the design of engineered ecosystems for synthetic biol. applications.
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  18. 18
    Yang, S.; Pieters, P. A.; Joesaar, A.; Bögels, B. W.; Brouwers, R.; Myrgorodska, I.; Mann, S.; de Greef, T. F. Light-Activated Signaling in DNA-Encoded Sender-Receiver Architectures. ACS Nano 2020, 14, 15992– 16002,  DOI: 10.1021/acsnano.0c07537
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    18
    Light-Activated Signaling in DNA-Encoded Sender-Receiver Architectures
    Yang Shuo; Pieters Pascal A; Joesaar Alex; Bogels Bas W A; Brouwers Rens; de Greef Tom F A; Myrgorodska Iuliia; Mann Stephen; de Greef Tom F A
    ACS nano (2020), 14 (11), 15992-16002 ISSN:.
    Collective decision making by living cells is facilitated by exchange of diffusible signals where sender cells release a chemical signal that is interpreted by receiver cells. A variety of nonliving artificial cell models have been developed in recent years that mimic various aspects of diffusion-based intercellular communication. However, localized secretion of diffusive signals from individual protocells, which is critical for mimicking biological sender-receiver systems, has remained challenging to control precisely. Here, we engineer light-responsive, DNA-encoded sender-receiver architectures, where protein-polymer microcapsules act as cell mimics and molecular communication occurs through diffusive DNA signals. We prepare spatial distributions of sender and receiver protocells using a microfluidic trapping array and set up a signaling gradient from a single sender cell using light, which activates surrounding receivers through DNA strand displacement. Our systematic analysis reveals how the effective signal range of a single sender is determined by various factors including the density and permeability of receivers, extracellular signal degradation, signal consumption, and catalytic regeneration. In addition, we construct a three-population configuration where two sender cells are embedded in a dense array of receivers that implement Boolean logic and investigate spatial integration of nonidentical input cues. The results offer a means for studying diffusion-based sender-receiver topologies and present a strategy to achieve the congruence of reaction-diffusion and positional information in chemical communication systems that have the potential to reconstitute collective cellular patterns.
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    Niederholtmeyer, H.; Chaggan, C.; Devaraj, N. K. Communication and Quorum Sensing in Non-Living Mimics of Eukaryotic Cells. Nat. Commun. 2018, 9, 5027– 5034,  DOI: 10.1038/s41467-018-07473-7
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    19
    Communication and quorum sensing in non-living mimics of eukaryotic cells
    Niederholtmeyer Henrike; Chaggan Cynthia; Devaraj Neal K
    Nature communications (2018), 9 (1), 5027 ISSN:.
    Cells in tissues or biofilms communicate with one another through chemical and mechanical signals to coordinate collective behaviors. Non-living cell mimics provide simplified models of natural systems; however, it has remained challenging to implement communication capabilities comparable to living cells. Here we present a porous artificial cell-mimic containing a nucleus-like DNA-hydrogel compartment that is able to express and display proteins, and communicate with neighboring cell-mimics through diffusive protein signals. We show that communication between cell-mimics allows distribution of tasks, quorum sensing, and cellular differentiation according to local environment. Cell-mimics can be manufactured in large quantities, easily stored, chemically modified, and spatially organized into diffusively connected tissue-like arrangements, offering a means for studying communication in large ensembles of artificial cells.
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    Gardner, P. M.; Winzer, K.; Davis, B. G. Sugar Synthesis in a Protocellular Model Leads to a Cell Signalling Response in Bacteria. Nat. Chem. 2009, 1, 377– 383,  DOI: 10.1038/nchem.296
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    Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria
    Gardner, Paul M.; Winzer, Klaus; Davis, Benjamin G.
    Nature Chemistry (2009), 1 (5), 377-383, S377/1-S377/50CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
    The design of systems with life-like properties from simple chem. components may offer insights into biol. processes, with the ultimate goal of creating an artificial chem. cell that would be considered to be alive. Most efforts to create artificial cells have concd. on systems based on complex natural mols. such as DNA and RNA. Here we have constructed a lipid-bound protometabolism that synthesizes complex carbohydrates from simple feedstocks, which are capable of engaging the natural quorum sensing mechanism of the marine bacterium Vibrio harveyi and stimulating a proportional bioluminescent response. This encapsulated system may represent the first step towards the realization of a cellular mimic' and a starting point for bottom-up' designs of other chem. cells, which could perhaps display complex behaviors such as communication with natural cells.
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    Liu, Y.; Wu, H. C.; Chhuan, M.; Terrell, J. L.; Tsao, C. Y.; Bentley, W. E.; Payne, G. F. Functionalizing Soft Matter for Molecular Communication. ACS Biomater. Sci. Eng. 2015, 1, 320– 328,  DOI: 10.1021/ab500160e
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    Functionalizing Soft Matter for Molecular Communication
    Liu, Yi; Wu, Hsuan-Chen; Chhuan, Melanie; Terrell, Jessica L.; Tsao, Chen-Yu; Bentley, William E.; Payne, Gregory F.
    ACS Biomaterials Science & Engineering (2015), 1 (5), 320-328CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
    The information age was enabled by advances in microfabrication and communication theory that allowed information to be processed by electrons and transmitted by electromagnetic radiation. Despite immense capabilities, microelectronics has limited abilities to access and participate in the mol.-based communication that characterizes our biol. world. Here, we use biol. materials and methods to create components and fabricate devices to perform simple mol. communication functions based on bacterial quorum sensing (QS). Components were created by protein engineering to generate a multidomain fusion protein capable of sending a mol. QS signal, and by synthetic biol. to engineer E. coli to receive and report this QS signal. The device matrix was formed using stimuli-responsive hydrogel-forming biopolymers (alginate and gelatin). Assembly of the components within the device matrix was achieved by phys. entrapping the cell-based components, and covalently conjugating the protein-based components using the enzyme microbial transglutaminase. We demonstrate simple devices that can send or receive a mol. QS signal to/from the surrounding medium, and a two-component device in which one component generates the signal (i.e., issues a command) that is acted upon by the second component. These studies illustrate the broad potential of biofabrication to generate mol. communication devices.
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    Li, S.; Wang, X.; Mu, W.; Han, X. Chemical Signal Communication between Two Protoorganelles in a Lipid-Based Artificial Cell. Anal. Chem. 2019, 91, 6859– 6864,  DOI: 10.1021/acs.analchem.9b01128
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    22
    Chemical Signal Communication between Two Protoorganelles in a Lipid-Based Artificial Cell
    Li, Shubin; Wang, Xuejing; Mu, Wei; Han, Xiaojun
    Analytical Chemistry (Washington, DC, United States) (2019), 91 (10), 6859-6864CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The chem. signal communication among organelles in the cell is extremely important for life. We demonstrate here the chem. signal communication between two protoorganelles using cascade enzyme reactions in a lipid-based artificial cell. Two protoorganelles inside the artificial cell are large unilamellar vesicles contg. glucose oxidase (GOx-LUVs) and a vesicle contg. horseradish peroxidase (HRP) and Amplex red, resp. The glucose mols. outside the artificial cell penetrate the lipid bilayer through mellitin pores and enter into one protoroganelle (GOx-LUV) to produce H2O2, which subsequently is transported to the other protoorganelle to oxidize Amplex red into red resorufin catalyzed by HRP. The no. of GOx-LUVs in an artificial cell is controlled by using a GOx-LUV soln. with different d. during the electroformation. The reaction rate for resorufin in the protoorganelle increases with more GOx-LUVs inside the artificial cell. The artificial cell developed here paves the way for a more complicated signal transduction mechanism study in a eukaryocyte.
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    Wang, X.; Tian, L.; Du, H.; Li, M.; Mu, W.; Drinkwater, B. W.; Han, X.; Mann, S. Chemical Communication in Spatially Organized Protocell Colonies and Protocell/Living Cell Micro-Arrays. Chem. Sci. 2019, 10, 9446– 9453,  DOI: 10.1039/C9SC04522H
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    23
    Chemical communication in spatially organized protocell colonies and protocell/living cell micro-arrays
    Wang, Xuejing; Tian, Liangfei; Du, Hang; Li, Mei; Mu, Wei; Drinkwater, Bruce W.; Han, Xiaojun; Mann, Stephen
    Chemical Science (2019), 10 (41), 9446-9453CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    Micro-arrays of discrete or hemifused giant unilamellar lipid vesicles (GUVs) with controllable spatial geometries, lattice dimensions, trapped occupancies and compns. are prepd. by acoustic standing wave patterning, and employed as platforms to implement chem. signaling in GUV colonies and protocell/living cell consortia. The methodol. offers an alternative approach to GUV micro-array fabrication and provides new opportunities in protocell research and bottom-up synthetic biol.
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    Kučera, O.; Cifra, M. Cell-to-Cell Signaling through Light: Just a Ghost of Chance?. Cell Commun. Signaling 2013, 11, 87– 94,  DOI: 10.1186/1478-811X-11-87
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    24
    Cell-to-cell signaling through light: just a ghost of chance?
    Kucera Ondrej; Cifra Michal
    Cell communication and signaling : CCS (2013), 11 (), 87 ISSN:.
    Despite the large number of reports attributing the signaling between detached cell cultures to the electromagnetic phenomena, almost no report so far included a rigorous analysis of the possibility of such signaling.In this paper, we examine the physical feasibility of the electromagnetic communication between cells, especially through light, with regard to the ambient noise illumination. We compare theoretically attainable parameters of communication with experimentally obtained data of the photon emission from cells without a specially pronounced ability of bioluminescence.We show that the weak intensity of the emission together with an unfavorable signal-to-noise ratio, which is typical for natural conditions, represent an important obstacle to the signal detection by cells.
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    Martini, S.; Haddock, S. H. Quantification of Bioluminescence from the Surface to the Deep Sea Demonstrates Its Predominance as an Ecological Trait. Sci. Rep. 2017, 7, 45750– 45760,  DOI: 10.1038/srep45750
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    25
    Quantification of bioluminescence from the surface to the deep sea demonstrates its predominance as an ecological trait
    Martini, Severine; Haddock, Steven H. D.
    Scientific Reports (2017), 7 (), 45750CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
    The capability of animals to emit light, called bioluminescence, is considered to be a major factor in ecol. interactions. Because it occurs across diverse taxa, measurements of bioluminescence can be powerful to detect and quantify organisms in the ocean. In this study, 17 years of video observations were recorded by remotely operated vehicles during surveys off the California Coast, from the surface down to 3,900 m depth. More than 350,000 observations are classified for their bioluminescence capability based on literature descriptions. The organisms represented 553 phylogenetic concepts (species, genera or families, at the most precise taxonomic level defined from the images), distributed within 13 broader taxonomic categories. The importance of bioluminescent marine taxa is highlighted in the water column, as we showed that 76% of the obsd. individuals have bioluminescence capability. More than 97% of Cnidarians were bioluminescent, and 9 of the 13 taxonomic categories were found to be bioluminescent dominant. The percentage of bioluminescent animals is remarkably uniform over depth. Moreover, the proportion of bioluminescent and non-bioluminescent animals within taxonomic groups changes with depth for Ctenophora, Scyphozoa, Chaetognatha, and Crustacea. Given these results, bioluminescence has to be considered an important ecol. trait from the surface to the deep-sea.
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    Burford, B. P.; Robison, B. H. Bioluminescent Backlighting Illuminates the Complex Visual Signals of a Social Squid in the Deep Sea. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 8524– 8531,  DOI: 10.1073/pnas.1920875117
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    26
    Bioluminescent backlighting illuminates the complex visual signals of a social squid in the deep sea
    Burford, Benjamin P.; Robison, Bruce H.
    Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (15), 8524-8531CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Visual signals rapidly relay information, facilitating behaviors and ecol. interactions that shape ecosystems. However, most known signaling systems can be restricted by low light levels-a pervasive condition in the deep ocean, the largest inhabitable space on the planet. Resident visually cued animals have therefore been hypothesized to have simple signals with limited information-carrying capacity. We used cameras mounted on remotely operated vehicles to study the behavior of the Humboldt squid, Dosidicus gigas, in its natural deep-sea habitat. We show that specific pigmentation patterns from its diverse repertoire are selectively displayed during foraging and in social scenarios, and we investigate how these behaviors may be used syntactically for communication. We addnl. identify the probable mechanism by which D. gigas, and related squids, illuminate these patterns to create visual signals that can be readily perceived in the deep, dark ocean. Numerous small s.c. (s.c.) photophores (bioluminescent organs) embedded throughout the muscle tissue make the entire body glow, thereby backlighting the pigmentation patterns. Equipped with a mechanism by which complex information can be rapidly relayed through a visual pathway under low-light conditions, our data suggest that the visual signals displayed by D. gigas could share design features with advanced forms of animal communication. Visual signaling by deep-living cephalopods will likely be crit. in understanding how, and how much, information can be shared in one of the planet's most challenging environments for visual communication.
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    Widder, E. A. Bioluminescence in the Ocean: Origins of Biological, Chemical and Ecological Diversity. Science 2010, 328, 704– 708,  DOI: 10.1126/science.1174269
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    Bioluminescence in the ocean: Origins of biological, chemical, and ecological diversity
    Widder, E. A.
    Science (Washington, DC, United States) (2010), 328 (5979), 704-708CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    A review. From bacteria to fish, a remarkable variety of marine life depends on bioluminescence (the chem. generation of light) for finding food, attracting mates, and evading predators. Disparate biochem. systems and diverse phylogenetic distribution patterns of light-emitting organisms highlight the ecol. benefits of bioluminescence, with biochem. and genetic analyses providing new insights into the mechanisms of its evolution. The origins and functions of some bioluminescent systems, however, remain obscure. Here, the author reviews recent advances in understanding bioluminescence in the ocean and highlights future research efforts that will unite mol. details with ecol. and evolutionary relations.
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    Laager, F. Light Based Cellular Interactions: Hypotheses and Perspectives. Front. Phys. 2015, 3, 55,  DOI: 10.3389/fphy.2015.00055
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    Ghazvini, S.; Alonso, R.; Alhakamy, N.; Dhar, P. pH-Induced Changes in the Surface Viscosity of Unsaturated Phospholipids Monitored Using Active Interfacial Microrheology. Langmuir 2018, 34, 1159– 1170,  DOI: 10.1021/acs.langmuir.7b02803
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    29
    pH-Induced Changes in the Surface Viscosity of Unsaturated Phospholipids Monitored Using Active Interfacial Microrheology
    Ghazvini, Saba; Alonso, Ryan; Alhakamy, Nabil; Dhar, Prajnaparamita
    Langmuir (2018), 34 (3), 1159-1170CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Lipid membranes, a major component of cells, are subjected to significant changes in pH depending on their location in the cell: the outer leaflet of the cell membrane is exposed to a pH of 7.4 while lipid membranes that make up late endosomes and lysosomes are exposed to a pH as low as 4.4. The purpose of this study is to evaluate how changes in the environmental pH within cells alter the fluidity of phospholipid membranes. Specifically, we studied pH-induced alterations in the surface arrangement of monounsatd. lipids with zwitterionic head-groups [phosphoethanolamine (PE) and phosphocholine (PC)] that are abundant in the plasma membrane, as well as anionic lipids [phosphatidylserine (PS) and phosphatidylglycerol (PG)] that are abundant in inner membranes, using a combination of techniques including surface tension vs. area measurements, interfacial microrheol., and fluorescence/at. force microscopy. Using an active interfacial microrheol. technique, we found that phospholipids with zwitterionic head-groups showed a significant increase in the surface viscosity at acidic pH. This increase in surface viscosity was found to also depend on the size of the lipid head-group, with a smaller head-group showing a higher increase in viscosity. The obsd. pH-induced increase in viscosity was also accompanied by an increase in the cohesion pressure between zwitterionic mols. at acidic pH, as measured by fitting the surface pressure isotherms to well-established equations of state. Since fluorescence images showed no change in the phase of the lipids, we attributed this change in surface viscosity to pH induced reorientation of the P--N+ dipoles that form part of the polar lipid head-group, resulting in increased lipid-lipid interactions. Anionic PG head-groups did not demonstrate this pH induced change in viscosity, suggesting that the presence of a net neg. charge on the head-group causes electrostatic repulsion between the head-groups. The results also showed that active interfacial microrheol. is a sensitive technique to detect minute changes in the lipid head-group orientation induced by changes in the local membrane environment, even in unsatd. phospholipids with very high fluidity.
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  30. 30
    Valko, M.; Morris, H.; Cronin, M. T. D. Metals, Toxicity and Oxidative Stress. Curr. Med. Chem. 2005, 12, 1161– 1208,  DOI: 10.2174/0929867053764635
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    Metals, toxicity and oxidative stress
    Valko, M.; Morris, H.; Cronin, M. T. D.
    Current Medicinal Chemistry (2005), 12 (10), 1161-1208CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)
    A review of metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidn., and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsatd. fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal, and other exocyclic DNA adducts [etheno and(or) propano adducts]. While Fe, Cu, Cr, V, and Co undergo redox-cycling reactions, for a second group of metals, Hg, Cd, and Ni, the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. As is thought to bind directly to crit. thiols, however, other mechanisms, involving the formation of hydrogen peroxide under physiol. conditions, have been proposed. The unifying factor in detg. toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium, and cobalt primarily assocd. with mitochondria, microsomes, and peroxisomes. However, a recent discovery that the upper limit of free pools of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to the activation of mainly redox-sensitive transcription factors, involving NF-κB, AP-1, and p53. Antioxidants (both enzymic and non-enzymic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidn. may be assocd. rather with the level of non-enzymic antioxidants than the activity of enzymic antioxidants. However, a very recent epidemiol. study has shown that a daily intake of vitamin E of >400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidn. and does not promote protein oxidn. in humans in vitro. Exptl. results have also shown a link between vanadium and oxidative stress in the etiol. of diabetes. The impact of Zn on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress, and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiol. of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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    Vanuytsel, S.; Carniello, J.; Wallace, M. I. Artificial Signal Transduction across Membranes. ChemBioChem 2019, 20, 2569– 2580,  DOI: 10.1002/cbic.201900254
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    Artificial Signal Transduction across Membranes
    Vanuytsel, Steven; Carniello, Joanne; Wallace, Mark Ian
    ChemBioChem (2019), 20 (20), 2569-2580CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A key conundrum in the construction of an artificial cell is to simultaneously maintain a robust phys. barrier to the external environment, while also providing efficient exchange of information across this barrier. Biomimicry provides a no. of avenues by which such requirements might be met. Herein, we provide a brief introduction to the challenges facing this field and explore progress to date.
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  32. 32
    Guntas, G.; Hallett, R. A.; Zimmerman, S. P.; Williams, T.; Yumerefendi, H.; Bear, J. E.; Kuhlman, B. Engineering an Improved Light-Induced Dimer (iLID) for Controlling the Localization and Activity of Signaling Proteins. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 112– 117,  DOI: 10.1073/pnas.1417910112
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    32
    Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins
    Guntas, Gurkan; Hallett, Ryan A.; Zimmerman, Seth P.; Williams, Tishan; Yumerefendi, Hayretin; Bear, James E.; Kuhlman, Brian
    Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (1), 112-117CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The discovery of light-inducible protein-protein interactions has allowed for the spatial and temporal control of a variety of biol. processes. To be effective, a photodimerizer should have several characteristics: (1) it should show a large change in binding affinity upon light stimulation; (2) it should not cross-react with other mols. in the cell; and (3) it should be easily used in a variety of organisms to recruit proteins of interest to each other. To create a switch that meets these criteria we have embedded the bacterial SsrA peptide in the C-terminal helix of a naturally occurring photoswitch, the light-oxygen-voltage 2 (LOV2) domain from Avena sativa. In the dark the SsrA peptide is sterically blocked from binding its natural binding partner, SspB. When activated with blue light, the C-terminal helix of the LOV2 domain undocks from the protein, allowing the SsrA peptide to bind SspB. Without optimization, the switch exhibited a twofold change in binding affinity for SspB with light stimulation. Here, we describe the use of computational protein design, phage display, and high-throughput binding assays to create an improved light inducible dimer (iLID) that changes its affinity for SspB by over 50-fold with light stimulation. A crystal structure of iLID shows a crit. interaction between the surface of the LOV2 domain and a phenylalanine engineered to more tightly pin the SsrA peptide against the LOV2 domain in the dark. We demonstrate the functional utility of the switch through light-mediated subcellular localization in mammalian cell culture and reversible control of small GTPase signaling.
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    Chervyachkova, E.; Wegner, S. V. Reversible Social Self-Sorting of Colloidal Cell-Mimics with Blue Light Switchable Proteins. ACS Synth. Biol. 2018, 7, 1817– 1824,  DOI: 10.1021/acssynbio.8b00250
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    Reversible Social Self-Sorting of Colloidal Cell-Mimics with Blue Light Switchable Proteins
    Chervyachkova, Elizaveta; Wegner, Seraphine V.
    ACS Synthetic Biology (2018), 7 (7), 1817-1824CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    Toward the bottom-up assembly of synthetic cells from mol. building blocks, it is an ongoing challenge to assemble micrometer sized compartments that host different processes into precise multicompartmental assemblies, also called prototissues. The difficulty lies in controlling interactions between different compartments dynamically both in space and time, as these interactions det. how they organize with respect to each other and how they work together. The authors have been able to control the self-assembly and social self-sorting of four different types of colloids, which the authors use as a model for synthetic cells, into two sep. families with visible light. For this purpose the authors used two photoswitchable protein pairs (iLID/Nano and nHagHigh/pMagHigh) that both reversibly heterodimerize upon blue light exposure and dissoc. from each other in the dark. These photoswitchable proteins provide noninvasive, dynamic, and reversible remote control under biocompatible conditions over the self-assembly process with unprecedented spatial and temporal precision. In addn., each protein pair brings together specifically two different types of colloids. The orthogonality of the two protein pairs enables social self-sorting of a four component mixt. into two distinct families of colloidal aggregates with controlled arrangements. These results will ultimately pave the way for the bottom-up assembly of multicompartment synthetic prototissues of a higher complexity, enabling the authors to control precisely and dynamically the organization of different compartments in space and time.
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    Chakraborty, T.; Bartelt, S. M.; Steinkühler, J.; Dimova, R.; Wegner, S. V. Light Controlled Cell-to-Cell Adhesion and Chemical Communication in Minimal Synthetic Cells. Chem. Commun. 2019, 55, 9448– 9451,  DOI: 10.1039/C9CC04768A
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    Light controlled cell-to-cell adhesion and chemical communication in minimal synthetic cells
    Chakraborty, T.; Bartelt, S. M.; Steinkuehler, J.; Dimova, R.; Wegner, S. V.
    Chemical Communications (Cambridge, United Kingdom) (2019), 55 (64), 9448-9451CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Decorating GUVs, used as minimal synthetic cell models, with photoswitchable proteins allows controlling the adhesion between them and their assembly into multicellular structures with light. Thereby, the chem. communication between a sender and a receiver GUV, which strongly depends on their spatial proximity, can also be photoregulated.
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  35. 35
    Mueller, M.; Rasoulinejad, S.; Garg, S.; Wegner, S. V. The Importance of Cell-Cell Interaction Dynamics in Bottom-Up Tissue Engineering: Concepts of Colloidal Self-Assembly in the Fabrication of Multicellular Architectures. Nano Lett. 2020, 20, 2257– 2263,  DOI: 10.1021/acs.nanolett.9b04160
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    35
    The Importance of Cell-Cell Interaction Dynamics in Bottom-Up Tissue Engineering: Concepts of Colloidal Self-Assembly in the Fabrication of Multicellular Architectures
    Mueller, Marc; Rasoulinejad, Samaneh; Garg, Sukant; Wegner, Seraphine V.
    Nano Letters (2020), 20 (4), 2257-2263CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Building tissue from cells as the basic building block based on principles of self-assembly is a challenging and promising approach. Understanding how far principles of self-assembly and self-sorting known for colloidal particles apply to cells remains unanswered. In this study, we demonstrate that not just controlling the cell-cell interactions but also their dynamics is a crucial factor that dets. the formed multicellular structure, using photoswitchable interactions between cells that are activated with blue light and reverse in the dark. Tuning dynamics of the cell-cell interactions by pulsed light activation results in multicellular architectures with different sizes and shapes. When the interactions between cells are dynamic, compact and round multicellular clusters under thermodn. control form, while otherwise branched and loose aggregates under kinetic control assemble. These structures parallel what is known for colloidal assemblies under reaction- and diffusion-limited cluster aggregation, resp. Similarly, dynamic interactions between cells are essential for cells to self-sort into distinct groups. Using four different cell types, which expressed two orthogonal cell-cell interaction pairs, the cells sorted into two sep. assemblies. Bringing concepts of colloidal self-assembly to bottom-up tissue engineering provides a new theor. framework and will help in the design of more predictable tissue-like structures.
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  36. 36
    Senturk, O. I.; Chervyachkova, E.; Ji, Y.; Wegner, S. V. Independent Blue and Red Light Triggered Narcissistic Self-Sorting Self-Assembly of Colloidal Particles. Small 2019, 15, 1901801,  DOI: 10.1002/smll.201901801
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    Bartelt, S. M.; Steinkühler, J.; Dimova, R.; Wegner, S. V. Light-Guided Motility of a Minimal Synthetic Cell. Nano Lett. 2018, 18, 7268– 7274,  DOI: 10.1021/acs.nanolett.8b03469
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    Light-Guided Motility of a Minimal Synthetic Cell
    Bartelt, Solveig M.; Steinkuehler, Jan; Dimova, Rumiana; Wegner, Seraphine V.
    Nano Letters (2018), 18 (11), 7268-7274CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Cell motility is an important but complex process; as cells move, new adhesions form at the front and adhesions disassemble at the back. To replicate this dynamic and spatiotemporally controlled asymmetry of adhesions and achieve motility in a minimal synthetic cell, we controlled the adhesion of a model giant unilamellar vesicle (GUV) to the substrate with light. For this purpose, we immobilized the proteins iLID and Micro, which interact under blue light and dissoc. from each other in the dark, on a substrate and a GUV, resp. Under blue light, the protein interaction leads to adhesion of the vesicle to the substrate, which is reversible in the dark. The high spatiotemporal control provided by light, allowed partly illuminating the GUV and generating an asymmetry in adhesions. Consequently, the GUV moves into the illuminated area, a process that can be repeated over multiple cycles. Thus, our system reproduces the dynamic spatiotemporal distribution of adhesions and establishes mimetic motility of a synthetic cell.
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    Berglund, K.; Tung, J. K.; Higashikubo, B.; Gross, R. E.; Moore, C. I.; Hochgeschwender, U. Combined Optogenetic and Chemogenetic Control of Neurons. Methods Mol. Biol. 2016, 1408, 207– 225,  DOI: 10.1007/978-1-4939-3512-3_14
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    Combined optogenetic and chemogenetic control of neurons
    Berglund, Ken; Tung, Jack K.; Higashikubo, Bryan; Gross, Robert E.; Moore, Christopher I.; Hochgeschwender, Ute
    Methods in Molecular Biology (New York, NY, United States) (2016), 1408 (Optogenetics), 207-225CODEN: MMBIED; ISSN:1940-6029. (Springer)
    A review. Optogenetics provides an array of elements for specific biophys. control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same exptl. animal. Light-sensing mols. (opsins) are activated by biol. produced light through luciferases upon peripheral injection of a small mol. substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo.
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  39. 39
    Berglund, K.; Clissold, K.; Li, H. E.; Wen, L.; Park, S. Y.; Gleixner, J.; Klein, M. E.; Lu, D.; Barter, J. W.; Rossi, M. A.; Augustine, G. J.; Yin, H. H.; Hochgeschwender, U. Luminopsins Integrate Opto- and Chemogenetics by Using Physical and Biological Light Sources for Opsin Activation. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E358– E367,  DOI: 10.1073/pnas.1510899113
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    39
    Luminopsins integrate opto- and chemogenetics by using physical and biological light sources for opsin activation
    Berglund, Ken; Clissold, Kara; Li, Haofang E.; Wen, Lei; Park, Sung Young; Gleixner, Jan; Klein, Marguerita E.; Lu, Dongye; Barter, Joseph W.; Rossi, Mark A.; Augustine, George J.; Yin, Henry H.; Hochgeschwender, Ute
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (3), E358-E367CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Luminopsins are fusion proteins of luciferase and opsin that allow interrogation of neuronal circuits at different temporal and spatial resolns. by choosing either extrinsic phys. or intrinsic biol. light for its activation. Building on previous development of fusions of wild-type Gaussia luciferase with channelrhodopsin, here we expanded the utility of luminopsins by fusing bright Gaussia luciferase variants with either channelrhodopsin to excite neurons (luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO, iLMO). These improved LMOs could reliably activate or silence neurons in vitro and in vivo. Expression of the improved LMO in hippocampal circuits not only enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal resoln. but also could drive rhythmic circuit excitation over a large spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or iLMO in the substantia nigra in vivo produced not only the expected bidirectional control of single unit activity but also opposing effects on circling behavior in response to systemic injection of a luciferase substrate. Thus, although preserving the ability to be activated by external light sources, LMOs expand the use of optogenetics by making the same opsins accessible to noninvasive, chemogenetic control, thereby allowing the same probe to manipulate neuronal activity over a range of spatial and temporal scales.
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    Kim, C. K.; Cho, K. F.; Kim, M. W.; Ting, A. Y. Luciferase-LOV BRET Enables Versatile and Specific Transcriptional Readout of Cellular Protein-Protein Interactions. eLife 2019, 8, 43826– 43846,  DOI: 10.7554/eLife.43826
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    Luciferase-LOV BRET enables versatile and specific transcriptional readout of cellular protein-protein interactions
    Kim, Christina K.; Cho, Kelvin F.; Kim, Min Woo; Ting, Alice Y.
    eLife (2019), 8 (), e43826/1-e43826/21CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
    Technologies that convert transient protein-protein interactions (PPIs) into stable expression of a reporter gene are useful for genetic selections, high-throughput screening, and multiplexing with omics technologies. We previously reported SPARK (Kim et al., 2017), a transcription factor that is activated by the coincidence of blue light and a PPI. Here, we report an improved, second-generation SPARK2 that incorporates a luciferase moiety to control the lightsensitive LOV domain. SPARK2 can be temporally gated by either external light or addn. of a small-mol. luciferin, which causes luciferase to open LOV via proximity-dependent BRET. Furthermore, the nested 'AND' gate design of SPARK2-in which both protease recruitment to the membrane-anchored transcription factor and LOV domain opening are regulated by the PPI of interest-yields a lower-background system and improved PPI specificity. We apply SPARK2 to high-throughput screening for GPCR agonists and for the detection of trans-cellular contacts, all with versatile transcriptional readout.
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    Salinas, F.; Rojas, V.; Delgado, V.; López, J.; Agosin, E.; Larrondo, L. F. Fungal Light-Oxygen-Voltage Domains for Optogenetic Control of Gene Expression and Flocculation in Yeast. mBio 2018, 9, e00626-18  DOI: 10.1128/mBio.00626-18
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    Parag-Sharma, K.; O’Banion, C. P.; Henry, E. C.; Musicant, A. M.; Cleveland, J. L.; Lawrence, D. S.; Amelio, A. L. Engineered BRET-Based Biologic Light Sources Enable Spatiotemporal Control Over Diverse Optogenetic Systems. ACS Synth. Biol. 2020, 9, 1– 9,  DOI: 10.1021/acssynbio.9b00277
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    42
    Engineered BRET-Based Biologic Light Sources Enable Spatiotemporal Control over Diverse Optogenetic Systems
    Parag-Sharma, Kshitij; O'Banion, Colin P.; Henry, Erin C.; Musicant, Adele M.; Cleveland, John L.; Lawrence, David S.; Amelio, Antonio L.
    ACS Synthetic Biology (2020), 9 (1), 1-9CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
    Light-inducible optogenetic systems offer precise spatiotemporal control over a myriad of biol. processes. Unfortunately, current systems are inherently limited by their dependence on external light sources for their activation. Further, the utility of laser/LED-based illumination strategies are often constrained by the need for invasive surgical procedures to deliver such devices and local heat prodn., photobleaching and phototoxicity that compromises cell and tissue viability. To overcome these limitations, we developed a novel BRET-activated optogenetics (BEACON) system that employs biol. light to control optogenetic tools. BEACON is driven by self-illuminating bioluminescent-fluorescent proteins that generate "spectrally tuned" biol. light via bioluminescence resonance energy transfer (BRET). Notably, BEACON robustly activates a variety of commonly used optogenetic systems in a spatially restricted fashion, and at physiol. relevant time scales, to levels that are achieved by conventional laser/LED light sources.
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  43. 43
    Chen, F.; Warnock, R. L.; Van der Meer, J. R.; Wegner, S. V. Bioluminescence-Triggered Photoswitchable Bacterial Adhesions Enable Higher Sensitivity and Dual-Readout Bacterial Biosensors for Mercury. ACS Sens. 2020, 5, 2205– 2210,  DOI: 10.1021/acssensors.0c00855
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    ACS Sensors (2020), 5 (7), 2205-2210CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
    The authors present a new concept for whole-cell biosensors that couples the response to Hg2+ with bioluminescence and bacterial aggregation. This allows the authors to use the bacterial aggregation to preconc. the bioluminescent bacteria at the substrate surface and increase the sensitivity of Hg2+ detection. This whole-cell biosensor combines a Hg2+-sensitive bioluminescence reporter and light-responsive bacterial cell-cell adhesions. The blue luminescence in response to Hg2+ is able to photoactivate bacterial aggregation, which provides a second readout for Hg2+ detection. In return, the Hg2+-triggered bacterial aggregation leads to faster sedimentation and more efficient formation of biofilms. At low Hg2+ concns., the enrichment of the bacteria in biofilms leads to an up to 10-fold increase in the signal. The activation of photoswitchable proteins with biol. light is a new concept in optogenetics, and the presented bacterial biosensor design is transferable to other bioluminescent reporters with particular interest for environmental monitoring.
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    Biochemistry (2005), 44 (8), 2811-2821CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    We have investigated the phospholipase A2 catalyzed hydrolysis of supported phospholipid bilayers using neutron reflection and ellipsometry. At the hydrophilic silica-water interface, hydrolysis of phosphatidylcholine bilayers by phospholipase A2 from Naja mossambica mossambica venom is accompanied by destruction of the bilayer at an initial rate, which is comparable for DOPC and DPPC but is doubled for POPC. The extent of bilayer destruction at 25 °C decreases from DOPC to POPC and is dramatically reduced for DPPC. Neutron reflectivity measurements indicate that the enzyme penetrates into the bilayers in increasing order for DOPC, POPC, and DPPC, while the amt. of enzyme adsorbed at the interface is smallest for DPPC and exhibits a max. for POPC. Penetration into the hydrophobic chain region in the bilayer is further supported by the fact that the enzyme adsorbs strongly and irreversibly to a hydrophobic monolayer of octadecyltrichlorosilane. These results are rationalized in terms of the properties of the reaction products and the effect of their accumulation in the membrane on the kinetics of enzyme catalysis.
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    To date, reconstitution of one of the fundamental methods of cell communication, the signaling pathway, has been unaddressed in the bottom-up construction of artificial cells (ACs). Such developments are needed to increase the functionality and biomimicry of ACs, accelerating their translation and application in biotechnol. Here, we report the construction of a de novo synthetic signaling pathway in microscale nested vesicles. Vesicle-cell models respond to external calcium signals through activation of an intracellular interaction between phospholipase A2 and a mechanosensitive channel present in the internal membranes, triggering content mixing between compartments and controlling cell fluorescence. Emulsion-based approaches to AC construction are therefore shown to be ideal for the quick design and testing of new signaling networks and can readily include synthetic mols. difficult to introduce to biol. cells. This work represents a foundation for the engineering of multicompartment-spanning designer pathways that can be utilized to control downstream events inside an AC, leading to the assembly of micromachines capable of sensing and responding to changes in their local environment.
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    Abstr.: In order to maintain tissue homeostasis, cells communicate with the outside environment by receiving mol. signals, transmitting them, and responding accordingly with signaling pathways. Thus, one key challenge in engineering mol. signaling systems involves the design and construction of different modules into a rationally integrated system that mimics the cascade of mol. events. Herein, we rationally design a DNA-based artificial mol. signaling system that uses the confined microenvironment of a giant vesicle, derived from a living cell. This system consists of two main components. First, we build an ATP (ATP)-driven DNA nanogatekeeper. Second, we encapsulate a signaling network in the biomimetic vesicle, consisting of distinct modules, able to sequentially initiate a series of downstream reactions playing the roles of reception, transduction and response. Operationally, in the presence of ATP, nanogatekeeper switches from the closed to open state. The open state then triggers the sequential activation of confined downstream signaling modules.
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    We report natural light-oxygen-voltage (LOV) photoreceptors with a blue light-switched, high-affinity (KD = ∼10-7 M), and direct electrostatic interaction with anionic phospholipids. Membrane localization of one such photoreceptor, BcLOV4 from Botrytis cinerea, was directly coupled to its flavin photocycle, and was mediated by a polybasic amphipathic helix in the linker region between the LOV sensor and its C-terminal domain of unknown function (DUF), as revealed through a combination of bioinformatics, computational protein modeling, structure-function studies, and optogenetic assays in yeast and mammalian cell line expression systems. In model systems, BcLOV4 rapidly translocated from the cytosol to plasma membrane (∼1 s). The reversible electrostatic interaction was nonselective among anionic phospholipids, exhibiting binding strengths dependent on the total anionic content of the membrane without preference for a specific headgroup. The in vitro and cellular responses were also obsd. with a BcLOV4 homolog and thus are likely to be general across the dikarya LOV class, whose members are assocd. with regulator of G-protein signaling (RGS) domains. Natural photoreceptors are not previously known to directly assoc. with membrane phospholipids in a light-dependent manner, and thus this work establishes both a photosensory signal transmission mode and a single-component optogenetic tool with rapid membrane localization kinetics that approaches the diffusion limit.
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    In preclin. cancer research, bioluminescence imaging with firefly luciferase and -luciferin has become a std. to monitor biol. processes both in vitro and in vivo. However, the emission max. (λmax) of bioluminescence produced by -luciferin is 562 nm where light is not highly penetrable in biol. tissues. This emphasizes a need for developing a red-shifted bioluminescence imaging system to improve detection sensitivity of targets in deep tissue. Here we characterize the bioluminescent properties of the newly synthesized luciferin analog, AkaLumine-HCl. The bioluminescence produced by AkaLumine-HCl in reactions with native firefly luciferase is in the near-IR wavelength ranges (λmax=677 nm), and yields significantly increased target-detection sensitivity from deep tissues with maximal signals attained at very low concns., as compared with -luciferin and emerging synthetic luciferin CycLuc1. These characteristics offer a more sensitive and accurate method for non-invasive bioluminescence imaging with native firefly luciferase in various animal models.
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  • Abstract

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    Figure 1

    Figure 1. Design of cell to cell communication through light between synthetic predator and prey cells. Predator GUVs are loaded with renilla luciferase and generate an intrinsic light signal upon addition of the substrate coelenterazine. (1) The bioluminescence of the predator GUV, activates the light dependent adhesion of predator (functionalized with iLID, membrane labeled in green) and prey (functionalized with Nano, membrane labeled in red) GUVs, due to the photoswitchable binding of iLID and Nano. (2) The blocker of the α-HL pores is displaced at the adhesion site of the predator and prey GUV and (3) allows for the contact dependent transfer of Ca2+, as a secondary soluble signal, from the predator to the prey GUV. (4) Ca2+ binds and activates apo-PLA2 and the Ca2+ sensitive fluorescent dye Rhod2. (5) PLA2 cleaves the phospholipid membrane of the prey GUV and results in its lysis.

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    Figure 2

    Figure 2. Photoactivation of extracellular iLID and Nano through intracellular bioluminescence. (a) Luminescent of renilla luciferase (100 nM) loaded GUVs(orange) and the external GUV buffer after washing the GUVs (gray, negative control) upon addition of external substrate, coelenterazine (10 μM, orange). The luminescence of the GUVs has a half-life of 15.4 min based on first order kinetic kinetics. (b) Schematic representation of mOrange-Nano protein recruitment due to the bioluminescence of iLID-functionalized GUVs. As the bioluminescence decreases over time mOrange-Nano dissociates from the GUV. (c) Confocal images of an iLID functionalized GUV loaded with renilla luciferase (DiD dye on membrane, shown in red) in the presence of mOrange-Nano (2.5 μM, shown in green) upon addition of coelenterazine (10 μM). Scale bar is 10 μm. (d) Change in mOrange-Nano fluorescence intensity at the GUV membrane over time for the GUV in c. mOrange-Nano was recruited over the first 15 min, remained stable for 50 min and declined to the baseline after 60 min.

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    Figure 3

    Figure 3. Intrinsic luminescence signal induced adhesion between sender and receiver GUVs. (a) Schematic representation of cell to cell communication through intracellular light. The sender GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM), and the receiver GUV (shown in red) is functionalized with Nano. Upon addition of coelenterazine, the sender GUV generates intracellular light, activates iLID on the membrane, which results in the adhesion to the receiver GUV. (b) Confocal images of sender (Dil membrane dye, shown in green) and receiver (DiD membrane dye, shown in red) GUVs in the presence of coelenterazine (10 μM) (luminescence) and in the absence of coelenterazine either in dark (negative control) or under blue light (positive control) after 30 min. Scale bars are 30 μm. (c) Average area of objects (single and clustered GUVs, see Methods for details) described in (b). Sender and receiver GUVs cluster under luminescence as efficiently as under blue light illumination. (d) Average area of objects over time after the addition of coelenterazine to luminescence and dark sample in (b). Luminescence triggered GUV clustering increased over the first 60 min and decreased after 120 min as the luminescence decreased. The average of three technical replicates was reported and statistical significance was evaluated with one-way ANOVA, ***p < 0.001.

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    Figure 4

    Figure 4. Coupling cell to cell communication through light to contact dependent chemical communication. (a) Schematic representation of contact dependent transfer of a secondary soluble signal following light triggered adhesion. The sender GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM) and Ca2+ (2 mM) and the receiver GUV (shown in red) is functionalized with Nano and loaded with Rhod2. Both types of GUVs contained α-HL (25 ng/μL), which were blocked by TRIMEB (4 mM). Upon addition of coelenterazine (10 μM), the sender GUV generates intracellular light and activates the adhesion to the receiver GUV. The blocker is displaced at the adhesion interphase and the secondary Ca2+ signal is transferred from the sender to the receiver GUV, visible as an increase in fluorescence of Rhod2. (b) Confocal images of sender (Dil membrane dye, shown in green) and receiver (DiD membrane dye, shown in red and intracellular Rhod2, shown in green) GUVs in the presence of coelenterazine (luminescence) and in the absence of coelenterazine either in the dark (negative control) or under blue light (positive control) after 40 min. The intracellular Rhod2 fluorescence increases in the luminescence and the blue light sample, where the sender GUVs adhere to receiver GUVs. Scale bars are 30 μm. (c) Mean Rhod2 fluorescence intensity inside receiver GUVs (n = 30) in (b). In the luminescent and blue light sample, two populations of receiver GUVs were defined as proximal if in close contact with a sender GUV and as distal if not. Statistical significance was evaluated with the one-way ANOVA test, ***p < 0.001.

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    Figure 5

    Figure 5. Lysis of prey GUVs by luminescent predator GUVs in a synthetic cell community. (a) Schematic representation of a luminescent predator GUV lysing the prey GUV. The predator GUV (shown in green) is functionalized with iLID and loaded with renilla luciferase (100 nM), Ca2+ (2 mM), and the prey GUV (shown in red) is functionalized with Nano and loaded with apo-PLA2 enzyme and Rhod2. Both types of GUVs contained α-HL (25 ng/μL), which were blocked by TRIMEB (4 mM). Upon addition of coelenterazine (10 μM), the predator GUV generates intracellular light, adheres to the prey GUV, and transfers Ca2+ to the prey GUV. Ca2+ activates PLA2, which cleaves the phospholipid bilayer of the prey GUV and results in its lysis. (b) Confocal images of a predator GUV (Dil membrane dye, shown in green), which first adhered to a prey GUV (DiD membrane dye, shown in red) in the presence of coelenterazine and subsequently lysis. See Movie 2. Scale bars are 20 μm. (c) Confocal images of predator and prey GUVs in the absence and presence of coelenterazine after 40 min. Predator GUVs not loaded with Ca2+ and prey GUVs not loaded with PLA2 were used as negative controls. Prey GUVs only lysed when the predator GUV generated intracellular luminescence, contained the secondary Ca2+ signal and the prey GUV was loaded with PLA2. Scale bars are 20 μm. (d) Number of predator or prey GUVs present in (c). The number of prey and predator GUVs was similar in all samples except for the prey GUVs in the presence of coelenterazine, PLA2 and Ca2+, which was reduced due to their lysis.

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      Engineering genetic circuit interactions within and between synthetic minimal cells
      Adamala, Katarzyna P.; Martin-Alarcon, Daniel A.; Guthrie-Honea, Katriona R.; Boyden, Edward S.
      Nature Chemistry (2017), 9 (5), 431-439CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Genetic circuits and reaction cascades are of great importance for synthetic biol., biochem. and bioengineering. An open question is how to maximize the modularity of their design to enable the integration of different reaction networks and to optimize their scalability and flexibility. One option is encapsulation within liposomes, which enables chem. reactions to proceed in well-isolated environments. Here we adapt liposome encapsulation to enable the modular, controlled compartmentalization of genetic circuits and cascades. We demonstrate that it is possible to engineer genetic circuit-contg. synthetic minimal cells (synells) to contain multiple-part genetic cascades, and that these cascades can be controlled by external signals as well as inter-liposomal communication without crosstalk. We also show that liposomes that contain different cascades can be fused in a controlled way so that the products of incompatible reactions can be brought together. Synells thus enable a more modular creation of synthetic biol. cascades, an essential step towards their ultimate programmability.
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    14. 14
      Dupin, A.; Simmel, F. C. Signalling and Differentiation in Emulsion-Based Multi-Compartmentalized in vitro Gene Circuits. Nat. Chem. 2019, 11, 32– 39,  DOI: 10.1038/s41557-018-0174-9
      14
      Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits
      Dupin, Aurore; Simmel, Friedrich C.
      Nature Chemistry (2019), 11 (1), 32-39CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Multicellularity enables the growth of complex life forms as it allows for the specialization of cell types, differentiation and large-scale spatial organization. In a similar way, modular construction of synthetic multicellular systems will lead to dynamic biomimetic materials that can respond to their environment in complex ways. To achieve this goal, artificial cellular communication and developmental programs still have to be established. Here, we create geometrically controlled spatial arrangements of emulsion-based artificial cellular compartments contg. synthetic in vitro gene circuitry, sepd. by lipid bilayer membranes. We quant. det. the membrane pore-dependent response of the circuits to artificial morphogen gradients, which are established via diffusion from dedicated organizer cells. Utilizing different types of feedforward and feedback in vitro gene circuits, we then implement artificial signalling and differentiation processes, demonstrating the potential for the realization of complex spatiotemporal dynamics in artificial multicellular systems.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlWnu7%252FF&md5=3b72ac686350f6e956e890823c9ca086
    15. 15
      Qiao, Y.; Li, M.; Booth, R.; Mann, S. Predatory Behaviour in Synthetic Protocell Communities. Nat. Chem. 2017, 9, 110– 119,  DOI: 10.1038/nchem.2617
      15
      Predatory behaviour in synthetic protocell communities
      Qiao, Yan; Li, Mei; Booth, Richard; Mann, Stephen
      Nature Chemistry (2017), 9 (2), 110-119CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      Recent progress in the chem. construction of colloidal objects comprising integrated biomimetic functions is paving the way towards rudimentary forms of artificial cell-like entities (protocells). Although several new types of protocells are currently available, the design of synthetic protocell communities and investigation of their collective behavior has received little attention. Here we demonstrate an artificial form of predatory behavior in a community of protease-contg. coacervate microdroplets and protein-polymer microcapsules (proteinosomes) that interact via electrostatic binding. The coacervate microdroplets act as killer protocells for the obliteration of the target proteinosome population by protease-induced lysis of the protein-polymer membrane. As a consequence, the proteinosome payload (dextran, single-stranded DNA, platinum nanoparticles) is trafficked into the attached coacervate microdroplets, which are then released as functionally modified killer protocells capable of rekilling. Our results highlight opportunities for the development of interacting artificial protocell communities, and provide a strategy for inducing collective behavior in soft matter microcompartmentalized systems and synthetic protocell consortia.
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    16. 16
      Balagaddé, F. K.; Song, H.; Ozaki, J.; Collins, C. H.; Barnet, M.; Arnold, F. H.; Quake, S. R.; You, L. A Synthetic Escherichia coli Predator-Prey Ecosystem. Mol. Syst. Biol. 2008, 4, 187– 194,  DOI: 10.1038/msb.2008.24
      16
      A synthetic Escherichia coli predator-prey ecosystem
      Balagadde Frederick K; Song Hao; Ozaki Jun; Collins Cynthia H; Barnet Matthew; Arnold Frances H; Quake Stephen R; You Lingchong
      Molecular systems biology (2008), 4 (), 187 ISSN:.
      We have constructed a synthetic ecosystem consisting of two Escherichia coli populations, which communicate bi-directionally through quorum sensing and regulate each other's gene expression and survival via engineered gene circuits. Our synthetic ecosystem resembles canonical predator-prey systems in terms of logic and dynamics. The predator cells kill the prey by inducing expression of a killer protein in the prey, while the prey rescue the predators by eliciting expression of an antidote protein in the predator. Extinction, coexistence and oscillatory dynamics of the predator and prey populations are possible depending on the operating conditions as experimentally validated by long-term culturing of the system in microchemostats. A simple mathematical model is developed to capture these system dynamics. Coherent interplay between experiments and mathematical analysis enables exploration of the dynamics of interacting populations in a predictable manner.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3lsVSitg%253D%253D&md5=f8226ce193c6cce3fb064ffb30960ec6
    17. 17
      Liu, F.; Mao, J.; Lu, T.; Hua, Q. Synthetic, Context-Dependent Microbial Consortium of Predator and Prey. ACS Synth. Biol. 2019, 8, 1713– 1722,  DOI: 10.1021/acssynbio.9b00110
      17
      Synthetic, Context-Dependent Microbial Consortium of Predator and Prey
      Liu, Feng; Mao, Junwen; Lu, Ting; Hua, Qiang
      ACS Synthetic Biology (2019), 8 (8), 1713-1722CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
      Synthetic microbial consortia are a rapidly growing area of synthetic biol. So far, most consortia are designed without considering their environments; however, in nature, microbial interactions are constantly modulated by cellular contexts, which, in principle, can dramatically alter community behaviors. We present the construction, validation, and characterization of an engineered bacterial predator-prey consortium that involves a chloramphenicol (CM)-mediated, context-dependent cellular interaction. Varying the CM level in the environment can induce success in the ecosystem with distinct patterns from predator dominance to prey-predator crossover to ecosystem collapse. A math. model successfully captures the essential dynamics of the exptl. obsd. patterns. We also illustrate that such a dependence enriches community dynamics under different initial conditions and further test the resistance of the consortium to invasion with engineered bacterial strains. This work exemplifies the role of the context dependence of microbial interactions in modulating ecosystem dynamics, underscoring the importance of including contexts into the design of engineered ecosystems for synthetic biol. applications.
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    18. 18
      Yang, S.; Pieters, P. A.; Joesaar, A.; Bögels, B. W.; Brouwers, R.; Myrgorodska, I.; Mann, S.; de Greef, T. F. Light-Activated Signaling in DNA-Encoded Sender-Receiver Architectures. ACS Nano 2020, 14, 15992– 16002,  DOI: 10.1021/acsnano.0c07537
      18
      Light-Activated Signaling in DNA-Encoded Sender-Receiver Architectures
      Yang Shuo; Pieters Pascal A; Joesaar Alex; Bogels Bas W A; Brouwers Rens; de Greef Tom F A; Myrgorodska Iuliia; Mann Stephen; de Greef Tom F A
      ACS nano (2020), 14 (11), 15992-16002 ISSN:.
      Collective decision making by living cells is facilitated by exchange of diffusible signals where sender cells release a chemical signal that is interpreted by receiver cells. A variety of nonliving artificial cell models have been developed in recent years that mimic various aspects of diffusion-based intercellular communication. However, localized secretion of diffusive signals from individual protocells, which is critical for mimicking biological sender-receiver systems, has remained challenging to control precisely. Here, we engineer light-responsive, DNA-encoded sender-receiver architectures, where protein-polymer microcapsules act as cell mimics and molecular communication occurs through diffusive DNA signals. We prepare spatial distributions of sender and receiver protocells using a microfluidic trapping array and set up a signaling gradient from a single sender cell using light, which activates surrounding receivers through DNA strand displacement. Our systematic analysis reveals how the effective signal range of a single sender is determined by various factors including the density and permeability of receivers, extracellular signal degradation, signal consumption, and catalytic regeneration. In addition, we construct a three-population configuration where two sender cells are embedded in a dense array of receivers that implement Boolean logic and investigate spatial integration of nonidentical input cues. The results offer a means for studying diffusion-based sender-receiver topologies and present a strategy to achieve the congruence of reaction-diffusion and positional information in chemical communication systems that have the potential to reconstitute collective cellular patterns.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3s7jslSrug%253D%253D&md5=f1fb36d238ae36169e938a77328d54a1
    19. 19
      Niederholtmeyer, H.; Chaggan, C.; Devaraj, N. K. Communication and Quorum Sensing in Non-Living Mimics of Eukaryotic Cells. Nat. Commun. 2018, 9, 5027– 5034,  DOI: 10.1038/s41467-018-07473-7
      19
      Communication and quorum sensing in non-living mimics of eukaryotic cells
      Niederholtmeyer Henrike; Chaggan Cynthia; Devaraj Neal K
      Nature communications (2018), 9 (1), 5027 ISSN:.
      Cells in tissues or biofilms communicate with one another through chemical and mechanical signals to coordinate collective behaviors. Non-living cell mimics provide simplified models of natural systems; however, it has remained challenging to implement communication capabilities comparable to living cells. Here we present a porous artificial cell-mimic containing a nucleus-like DNA-hydrogel compartment that is able to express and display proteins, and communicate with neighboring cell-mimics through diffusive protein signals. We show that communication between cell-mimics allows distribution of tasks, quorum sensing, and cellular differentiation according to local environment. Cell-mimics can be manufactured in large quantities, easily stored, chemically modified, and spatially organized into diffusively connected tissue-like arrangements, offering a means for studying communication in large ensembles of artificial cells.
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    20. 20
      Gardner, P. M.; Winzer, K.; Davis, B. G. Sugar Synthesis in a Protocellular Model Leads to a Cell Signalling Response in Bacteria. Nat. Chem. 2009, 1, 377– 383,  DOI: 10.1038/nchem.296
      20
      Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria
      Gardner, Paul M.; Winzer, Klaus; Davis, Benjamin G.
      Nature Chemistry (2009), 1 (5), 377-383, S377/1-S377/50CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
      The design of systems with life-like properties from simple chem. components may offer insights into biol. processes, with the ultimate goal of creating an artificial chem. cell that would be considered to be alive. Most efforts to create artificial cells have concd. on systems based on complex natural mols. such as DNA and RNA. Here we have constructed a lipid-bound protometabolism that synthesizes complex carbohydrates from simple feedstocks, which are capable of engaging the natural quorum sensing mechanism of the marine bacterium Vibrio harveyi and stimulating a proportional bioluminescent response. This encapsulated system may represent the first step towards the realization of a cellular mimic' and a starting point for bottom-up' designs of other chem. cells, which could perhaps display complex behaviors such as communication with natural cells.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptVSjsrY%253D&md5=ad496ab10f8ec2775e43fbae9d4b25e8
    21. 21
      Liu, Y.; Wu, H. C.; Chhuan, M.; Terrell, J. L.; Tsao, C. Y.; Bentley, W. E.; Payne, G. F. Functionalizing Soft Matter for Molecular Communication. ACS Biomater. Sci. Eng. 2015, 1, 320– 328,  DOI: 10.1021/ab500160e
      21
      Functionalizing Soft Matter for Molecular Communication
      Liu, Yi; Wu, Hsuan-Chen; Chhuan, Melanie; Terrell, Jessica L.; Tsao, Chen-Yu; Bentley, William E.; Payne, Gregory F.
      ACS Biomaterials Science & Engineering (2015), 1 (5), 320-328CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)
      The information age was enabled by advances in microfabrication and communication theory that allowed information to be processed by electrons and transmitted by electromagnetic radiation. Despite immense capabilities, microelectronics has limited abilities to access and participate in the mol.-based communication that characterizes our biol. world. Here, we use biol. materials and methods to create components and fabricate devices to perform simple mol. communication functions based on bacterial quorum sensing (QS). Components were created by protein engineering to generate a multidomain fusion protein capable of sending a mol. QS signal, and by synthetic biol. to engineer E. coli to receive and report this QS signal. The device matrix was formed using stimuli-responsive hydrogel-forming biopolymers (alginate and gelatin). Assembly of the components within the device matrix was achieved by phys. entrapping the cell-based components, and covalently conjugating the protein-based components using the enzyme microbial transglutaminase. We demonstrate simple devices that can send or receive a mol. QS signal to/from the surrounding medium, and a two-component device in which one component generates the signal (i.e., issues a command) that is acted upon by the second component. These studies illustrate the broad potential of biofabrication to generate mol. communication devices.
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    22. 22
      Li, S.; Wang, X.; Mu, W.; Han, X. Chemical Signal Communication between Two Protoorganelles in a Lipid-Based Artificial Cell. Anal. Chem. 2019, 91, 6859– 6864,  DOI: 10.1021/acs.analchem.9b01128
      22
      Chemical Signal Communication between Two Protoorganelles in a Lipid-Based Artificial Cell
      Li, Shubin; Wang, Xuejing; Mu, Wei; Han, Xiaojun
      Analytical Chemistry (Washington, DC, United States) (2019), 91 (10), 6859-6864CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The chem. signal communication among organelles in the cell is extremely important for life. We demonstrate here the chem. signal communication between two protoorganelles using cascade enzyme reactions in a lipid-based artificial cell. Two protoorganelles inside the artificial cell are large unilamellar vesicles contg. glucose oxidase (GOx-LUVs) and a vesicle contg. horseradish peroxidase (HRP) and Amplex red, resp. The glucose mols. outside the artificial cell penetrate the lipid bilayer through mellitin pores and enter into one protoroganelle (GOx-LUV) to produce H2O2, which subsequently is transported to the other protoorganelle to oxidize Amplex red into red resorufin catalyzed by HRP. The no. of GOx-LUVs in an artificial cell is controlled by using a GOx-LUV soln. with different d. during the electroformation. The reaction rate for resorufin in the protoorganelle increases with more GOx-LUVs inside the artificial cell. The artificial cell developed here paves the way for a more complicated signal transduction mechanism study in a eukaryocyte.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXot1OqurY%253D&md5=fd65abe2f867b01ea5446378f3554521
    23. 23
      Wang, X.; Tian, L.; Du, H.; Li, M.; Mu, W.; Drinkwater, B. W.; Han, X.; Mann, S. Chemical Communication in Spatially Organized Protocell Colonies and Protocell/Living Cell Micro-Arrays. Chem. Sci. 2019, 10, 9446– 9453,  DOI: 10.1039/C9SC04522H
      23
      Chemical communication in spatially organized protocell colonies and protocell/living cell micro-arrays
      Wang, Xuejing; Tian, Liangfei; Du, Hang; Li, Mei; Mu, Wei; Drinkwater, Bruce W.; Han, Xiaojun; Mann, Stephen
      Chemical Science (2019), 10 (41), 9446-9453CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Micro-arrays of discrete or hemifused giant unilamellar lipid vesicles (GUVs) with controllable spatial geometries, lattice dimensions, trapped occupancies and compns. are prepd. by acoustic standing wave patterning, and employed as platforms to implement chem. signaling in GUV colonies and protocell/living cell consortia. The methodol. offers an alternative approach to GUV micro-array fabrication and provides new opportunities in protocell research and bottom-up synthetic biol.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslyqt7bK&md5=07d8659b3475a5879e1fe01d00d1d227
    24. 24
      Kučera, O.; Cifra, M. Cell-to-Cell Signaling through Light: Just a Ghost of Chance?. Cell Commun. Signaling 2013, 11, 87– 94,  DOI: 10.1186/1478-811X-11-87
      24
      Cell-to-cell signaling through light: just a ghost of chance?
      Kucera Ondrej; Cifra Michal
      Cell communication and signaling : CCS (2013), 11 (), 87 ISSN:.
      Despite the large number of reports attributing the signaling between detached cell cultures to the electromagnetic phenomena, almost no report so far included a rigorous analysis of the possibility of such signaling.In this paper, we examine the physical feasibility of the electromagnetic communication between cells, especially through light, with regard to the ambient noise illumination. We compare theoretically attainable parameters of communication with experimentally obtained data of the photon emission from cells without a specially pronounced ability of bioluminescence.We show that the weak intensity of the emission together with an unfavorable signal-to-noise ratio, which is typical for natural conditions, represent an important obstacle to the signal detection by cells.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2c7ls1ShtA%253D%253D&md5=41e13b69e4d2776bd308c7b353014a93
    25. 25
      Martini, S.; Haddock, S. H. Quantification of Bioluminescence from the Surface to the Deep Sea Demonstrates Its Predominance as an Ecological Trait. Sci. Rep. 2017, 7, 45750– 45760,  DOI: 10.1038/srep45750
      25
      Quantification of bioluminescence from the surface to the deep sea demonstrates its predominance as an ecological trait
      Martini, Severine; Haddock, Steven H. D.
      Scientific Reports (2017), 7 (), 45750CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      The capability of animals to emit light, called bioluminescence, is considered to be a major factor in ecol. interactions. Because it occurs across diverse taxa, measurements of bioluminescence can be powerful to detect and quantify organisms in the ocean. In this study, 17 years of video observations were recorded by remotely operated vehicles during surveys off the California Coast, from the surface down to 3,900 m depth. More than 350,000 observations are classified for their bioluminescence capability based on literature descriptions. The organisms represented 553 phylogenetic concepts (species, genera or families, at the most precise taxonomic level defined from the images), distributed within 13 broader taxonomic categories. The importance of bioluminescent marine taxa is highlighted in the water column, as we showed that 76% of the obsd. individuals have bioluminescence capability. More than 97% of Cnidarians were bioluminescent, and 9 of the 13 taxonomic categories were found to be bioluminescent dominant. The percentage of bioluminescent animals is remarkably uniform over depth. Moreover, the proportion of bioluminescent and non-bioluminescent animals within taxonomic groups changes with depth for Ctenophora, Scyphozoa, Chaetognatha, and Crustacea. Given these results, bioluminescence has to be considered an important ecol. trait from the surface to the deep-sea.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlvVelurk%253D&md5=9a69b777773af9311f9d5dc3d60ab581
    26. 26
      Burford, B. P.; Robison, B. H. Bioluminescent Backlighting Illuminates the Complex Visual Signals of a Social Squid in the Deep Sea. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 8524– 8531,  DOI: 10.1073/pnas.1920875117
      26
      Bioluminescent backlighting illuminates the complex visual signals of a social squid in the deep sea
      Burford, Benjamin P.; Robison, Bruce H.
      Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (15), 8524-8531CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Visual signals rapidly relay information, facilitating behaviors and ecol. interactions that shape ecosystems. However, most known signaling systems can be restricted by low light levels-a pervasive condition in the deep ocean, the largest inhabitable space on the planet. Resident visually cued animals have therefore been hypothesized to have simple signals with limited information-carrying capacity. We used cameras mounted on remotely operated vehicles to study the behavior of the Humboldt squid, Dosidicus gigas, in its natural deep-sea habitat. We show that specific pigmentation patterns from its diverse repertoire are selectively displayed during foraging and in social scenarios, and we investigate how these behaviors may be used syntactically for communication. We addnl. identify the probable mechanism by which D. gigas, and related squids, illuminate these patterns to create visual signals that can be readily perceived in the deep, dark ocean. Numerous small s.c. (s.c.) photophores (bioluminescent organs) embedded throughout the muscle tissue make the entire body glow, thereby backlighting the pigmentation patterns. Equipped with a mechanism by which complex information can be rapidly relayed through a visual pathway under low-light conditions, our data suggest that the visual signals displayed by D. gigas could share design features with advanced forms of animal communication. Visual signaling by deep-living cephalopods will likely be crit. in understanding how, and how much, information can be shared in one of the planet's most challenging environments for visual communication.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntFOitLg%253D&md5=09f406ad306dfafc2883f880cc8949fc
    27. 27
      Widder, E. A. Bioluminescence in the Ocean: Origins of Biological, Chemical and Ecological Diversity. Science 2010, 328, 704– 708,  DOI: 10.1126/science.1174269
      27
      Bioluminescence in the ocean: Origins of biological, chemical, and ecological diversity
      Widder, E. A.
      Science (Washington, DC, United States) (2010), 328 (5979), 704-708CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A review. From bacteria to fish, a remarkable variety of marine life depends on bioluminescence (the chem. generation of light) for finding food, attracting mates, and evading predators. Disparate biochem. systems and diverse phylogenetic distribution patterns of light-emitting organisms highlight the ecol. benefits of bioluminescence, with biochem. and genetic analyses providing new insights into the mechanisms of its evolution. The origins and functions of some bioluminescent systems, however, remain obscure. Here, the author reviews recent advances in understanding bioluminescence in the ocean and highlights future research efforts that will unite mol. details with ecol. and evolutionary relations.
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    28. 28
      Laager, F. Light Based Cellular Interactions: Hypotheses and Perspectives. Front. Phys. 2015, 3, 55,  DOI: 10.3389/fphy.2015.00055
      There is no corresponding record for this reference.
    29. 29
      Ghazvini, S.; Alonso, R.; Alhakamy, N.; Dhar, P. pH-Induced Changes in the Surface Viscosity of Unsaturated Phospholipids Monitored Using Active Interfacial Microrheology. Langmuir 2018, 34, 1159– 1170,  DOI: 10.1021/acs.langmuir.7b02803
      29
      pH-Induced Changes in the Surface Viscosity of Unsaturated Phospholipids Monitored Using Active Interfacial Microrheology
      Ghazvini, Saba; Alonso, Ryan; Alhakamy, Nabil; Dhar, Prajnaparamita
      Langmuir (2018), 34 (3), 1159-1170CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Lipid membranes, a major component of cells, are subjected to significant changes in pH depending on their location in the cell: the outer leaflet of the cell membrane is exposed to a pH of 7.4 while lipid membranes that make up late endosomes and lysosomes are exposed to a pH as low as 4.4. The purpose of this study is to evaluate how changes in the environmental pH within cells alter the fluidity of phospholipid membranes. Specifically, we studied pH-induced alterations in the surface arrangement of monounsatd. lipids with zwitterionic head-groups [phosphoethanolamine (PE) and phosphocholine (PC)] that are abundant in the plasma membrane, as well as anionic lipids [phosphatidylserine (PS) and phosphatidylglycerol (PG)] that are abundant in inner membranes, using a combination of techniques including surface tension vs. area measurements, interfacial microrheol., and fluorescence/at. force microscopy. Using an active interfacial microrheol. technique, we found that phospholipids with zwitterionic head-groups showed a significant increase in the surface viscosity at acidic pH. This increase in surface viscosity was found to also depend on the size of the lipid head-group, with a smaller head-group showing a higher increase in viscosity. The obsd. pH-induced increase in viscosity was also accompanied by an increase in the cohesion pressure between zwitterionic mols. at acidic pH, as measured by fitting the surface pressure isotherms to well-established equations of state. Since fluorescence images showed no change in the phase of the lipids, we attributed this change in surface viscosity to pH induced reorientation of the P--N+ dipoles that form part of the polar lipid head-group, resulting in increased lipid-lipid interactions. Anionic PG head-groups did not demonstrate this pH induced change in viscosity, suggesting that the presence of a net neg. charge on the head-group causes electrostatic repulsion between the head-groups. The results also showed that active interfacial microrheol. is a sensitive technique to detect minute changes in the lipid head-group orientation induced by changes in the local membrane environment, even in unsatd. phospholipids with very high fluidity.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1CisbzL&md5=04e232df3a1abd008c453507514221fe
    30. 30
      Valko, M.; Morris, H.; Cronin, M. T. D. Metals, Toxicity and Oxidative Stress. Curr. Med. Chem. 2005, 12, 1161– 1208,  DOI: 10.2174/0929867053764635
      30
      Metals, toxicity and oxidative stress
      Valko, M.; Morris, H.; Cronin, M. T. D.
      Current Medicinal Chemistry (2005), 12 (10), 1161-1208CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)
      A review of metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidn., and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsatd. fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal, and other exocyclic DNA adducts [etheno and(or) propano adducts]. While Fe, Cu, Cr, V, and Co undergo redox-cycling reactions, for a second group of metals, Hg, Cd, and Ni, the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. As is thought to bind directly to crit. thiols, however, other mechanisms, involving the formation of hydrogen peroxide under physiol. conditions, have been proposed. The unifying factor in detg. toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium, and cobalt primarily assocd. with mitochondria, microsomes, and peroxisomes. However, a recent discovery that the upper limit of free pools of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to the activation of mainly redox-sensitive transcription factors, involving NF-κB, AP-1, and p53. Antioxidants (both enzymic and non-enzymic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidn. may be assocd. rather with the level of non-enzymic antioxidants than the activity of enzymic antioxidants. However, a very recent epidemiol. study has shown that a daily intake of vitamin E of >400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidn. and does not promote protein oxidn. in humans in vitro. Exptl. results have also shown a link between vanadium and oxidative stress in the etiol. of diabetes. The impact of Zn on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress, and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiol. of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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    31. 31
      Vanuytsel, S.; Carniello, J.; Wallace, M. I. Artificial Signal Transduction across Membranes. ChemBioChem 2019, 20, 2569– 2580,  DOI: 10.1002/cbic.201900254
      31
      Artificial Signal Transduction across Membranes
      Vanuytsel, Steven; Carniello, Joanne; Wallace, Mark Ian
      ChemBioChem (2019), 20 (20), 2569-2580CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A key conundrum in the construction of an artificial cell is to simultaneously maintain a robust phys. barrier to the external environment, while also providing efficient exchange of information across this barrier. Biomimicry provides a no. of avenues by which such requirements might be met. Herein, we provide a brief introduction to the challenges facing this field and explore progress to date.
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    32. 32
      Guntas, G.; Hallett, R. A.; Zimmerman, S. P.; Williams, T.; Yumerefendi, H.; Bear, J. E.; Kuhlman, B. Engineering an Improved Light-Induced Dimer (iLID) for Controlling the Localization and Activity of Signaling Proteins. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 112– 117,  DOI: 10.1073/pnas.1417910112
      32
      Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins
      Guntas, Gurkan; Hallett, Ryan A.; Zimmerman, Seth P.; Williams, Tishan; Yumerefendi, Hayretin; Bear, James E.; Kuhlman, Brian
      Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (1), 112-117CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The discovery of light-inducible protein-protein interactions has allowed for the spatial and temporal control of a variety of biol. processes. To be effective, a photodimerizer should have several characteristics: (1) it should show a large change in binding affinity upon light stimulation; (2) it should not cross-react with other mols. in the cell; and (3) it should be easily used in a variety of organisms to recruit proteins of interest to each other. To create a switch that meets these criteria we have embedded the bacterial SsrA peptide in the C-terminal helix of a naturally occurring photoswitch, the light-oxygen-voltage 2 (LOV2) domain from Avena sativa. In the dark the SsrA peptide is sterically blocked from binding its natural binding partner, SspB. When activated with blue light, the C-terminal helix of the LOV2 domain undocks from the protein, allowing the SsrA peptide to bind SspB. Without optimization, the switch exhibited a twofold change in binding affinity for SspB with light stimulation. Here, we describe the use of computational protein design, phage display, and high-throughput binding assays to create an improved light inducible dimer (iLID) that changes its affinity for SspB by over 50-fold with light stimulation. A crystal structure of iLID shows a crit. interaction between the surface of the LOV2 domain and a phenylalanine engineered to more tightly pin the SsrA peptide against the LOV2 domain in the dark. We demonstrate the functional utility of the switch through light-mediated subcellular localization in mammalian cell culture and reversible control of small GTPase signaling.
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    33. 33
      Chervyachkova, E.; Wegner, S. V. Reversible Social Self-Sorting of Colloidal Cell-Mimics with Blue Light Switchable Proteins. ACS Synth. Biol. 2018, 7, 1817– 1824,  DOI: 10.1021/acssynbio.8b00250
      33
      Reversible Social Self-Sorting of Colloidal Cell-Mimics with Blue Light Switchable Proteins
      Chervyachkova, Elizaveta; Wegner, Seraphine V.
      ACS Synthetic Biology (2018), 7 (7), 1817-1824CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
      Toward the bottom-up assembly of synthetic cells from mol. building blocks, it is an ongoing challenge to assemble micrometer sized compartments that host different processes into precise multicompartmental assemblies, also called prototissues. The difficulty lies in controlling interactions between different compartments dynamically both in space and time, as these interactions det. how they organize with respect to each other and how they work together. The authors have been able to control the self-assembly and social self-sorting of four different types of colloids, which the authors use as a model for synthetic cells, into two sep. families with visible light. For this purpose the authors used two photoswitchable protein pairs (iLID/Nano and nHagHigh/pMagHigh) that both reversibly heterodimerize upon blue light exposure and dissoc. from each other in the dark. These photoswitchable proteins provide noninvasive, dynamic, and reversible remote control under biocompatible conditions over the self-assembly process with unprecedented spatial and temporal precision. In addn., each protein pair brings together specifically two different types of colloids. The orthogonality of the two protein pairs enables social self-sorting of a four component mixt. into two distinct families of colloidal aggregates with controlled arrangements. These results will ultimately pave the way for the bottom-up assembly of multicompartment synthetic prototissues of a higher complexity, enabling the authors to control precisely and dynamically the organization of different compartments in space and time.
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    34. 34
      Chakraborty, T.; Bartelt, S. M.; Steinkühler, J.; Dimova, R.; Wegner, S. V. Light Controlled Cell-to-Cell Adhesion and Chemical Communication in Minimal Synthetic Cells. Chem. Commun. 2019, 55, 9448– 9451,  DOI: 10.1039/C9CC04768A
      34
      Light controlled cell-to-cell adhesion and chemical communication in minimal synthetic cells
      Chakraborty, T.; Bartelt, S. M.; Steinkuehler, J.; Dimova, R.; Wegner, S. V.
      Chemical Communications (Cambridge, United Kingdom) (2019), 55 (64), 9448-9451CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Decorating GUVs, used as minimal synthetic cell models, with photoswitchable proteins allows controlling the adhesion between them and their assembly into multicellular structures with light. Thereby, the chem. communication between a sender and a receiver GUV, which strongly depends on their spatial proximity, can also be photoregulated.
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    35. 35
      Mueller, M.; Rasoulinejad, S.; Garg, S.; Wegner, S. V. The Importance of Cell-Cell Interaction Dynamics in Bottom-Up Tissue Engineering: Concepts of Colloidal Self-Assembly in the Fabrication of Multicellular Architectures. Nano Lett. 2020, 20, 2257– 2263,  DOI: 10.1021/acs.nanolett.9b04160
      35
      The Importance of Cell-Cell Interaction Dynamics in Bottom-Up Tissue Engineering: Concepts of Colloidal Self-Assembly in the Fabrication of Multicellular Architectures
      Mueller, Marc; Rasoulinejad, Samaneh; Garg, Sukant; Wegner, Seraphine V.
      Nano Letters (2020), 20 (4), 2257-2263CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Building tissue from cells as the basic building block based on principles of self-assembly is a challenging and promising approach. Understanding how far principles of self-assembly and self-sorting known for colloidal particles apply to cells remains unanswered. In this study, we demonstrate that not just controlling the cell-cell interactions but also their dynamics is a crucial factor that dets. the formed multicellular structure, using photoswitchable interactions between cells that are activated with blue light and reverse in the dark. Tuning dynamics of the cell-cell interactions by pulsed light activation results in multicellular architectures with different sizes and shapes. When the interactions between cells are dynamic, compact and round multicellular clusters under thermodn. control form, while otherwise branched and loose aggregates under kinetic control assemble. These structures parallel what is known for colloidal assemblies under reaction- and diffusion-limited cluster aggregation, resp. Similarly, dynamic interactions between cells are essential for cells to self-sort into distinct groups. Using four different cell types, which expressed two orthogonal cell-cell interaction pairs, the cells sorted into two sep. assemblies. Bringing concepts of colloidal self-assembly to bottom-up tissue engineering provides a new theor. framework and will help in the design of more predictable tissue-like structures.
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    36. 36
      Senturk, O. I.; Chervyachkova, E.; Ji, Y.; Wegner, S. V. Independent Blue and Red Light Triggered Narcissistic Self-Sorting Self-Assembly of Colloidal Particles. Small 2019, 15, 1901801,  DOI: 10.1002/smll.201901801
      There is no corresponding record for this reference.
    37. 37
      Bartelt, S. M.; Steinkühler, J.; Dimova, R.; Wegner, S. V. Light-Guided Motility of a Minimal Synthetic Cell. Nano Lett. 2018, 18, 7268– 7274,  DOI: 10.1021/acs.nanolett.8b03469
      37
      Light-Guided Motility of a Minimal Synthetic Cell
      Bartelt, Solveig M.; Steinkuehler, Jan; Dimova, Rumiana; Wegner, Seraphine V.
      Nano Letters (2018), 18 (11), 7268-7274CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Cell motility is an important but complex process; as cells move, new adhesions form at the front and adhesions disassemble at the back. To replicate this dynamic and spatiotemporally controlled asymmetry of adhesions and achieve motility in a minimal synthetic cell, we controlled the adhesion of a model giant unilamellar vesicle (GUV) to the substrate with light. For this purpose, we immobilized the proteins iLID and Micro, which interact under blue light and dissoc. from each other in the dark, on a substrate and a GUV, resp. Under blue light, the protein interaction leads to adhesion of the vesicle to the substrate, which is reversible in the dark. The high spatiotemporal control provided by light, allowed partly illuminating the GUV and generating an asymmetry in adhesions. Consequently, the GUV moves into the illuminated area, a process that can be repeated over multiple cycles. Thus, our system reproduces the dynamic spatiotemporal distribution of adhesions and establishes mimetic motility of a synthetic cell.
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    38. 38
      Berglund, K.; Tung, J. K.; Higashikubo, B.; Gross, R. E.; Moore, C. I.; Hochgeschwender, U. Combined Optogenetic and Chemogenetic Control of Neurons. Methods Mol. Biol. 2016, 1408, 207– 225,  DOI: 10.1007/978-1-4939-3512-3_14
      38
      Combined optogenetic and chemogenetic control of neurons
      Berglund, Ken; Tung, Jack K.; Higashikubo, Bryan; Gross, Robert E.; Moore, Christopher I.; Hochgeschwender, Ute
      Methods in Molecular Biology (New York, NY, United States) (2016), 1408 (Optogenetics), 207-225CODEN: MMBIED; ISSN:1940-6029. (Springer)
      A review. Optogenetics provides an array of elements for specific biophys. control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same exptl. animal. Light-sensing mols. (opsins) are activated by biol. produced light through luciferases upon peripheral injection of a small mol. substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo.
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    39. 39
      Berglund, K.; Clissold, K.; Li, H. E.; Wen, L.; Park, S. Y.; Gleixner, J.; Klein, M. E.; Lu, D.; Barter, J. W.; Rossi, M. A.; Augustine, G. J.; Yin, H. H.; Hochgeschwender, U. Luminopsins Integrate Opto- and Chemogenetics by Using Physical and Biological Light Sources for Opsin Activation. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E358– E367,  DOI: 10.1073/pnas.1510899113
      39
      Luminopsins integrate opto- and chemogenetics by using physical and biological light sources for opsin activation
      Berglund, Ken; Clissold, Kara; Li, Haofang E.; Wen, Lei; Park, Sung Young; Gleixner, Jan; Klein, Marguerita E.; Lu, Dongye; Barter, Joseph W.; Rossi, Mark A.; Augustine, George J.; Yin, Henry H.; Hochgeschwender, Ute
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (3), E358-E367CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Luminopsins are fusion proteins of luciferase and opsin that allow interrogation of neuronal circuits at different temporal and spatial resolns. by choosing either extrinsic phys. or intrinsic biol. light for its activation. Building on previous development of fusions of wild-type Gaussia luciferase with channelrhodopsin, here we expanded the utility of luminopsins by fusing bright Gaussia luciferase variants with either channelrhodopsin to excite neurons (luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO, iLMO). These improved LMOs could reliably activate or silence neurons in vitro and in vivo. Expression of the improved LMO in hippocampal circuits not only enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal resoln. but also could drive rhythmic circuit excitation over a large spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or iLMO in the substantia nigra in vivo produced not only the expected bidirectional control of single unit activity but also opposing effects on circling behavior in response to systemic injection of a luciferase substrate. Thus, although preserving the ability to be activated by external light sources, LMOs expand the use of optogenetics by making the same opsins accessible to noninvasive, chemogenetic control, thereby allowing the same probe to manipulate neuronal activity over a range of spatial and temporal scales.
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    40. 40
      Kim, C. K.; Cho, K. F.; Kim, M. W.; Ting, A. Y. Luciferase-LOV BRET Enables Versatile and Specific Transcriptional Readout of Cellular Protein-Protein Interactions. eLife 2019, 8, 43826– 43846,  DOI: 10.7554/eLife.43826
      40
      Luciferase-LOV BRET enables versatile and specific transcriptional readout of cellular protein-protein interactions
      Kim, Christina K.; Cho, Kelvin F.; Kim, Min Woo; Ting, Alice Y.
      eLife (2019), 8 (), e43826/1-e43826/21CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
      Technologies that convert transient protein-protein interactions (PPIs) into stable expression of a reporter gene are useful for genetic selections, high-throughput screening, and multiplexing with omics technologies. We previously reported SPARK (Kim et al., 2017), a transcription factor that is activated by the coincidence of blue light and a PPI. Here, we report an improved, second-generation SPARK2 that incorporates a luciferase moiety to control the lightsensitive LOV domain. SPARK2 can be temporally gated by either external light or addn. of a small-mol. luciferin, which causes luciferase to open LOV via proximity-dependent BRET. Furthermore, the nested 'AND' gate design of SPARK2-in which both protease recruitment to the membrane-anchored transcription factor and LOV domain opening are regulated by the PPI of interest-yields a lower-background system and improved PPI specificity. We apply SPARK2 to high-throughput screening for GPCR agonists and for the detection of trans-cellular contacts, all with versatile transcriptional readout.
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    41. 41
      Salinas, F.; Rojas, V.; Delgado, V.; López, J.; Agosin, E.; Larrondo, L. F. Fungal Light-Oxygen-Voltage Domains for Optogenetic Control of Gene Expression and Flocculation in Yeast. mBio 2018, 9, e00626-18  DOI: 10.1128/mBio.00626-18
      There is no corresponding record for this reference.
    42. 42
      Parag-Sharma, K.; O’Banion, C. P.; Henry, E. C.; Musicant, A. M.; Cleveland, J. L.; Lawrence, D. S.; Amelio, A. L. Engineered BRET-Based Biologic Light Sources Enable Spatiotemporal Control Over Diverse Optogenetic Systems. ACS Synth. Biol. 2020, 9, 1– 9,  DOI: 10.1021/acssynbio.9b00277
      42
      Engineered BRET-Based Biologic Light Sources Enable Spatiotemporal Control over Diverse Optogenetic Systems
      Parag-Sharma, Kshitij; O'Banion, Colin P.; Henry, Erin C.; Musicant, Adele M.; Cleveland, John L.; Lawrence, David S.; Amelio, Antonio L.
      ACS Synthetic Biology (2020), 9 (1), 1-9CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
      Light-inducible optogenetic systems offer precise spatiotemporal control over a myriad of biol. processes. Unfortunately, current systems are inherently limited by their dependence on external light sources for their activation. Further, the utility of laser/LED-based illumination strategies are often constrained by the need for invasive surgical procedures to deliver such devices and local heat prodn., photobleaching and phototoxicity that compromises cell and tissue viability. To overcome these limitations, we developed a novel BRET-activated optogenetics (BEACON) system that employs biol. light to control optogenetic tools. BEACON is driven by self-illuminating bioluminescent-fluorescent proteins that generate "spectrally tuned" biol. light via bioluminescence resonance energy transfer (BRET). Notably, BEACON robustly activates a variety of commonly used optogenetic systems in a spatially restricted fashion, and at physiol. relevant time scales, to levels that are achieved by conventional laser/LED light sources.
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    43. 43
      Chen, F.; Warnock, R. L.; Van der Meer, J. R.; Wegner, S. V. Bioluminescence-Triggered Photoswitchable Bacterial Adhesions Enable Higher Sensitivity and Dual-Readout Bacterial Biosensors for Mercury. ACS Sens. 2020, 5, 2205– 2210,  DOI: 10.1021/acssensors.0c00855
      43
      Bioluminescence-Triggered Photoswitchable Bacterial Adhesions Enable Higher Sensitivity and Dual-Readout Bacterial Biosensors for Mercury
      Chen, Fei; Warnock, Rachel L.; Van der Meer, Jan Roelof; Wegner, Seraphine V.
      ACS Sensors (2020), 5 (7), 2205-2210CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      The authors present a new concept for whole-cell biosensors that couples the response to Hg2+ with bioluminescence and bacterial aggregation. This allows the authors to use the bacterial aggregation to preconc. the bioluminescent bacteria at the substrate surface and increase the sensitivity of Hg2+ detection. This whole-cell biosensor combines a Hg2+-sensitive bioluminescence reporter and light-responsive bacterial cell-cell adhesions. The blue luminescence in response to Hg2+ is able to photoactivate bacterial aggregation, which provides a second readout for Hg2+ detection. In return, the Hg2+-triggered bacterial aggregation leads to faster sedimentation and more efficient formation of biofilms. At low Hg2+ concns., the enrichment of the bacteria in biofilms leads to an up to 10-fold increase in the signal. The activation of photoswitchable proteins with biol. light is a new concept in optogenetics, and the presented bacterial biosensor design is transferable to other bioluminescent reporters with particular interest for environmental monitoring.
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    44. 44
      Woo, J.; von Arnim, A. G Mutational Optimization of the Coelenterazine-Dependent Luciferase from Renilla. Plant Methods 2008, 4, 23– 33,  DOI: 10.1186/1746-4811-4-23
      44
      Mutational optimization of the coelenterazine-dependent luciferase from Renilla
      Woo Jongchan; von Arnim Albrecht G
      Plant methods (2008), 4 (), 23 ISSN:.
      Renilla luciferase (RLUC) is a popular reporter enzyme for gene expression and biosensor applications, but it is an unstable enzyme whose catalytic mechanism remains to be elucidated. We titrated that one RLUC molecule can turn over about one hundred molecules of coelenterazine substrate. Mutagenesis of active site residue Pro220 extended the half-life of photon emission, yielding brighter luminescence in E. coli. Random mutagenesis uncovered two new mutations that stabilized and increased photon emission in vivo and in vitro, while ameliorating substrate inhibition. Further amended with a previously identified mutation, a new triple mutant showed a threefold improved kcat, as well as elevated luminescence in Arabidopsis. This advances the utility of RLUC as a reporter protein, biosensor, or resonance energy donor.
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    45. 45
      Thomas, J. M.; Friddin, M. S.; Ces, O.; Elani, Y. Programming Membrane Permeability Using Integrated Membrane Pores and Blockers as Molecular Regulators. Chem. Commun. 2017, 53, 12282– 12285,  DOI: 10.1039/C7CC05423H
      45
      Programming membrane permeability using integrated membrane pores and blockers as molecular regulators
      Thomas, Julia M.; Friddin, Mark S.; Ces, Oscar; Elani, Yuval
      Chemical Communications (Cambridge, United Kingdom) (2017), 53 (91), 12282-12285CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      We report a bottom-up synthetic biol. approach to engineering vesicles with programmable permeabilities. Exploiting the concn.-dependent relation between constitutively active pores (α-hemolysin) and blockers allows the blockers to behave as mol. regulators for tuning permeability, enabling us to systematically modulate cargo release kinetics without changing the lipid fabric of the system.
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    46. 46
      Vacklin, H. P.; Tiberg, F.; Fragneto, G.; Thomas, R. K. Phospholipase A2 Hydrolysis of Supported Phospholipid Bilayers: A Neutron Reflectivity and Ellipsometry Study. Biochemistry 2005, 44, 2811– 2821,  DOI: 10.1021/bi047727a
      46
      Phospholipase A2 Hydrolysis of Supported Phospholipid Bilayers: A Neutron Reflectivity and Ellipsometry Study
      Vacklin, Hanna P.; Tiberg, Fredrik; Fragneto, Giovanna; Thomas, R. K.
      Biochemistry (2005), 44 (8), 2811-2821CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      We have investigated the phospholipase A2 catalyzed hydrolysis of supported phospholipid bilayers using neutron reflection and ellipsometry. At the hydrophilic silica-water interface, hydrolysis of phosphatidylcholine bilayers by phospholipase A2 from Naja mossambica mossambica venom is accompanied by destruction of the bilayer at an initial rate, which is comparable for DOPC and DPPC but is doubled for POPC. The extent of bilayer destruction at 25 °C decreases from DOPC to POPC and is dramatically reduced for DPPC. Neutron reflectivity measurements indicate that the enzyme penetrates into the bilayers in increasing order for DOPC, POPC, and DPPC, while the amt. of enzyme adsorbed at the interface is smallest for DPPC and exhibits a max. for POPC. Penetration into the hydrophobic chain region in the bilayer is further supported by the fact that the enzyme adsorbs strongly and irreversibly to a hydrophobic monolayer of octadecyltrichlorosilane. These results are rationalized in terms of the properties of the reaction products and the effect of their accumulation in the membrane on the kinetics of enzyme catalysis.
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    47. 47
      Kai, S.; Li, X.; Li, B.; Han, X.; Lu, X. Calcium-Dependent Hydrolysis of Supported Planar Lipids was Triggered by Honey Bee Venom Phospholipase A2 with the Right Orientation at the Interface. Phys. Chem. Chem. Phys. 2018, 20, 63– 67,  DOI: 10.1039/C7CP06344J
      47
      Calcium-dependent hydrolysis of supported planar lipids was triggered by honey bee venom phospholipase A2 with the right orientation at the interface
      Kai, Siqi; Li, Xu; Li, Bolin; Han, Xiaofeng; Lu, Xiaolin
      Physical Chemistry Chemical Physics (2018), 20 (1), 63-67CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      Hydrolysis of planar phospholipids catalyzed by honey bee venom phospholipase A2 (bvPLA2) was studied. Expts. demonstrated that Ca2+ ions mediated between the lipids and bvPLA2, induced reorientation of bvPLA2, and activated hydrolysis. One of the hydrolysis products, fatty acids, was desorbed, and the other one, lysophospholipids, self-organized at the interface.
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    48. 48
      Bartelt, S. M.; Chervyachkova, E.; Steinkühler, J.; Ricken, J.; Wieneke, R.; Tampe, R.; Dimova, R.; Wegner, S. V. Dynamic Blue Light-Switchable Protein Patterns on Giant Unilamellar Vesicles. Chem. Commun. 2018, 54, 948– 951,  DOI: 10.1039/C7CC08758F
      48
      Dynamic blue light-switchable protein patterns on giant unilamellar vesicles
      Bartelt, S. M.; Chervyachkova, E.; Steinkuehler, J.; Ricken, J.; Wieneke, R.; Tampe, R.; Dimova, R.; Wegner, S. V.
      Chemical Communications (Cambridge, United Kingdom) (2018), 54 (8), 948-951CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      The blue light-dependent interaction between the proteins iLID and Nano allows recruiting and patterning proteins on GUV membranes, which thereby capture key features of patterns obsd. in nature. This photoswitchable protein interaction provides non-invasive, reversible and dynamic control over protein patterns of different sizes with high specificity and spatiotemporal resoln.
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    49. 49
      Daneshpour, H.; Youk, H. Modeling Cell-Cell Communication for Immune Systems across Space and Time. Curr. Opin. Syst. Biol. 2019, 18, 44– 52,  DOI: 10.1016/j.coisb.2019.10.008
      49
      Modeling cell-cell communication for immune systems across space and time
      Daneshpour Hirad; Youk Hyun; Daneshpour Hirad; Youk Hyun; Youk Hyun
      Current opinion in systems biology (2019), 18 (), 44-52 ISSN:2452-3100.
      Communicating is crucial for cells to coordinate their behaviors. Immunological processes, involving diverse cytokines and cell types, are ideal for developing frameworks for modeling coordinated behaviors of cells. Here, we review recent studies that combine modeling and experiments to reveal how immune systems use autocrine, paracrine, and juxtacrine signals to achieve behaviors such as controlling population densities and hair regenerations. We explain that models are useful because one can computationally vary numerous parameters, in experimentally infeasible ways, to evaluate alternate immunological responses. For each model, we focus on the length-scales and time-scales involved and explain why integrating multiple length-scales and time-scales in a model remain challenging. We suggest promising modeling strategies for meeting this challenge and their practical consequences.
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    50. 50
      Hindley, J. W.; Zheleva, D. G.; Elani, Y.; Charalambous, K.; Barter, L. M.; Booth, P. J.; Bevan, C. L.; Law, R. V.; Ces, O. Building a Synthetic Mechanosensitive Signaling Pathway in Compartmentalized Artificial Cells. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 16711– 16716,  DOI: 10.1073/pnas.1903500116
      50
      Building a synthetic mechanosensitive signaling pathway in compartmentalized artificial cells
      Hindley, James W.; Zheleva, Daniela G.; Elani, Yuval; Charalambous, Kalypso; Barter, Laura M. C.; Booth, Paula J.; Bevan, Charlotte L.; Law, Robert V.; Ces, Oscar
      Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (34), 16711-16716CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      To date, reconstitution of one of the fundamental methods of cell communication, the signaling pathway, has been unaddressed in the bottom-up construction of artificial cells (ACs). Such developments are needed to increase the functionality and biomimicry of ACs, accelerating their translation and application in biotechnol. Here, we report the construction of a de novo synthetic signaling pathway in microscale nested vesicles. Vesicle-cell models respond to external calcium signals through activation of an intracellular interaction between phospholipase A2 and a mechanosensitive channel present in the internal membranes, triggering content mixing between compartments and controlling cell fluorescence. Emulsion-based approaches to AC construction are therefore shown to be ideal for the quick design and testing of new signaling networks and can readily include synthetic mols. difficult to introduce to biol. cells. This work represents a foundation for the engineering of multicompartment-spanning designer pathways that can be utilized to control downstream events inside an AC, leading to the assembly of micromachines capable of sensing and responding to changes in their local environment.
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    51. 51
      Peng, R.; Xu, L.; Wang, H.; Lyu, Y.; Wang, D.; Bi, C.; Cui, C.; Fan, C.; Liu, Q.; Zhang, X.; Tan, W. DNA-Based Artificial Molecular Signaling System That Mimics Basic Elements of Reception and Response. Nat. Commun. 2020, 11, 978– 987,  DOI: 10.1038/s41467-020-14739-6
      51
      DNA-based artificial molecular signaling system that mimics basic elements of reception and response
      Peng, Ruizi; Xu, Liujun; Wang, Huijing; Lyu, Yifan; Wang, Dan; Bi, Cheng; Cui, Cheng; Fan, Chunhai; Liu, Qiaoling; Zhang, Xiaobing; Tan, Weihong
      Nature Communications (2020), 11 (1), 978CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: In order to maintain tissue homeostasis, cells communicate with the outside environment by receiving mol. signals, transmitting them, and responding accordingly with signaling pathways. Thus, one key challenge in engineering mol. signaling systems involves the design and construction of different modules into a rationally integrated system that mimics the cascade of mol. events. Herein, we rationally design a DNA-based artificial mol. signaling system that uses the confined microenvironment of a giant vesicle, derived from a living cell. This system consists of two main components. First, we build an ATP (ATP)-driven DNA nanogatekeeper. Second, we encapsulate a signaling network in the biomimetic vesicle, consisting of distinct modules, able to sequentially initiate a series of downstream reactions playing the roles of reception, transduction and response. Operationally, in the presence of ATP, nanogatekeeper switches from the closed to open state. The open state then triggers the sequential activation of confined downstream signaling modules.
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    52. 52
      Glantz, S. T.; Berlew, E. E.; Jaber, Z.; Schuster, B. S.; Gardner, K. H.; Chow, B. Y. Directly Light-Regulated Binding of RGS-LOV Photoreceptors to Anionic Membrane Phospholipids. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E7720– E7727,  DOI: 10.1073/pnas.1802832115
      52
      Directly light-regulated binding of RGS-LOV photoreceptors to anionic membrane phospholipids
      Glantz, Spencer T.; Berlew, Erin E.; Jaber, Zaynab; Schuster, Benjamin S.; Gardner, Kevin H.; Chow, Brian Y.
      Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (33), E7720-E7727CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      We report natural light-oxygen-voltage (LOV) photoreceptors with a blue light-switched, high-affinity (KD = ∼10-7 M), and direct electrostatic interaction with anionic phospholipids. Membrane localization of one such photoreceptor, BcLOV4 from Botrytis cinerea, was directly coupled to its flavin photocycle, and was mediated by a polybasic amphipathic helix in the linker region between the LOV sensor and its C-terminal domain of unknown function (DUF), as revealed through a combination of bioinformatics, computational protein modeling, structure-function studies, and optogenetic assays in yeast and mammalian cell line expression systems. In model systems, BcLOV4 rapidly translocated from the cytosol to plasma membrane (∼1 s). The reversible electrostatic interaction was nonselective among anionic phospholipids, exhibiting binding strengths dependent on the total anionic content of the membrane without preference for a specific headgroup. The in vitro and cellular responses were also obsd. with a BcLOV4 homolog and thus are likely to be general across the dikarya LOV class, whose members are assocd. with regulator of G-protein signaling (RGS) domains. Natural photoreceptors are not previously known to directly assoc. with membrane phospholipids in a light-dependent manner, and thus this work establishes both a photosensory signal transmission mode and a single-component optogenetic tool with rapid membrane localization kinetics that approaches the diffusion limit.
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    53. 53
      Charalambous, K.; Booth, P. J.; Woscholski, R.; Seddon, J. M.; Templer, R. H.; Law, R. V.; Barter, L. M.; Ces, O. Engineering de Novo Membrane-Mediated Protein-Protein Communication Networks. J. Am. Chem. Soc. 2012, 134, 5746– 5749,  DOI: 10.1021/ja300523q
      53
      Engineering de Novo Membrane-Mediated Protein-Protein Communication Networks
      Charalambous, Kalypso; Booth, Paula J.; Woscholski, Rudiger; Seddon, John M.; Templer, Richard H.; Law, Robert V.; Barter, Laura M. C.; Ces, Oscar
      Journal of the American Chemical Society (2012), 134 (13), 5746-5749CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Mech. properties of biol. membranes are known to regulate membrane protein function. Despite this, current models of protein communication typically feature only direct protein-protein or protein-small mol. interactions. By harnessing nanoscale mech. energy within biol. membranes, it is possible to promote controlled communication between proteins. By coupling lipid-protein modules and matching their response to the mech. properties of the membrane, the action of phospholipase A2 on acyl-based phospholipids triggers the opening of the mechanosensitive channel, MscL, by generating membrane asymmetry. The authors' findings confirm that the global phys. properties of biol. membranes can act as information pathways between proteins, a novel mechanism of membrane-mediated protein-protein communication that has important implications for (1) the underlying structure of signaling pathways, (2) the authors' understanding of in vivo communication networks, and (3) the generation of building blocks for artificial protein networks.
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    54. 54
      Birkner, E.; Berglund, K.; Klein, M. E.; Augustine, G. J.; Hochgeschwender, U. Non-Invasive Activation of Optogenetic Actuators. Proc. SPIE 2014, 8928, 89282F,  DOI: 10.1117/12.2044157
      There is no corresponding record for this reference.
    55. 55
      Kuchimaru, T.; Iwano, S.; Kiyama, M.; Mitsumata, S.; Kadonosono, T.; Niwa, H.; Maki, S.; Kizaka-Kondoh, S. A Luciferin Analogue Generating Near-Infrared Bioluminescence Achieves Highly Sensitive Deep-Tissue Imaging. Nat. Commun. 2016, 7, 11856– 11863,  DOI: 10.1038/ncomms11856
      55
      A luciferin analogue generating near-infrared bioluminescence achieves highly sensitive deep-tissue imaging
      Kuchimaru, Takahiro; Iwano, Satoshi; Kiyama, Masahiro; Mitsumata, Shun; Kadonosono, Tetsuya; Niwa, Haruki; Maki, Shojiro; Kizaka-Kondoh, Shinae
      Nature Communications (2016), 7 (), 11856CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      In preclin. cancer research, bioluminescence imaging with firefly luciferase and -luciferin has become a std. to monitor biol. processes both in vitro and in vivo. However, the emission max. (λmax) of bioluminescence produced by -luciferin is 562 nm where light is not highly penetrable in biol. tissues. This emphasizes a need for developing a red-shifted bioluminescence imaging system to improve detection sensitivity of targets in deep tissue. Here we characterize the bioluminescent properties of the newly synthesized luciferin analog, AkaLumine-HCl. The bioluminescence produced by AkaLumine-HCl in reactions with native firefly luciferase is in the near-IR wavelength ranges (λmax=677 nm), and yields significantly increased target-detection sensitivity from deep tissues with maximal signals attained at very low concns., as compared with -luciferin and emerging synthetic luciferin CycLuc1. These characteristics offer a more sensitive and accurate method for non-invasive bioluminescence imaging with native firefly luciferase in various animal models.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.1c01600.

    • Details of protein purification, absorbance spectrum of iLID and luminescence spectrum of RLuc, additional examples of mOrange-Nano recruitment to luminescent GUVs decorated with iLID, detailed analysis of luminescence induced adhesion and its reversion between iLID and Nano functionalized GUVs, additional examples of predator GUVs lysing prey GUVs including negative controls, SDS-PAGE of proteins, RLuc plasmid map and sequence (PDF)

    • Receiver GUVs lysis with presence of ionomycin and calcium (AVI)

    • Prey GUVs lysing after forming adhesions with luminescent predator (AVI)

    • Prey GUVs lysing after forming adhesions with luminescent predator (AVI)

    • Prey GUVs not lysing when luminescent predator GUVs pass by without forming adhesions (AVI)

    • Prey GUVs lysing after forming adhesions with predator GUVs under blue light (AVI)

    • Prey GUVs lysing after forming adhesions with predator GUVs under blue light (AVI)


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