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CommunicationSeptember 15, 2020

Generation of SARS-CoV-2 S1 Spike Glycoprotein Putative Antigenic Epitopes in Vitro by Intracellular Aminopeptidases
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George Stamatakis
George Stamatakis
Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Martina Samiotaki
Martina Samiotaki
Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Anastasia Mpakali
Anastasia Mpakali
National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece
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http://orcid.org/0000-0003-0869-9680
George Panayotou
George Panayotou
Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Efstratios Stratikos*
Efstratios Stratikos
National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece
*Email: [email protected], [email protected]
More by Efstratios Stratikos
http://orcid.org/0000-0002-3566-2309

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Journal of Proteome Research

Cite this: J. Proteome Res. 2020, 19, 11, 4398–4406

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https://doi.org/10.1021/acs.jproteome.0c00457

Published September 15, 2020

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Abstract

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Presentation of antigenic peptides by MHCI is central to cellular immune responses against viral pathogens. While adaptive immune responses versus SARS-CoV-2 can be of critical importance to both recovery and vaccine efficacy, how protein antigens from this pathogen are processed to generate antigenic peptides is largely unknown. Here, we analyzed the proteolytic processing of overlapping precursor peptides spanning the entire sequence of the S1 spike glycoprotein of SARS-CoV-2, by three key enzymes that generate antigenic peptides, aminopeptidases ERAP1, ERAP2, and IRAP. All enzymes generated shorter peptides with sequences suitable for binding onto HLA alleles, but with distinct specificity fingerprints. ERAP1 was the most efficient in generating peptides 8–11 residues long, the optimal length for HLA binding, while IRAP was the least efficient. The combination of ERAP1 with ERAP2 greatly limited the variability of peptide sequences produced. Less than 7% of computationally predicted epitopes were found to be produced experimentally, suggesting that aminopeptidase processing may constitute a significant filter to epitope presentation. These experimentally generated putative epitopes could be prioritized for SARS-CoV-2 immunogenicity studies and vaccine design. We furthermore propose that this in vitro trimming approach could constitute a general filtering method to enhance the prediction robustness for viral antigenic epitopes.

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SPECIAL ISSUE

This article is part of the Proteomics in Pandemic Disease special issue.

Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

Introduction

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for coronavirus disease 19 (COVID-19) that is behind a major ongoing pandemic. (1−3) Virus entry into host cells is dependent on the S1 spike glycoprotein that forms homotrimers on the surface of the virion and interacts with the ACE2 receptor in susceptible cells. (4−6)

Many studies on clinical characteristics and mortality resulting from SARS-CoV-2 infection have highlighted the need for a detailed understanding of immune responses against this pathogen. (7) While appropriate innate and adaptive immune responses are necessary for recovery from infection, aberrant immune responses can be a major contributing factor to mortality. (8,9) In parallel, understanding immune recognition of SARS-CoV-2 is crucial to the ongoing massive global effort into developing an effecting vaccine against this pathogen. (10) Although early analyses have focused on the development of neutralizing antibodies, cellular immune responses are emerging of vital importance (11) both for understanding normal immune response against this pathogen and for designing and optimizing vaccines. (12) In particular, T-cell mediated immunity appears to be important for both viral clearance and for long-term immunity. (11) Thus, analysis of antigenic epitopes from SARS-CoV-2 should be a priority for the design of vaccines that induce effective and long-lasting cellular immune responses. (13)

Cytotoxic T-cell responses against virus-infected cells hinge on the presentation of small peptidic fragments of viral proteins, called antigenic peptides, by specialized proteins on the cell surface that belong to the Major Histocompatibility Class I complex (MHCI, also called Human Leukocyte Antigens, HLA, in humans). Antigenic peptides are derived from viral proteins that are proteolytically degraded by complex proteolytic cascades. (14) Intracellular aminopeptidases, ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP) play important roles in producing antigenic peptides, by down-sizing longer peptides to the correct length for binding onto MHCI. (15) Appropriate processing of pathogen antigens by these enzymes can determine the generation of cytotoxic immune responses, and aberrant processing can lead to immune evasion. (16) Thus, it is important to understand how these enzymes process SARS-CoV-2 antigens, so as to gain insight into the efficacy of antiviral cytotoxic responses and reveal possible avenues to enhance them.

In this study, we utilized a novel approach to analyze antigen trimming by intracellular aminopeptidases ERAP1, ERAP2, and IRAP, focusing on the largest antigen of SARS-CoV-2, namely, S1 spike glycoprotein. By using tandem LC-MS/MS analysis, we were able to follow trimming in parallel of a large ensemble of peptides derived from the full length of S1 protein. This approach was inspired by two established observations: (i) that these enzymes are expected to normally encounter a very large number of potential substrates concurrently in the cell and (ii) accommodation of peptides inside a large cavity of each enzyme can lead to complex interactions between substrates that have to compete for the same space in the cavity. (17−19) Our analysis provides novel insight into the differences in substrate specificity between the three enzymes and provides a potential filter of traditional bioinformatic approaches that aim to predict antigenic epitopes. Finally, we propose a limited list of peptides that are potential ligands for common HLA alleles and could be prioritized for further immunological analyses and vaccine design efforts.

Experimental Procedures

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Enzyme Expression and Purification

Recombinant ERAP1, ERAP2, and IRAP were expressed and purified as described previously. Briefly, ERAP1 and ERAP2 were expressed by Hi5 insect cells in culture after infection with baculovirus carrying the appropriate gene and purified by affinity chromatography using a C-terminal his tag. (20,21) The enzymatic extracellular domain of IRAP was expressed by stably transfected HEK 293S GnTI⁽⁻⁾ cells and purified by affinity chromatography using a C-terminal Rhodopsin 1D4 tag. (22) Enzymes were stored with 10% glycerol in aliquots at −80 °C until needed.

Peptides

The PepMix SARS-CoV-2 peptide mixture was purchased by JBT Peptide Technologies GmbH. Peptide pools were dissolved in DMSO. Prior to reactions the two peptide collections (158 and 157 peptides respectively) were mixed at equimolar concentrations and diluted in buffer containing 10 mM Hepes pH 7, 100 mM NaCl to a final concentration of 48 μM.

Enzymatic Reactions

Enzymatic reactions were performed in triplicate in a total volume of 50 μL in 10 mM Hepes pH 7, 100 mM NaCl. Freshly thawed enzyme stocks were added to each reaction to a final concentration of 50 nM. Reactions were incubated at 37 °C for 2 h, stopped by the addition of 7.5 μL of a 10% TFA solution, flash frozen in liquid nitrogen, and stored at −80 °C until analysis.

LC-MS/MS Analysis

The sample was preconcentrated on a pepmap LC trapping column (0.3 × 5 mm) at a rate of 30 μL of Buffer A (0.1% Formic acid in water) in 5 min. The LC gradient used was 5% Buffer B (0.1% Formic acid in Acetonitrile) to 25% in 36 min followed by an increase to 36% in 5 min and a second increase to 80% in 0.5 min and then was kept constant for 2 min. The column was equilibrated for 15 min prior to the next injection. A full MS was acquired with a Q Exactive HF-X Hybrid Quadropole-Orbitrap mass spectrometer, in the scan range of 350–1400 m/z using 60K resolving power with an AGC of 3 × 10⁶ and max IT of 45 ms, followed by MS/MS scans of the 12 most abundant ions, using 15K resolving power with an AGC of 1 × 10⁵ and max IT of 22 ms and an NCE of 28.

Database Search

We employed the MaxQuant computational proteomics platform version 1.6.14.0 to search the peak lists against the Spike glycoprotein SARS2 FASTA file (SwissProt accession number P0DTC2) and a file containing 247 frequently observed contaminants. N-terminal acetylation (42.010565 Da) and methionine oxidation (15.994915 Da) were set as variable modifications. The second peptide identification option in Andromeda was enabled. The false discovery rate (FDR) was set to 0.01 for both peptides. The enzyme specificity was set as unspecific. The minimum peptide length was set to 6 amino acids. The initial allowed mass deviation of the precursor ion was set to 4.5 ppm and the maximum fragment mass deviation was set to 20 ppm.

Results and Discussion

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To investigate the trimming of antigenic epitope precursors by intracellular aminopeptidases that generate antigenic peptides, we used a mixture of 315 synthetic peptides derived from the sequence of the SARS-CoV-2 S1 spike glycoprotein. All peptides were 15 residues long and spanned the entire sequence of the protein with an 11 residue overlap between adjacent peptides. This mixture allows the systematic sampling of the entire sequence of the protein. The peptide mixture was incubated with either ERAP1, ERAP2, or IRAP at a substrate to enzyme ratio of 1000:1 and the digestion products analyzed by LC-MS/MS using a custom search database generated by in silico digestions of the full S1 protein sequence (UniProt ID: P0DTC2). We also tested an equimolar mixture of ERAP1 and ERAP2 since previous studies have suggested that these two proteins can form functional equimolar heterodimers in cells. (23,24) All analyses were performed on three biological replicates for each reaction, as well as a control reaction that was performed in the absence of enzymes. An additional technical replicate for the control sample was also analyzed. For statistical robustness, we performed a t test between the control sample and each reaction and selected for further analysis only the peptides for which the quantification value changed by a statistically significant degree (p-value < 0.05).

The relative abundance of each peptide before and after the reaction was compared by label-free quantification. Analysis identified 263 unique 15mers in the samples out of the total 315 in the mixture. This represents an 83% coverage of included peptides which may be due to poor ionization and detection for some peptide sequences. As a result, further analysis was limited to the peptides detectable by our experimental setup. On average, incubation with the enzyme reduced the relative abundance of the 15mer peptides indicating successful digestion (Figure 1A,B). This reduction was much more evident for ERAP1 and ERAP2 (and their mixture) than for IRAP. Each enzyme featured a unique digestion fingerprint, suggesting different selectivity, as suggested in previous studies. (25) The full list of generated peptides is shown in Supplemental Table S1. Since the majority of peptides presented by HLA are 8–11 residues long, we analyzed the comparative abundance of 8–11mers generated from each reaction (Figure 1C,D). Of the three enzymes, ERAP1 was the most efficient in generating peptides within this length range, consistent with previous reports on the mechanism of action of this enzyme. (17,26) ERAP2 and the ERAP1/ERAP2 mixture followed, while IRAP was the least efficient. Similar to the trimming of 15mers, the generation of 8–11mers followed a unique fingerprint for each enzyme. This is consistent with the previous hypotheses that each of these enzymes accommodate peptides in a large internal cavity and selectivity is driven by interactions with the whole sequence of the peptide. (17,21,22)

Figure 1. (A) Heatmap showing trimming of 15mers by aminopeptidases for each biological replicate. (B) Average label-free quantification (LFQ) signal of 15mers in the sample before and after incubation with the indicated enzyme. (C) Heatmap showing LFQ signal for 8–11mers produced after digestion. (D) Average signal of 8–11mers.

Indeed, comparing the peptide sequences generated by each enzyme, out of 1184 peptides identified, 142 were common between all three enzymes, 244 between ERAP1 and ERAP2 and 220 between ERAP1 and IRAP (Figure 2A). Furthermore, 169 peptides were unique for ERAP1, 234 for ERAP2, and 303 for IRAP. A similar situation was evident for 8–11mer peptides (Figure 2B). Strikingly, the mixture of ERAP1 with ERAP2 generated the fewest number of distinct sequences of 8–11mers (Figure 2C). This was in contrast to the finding that the ERAP1/ERAP2 mixture generated about the same average signal intensity as ERAP2 (Figure 1D). This was due to ERAP1/ERAP2 mixture generating fewer, in terms of sequence, distinct peptides, which were however relatively abundant. This finding is consistent with the proposed synergism of ERAP1 and ERAP2 (27) and suggests that the combination of these two enzymes is more efficient in trimming variable sequences and can thus overtrim peptides to lengths below 7 residues that are not detectable in our experimental setup and should not be able to stably bind onto MHCI (Figure 2C). As a result, incubation with ERAP1/ERAP2 mixture accumulates only peptides that are resistant to degradation by both enzymes.

Figure 2. Venn diagrams indicating overlap between peptide sequences produced by each enzyme. Numerals indicate number of peptides in each segment. Analysis was performed using BioVenn. (28) (A) Comparison of all peptides produced by each enzyme. (B) Comparison of 8–11mers produced by each enzyme. (C) Comparison of 8–11mers produced by ERAP1, ERAP2, as well as their mixture (ERAP1/2).

Since epitope length is a key parameter for binding onto MHCI (the majority of presented peptides are 9mers) we analyzed the distribution of lengths of peptides generated by each enzymatic reaction (Figure 3). ERAP1 was very efficient in trimming the 15mer substrates and generated primarily 9mer peptides, consistent with its proposed property as a “molecular ruler”. (26) Neither ERAP2 nor IRAP were able to accumulate 9mers preferably, but still generated significant numbers. The mixture of ERAP1 and ERAP2 showed a similar fractional distribution of peptide lengths (Figure 3B), but produced a much lower number of distinct peptide sequences (Figure 3A), presumably due to overtrimming to smaller lengths or even single amino acids.

Figure 3. Length distribution of peptides detected by LC-MS/MS after enzymatic digestion. (A) Number of peptides detected of each length. (B) Relative fraction of each length compared to the total number of peptides detected.

The main determinant in antigen presentation is stable binding of antigen-generated peptides onto MHCI. To evaluate the potential of the generated peptides to bind onto MHCI we used the HLAthena prediction server to rank the peptides for binding onto a collection of common HLA alleles (29) specifically HLA-A01:01, HLA-A02:01, HLA-A03:01, HLA-A24:02, HLA-A26:01, HLA-B07:02, HLA-B08:01, HLA-B27:05, HLA-B39:01, HLA-B40:01, HLA-B58:01, and HLA-B15:01 (Supplemental Table S2). For each peptide we selected the best scoring HLA-allele and plotted the calculated percentile rank of the predicted score for each enzymatic reaction (Figure 4A). The geometric mean of the predicted affinity was lowest for ERAP1 (indicating that the ERAP1 generated peptides had the highest average affinity for HLA), followed by IRAP and then ERAP2. Only a subset of generated peptides was predicted to bind with sufficient affinity onto at least one HLA: 23% for ERAP1, 22% for ERAP2, 6% for ERAP1/ERAP2 mixture, and 21% for IRAP (peptide sequences are listed in Table 1). These peptides spanned the whole sequence of the S1 spike glycoprotein, although each enzyme presented a unique signature onto this sequence (Figure 4B). Although currently we cannot know if any of these peptides can be antigenic, we compared them to known antigenic peptides for SARS-CoV-1 found in the immune epitope database (http://www.iedb.org/). (30) ERAP1 generated 5 antigenic peptides reported to be antigenic for SARS-CoV-1, ERAP2 generated 4, and IRAP 1. This finding indicates that some cross-reactivity between SARS-CoV-1 and SARS-CoV-2 may be mediated through the generation of appropriate epitopes by intracellular aminopeptidases.

Table 1. Peptides Generated by Each Aminopeptidase and Are Predicted to Bind onto at Least One of the Common HLA-Alleles^a

ERAP1			ERAP2			IRAP
peptide	score	allele	peptide	score	allele	peptide	score	allele
KFLPFQQF	0.01	A2402	EVFNATRF	0.00	A2601	EVFNATRF	0.00	A2601
VYYPDKVF	0.01	A2402	VLNDILSR	0.01	A0301	VLNDILSR	0.01	A0301
GYLQPRTF	0.05	A2402	GRLQSLQTY	0.06	B2705	HADQLTPTW	0.02	B5801
VRFPNITNL	0.05	B2705	YRFNGIGV	0.08	B2705	GYLQPRTF	0.05	A2402
GRLQSLQTY	0.06	B2705	NQKLIANQF	0.08	B1501	LADAGFIKQY	0.09	A0101
YRFNGIGV	0.08	B2705	DAGFIKQY	0.10	A2601	DAGFIKQY	0.10	A2601
NQKLIANQF	0.08	B1501	SLGAENSVAY	0.12	B1501	NYNYLYRL	0.18	A2402
NLREFVFK	0.09	A0301	VFKNIDGYFKI	0.14	A2402	STEKSNIIRGW	0.21	B5801
DAGFIKQY	0.10	A2601	STEKSNIIRGW	0.21	B5801	TLADAGFIK	0.25	A0301
DSFKEELDKY	0.10	A2601	ILSRLDKV	0.24	A0201	GVYYPDKVF	0.32	B1501
SVASQSIIAY	0.11	B1501	FKEELDKY	0.24	A0101	TLADAGFIKQY	0.39	A2601
TYVPAQEKNF	0.20	A2402	TRFASVYAWNR	0.25	B2705	ALNTLVKQL	0.48	A0201
KRFDNPVLPFN	0.21	B2705	QRNFYEPQI	0.35	B2705	KVTLADAGFIK	0.48	A0301
TLADAGFIK	0.25	A0301	IEDLLFNK	0.38	A0101	YADSFVIR	0.49	A0101
GVYYPDKVF	0.32	B1501	LPIGINITRF	0.39	B0702	PFGEVFNATRF	0.52	A2402
ATRFASVY	0.34	A0101	LGAENSVAY	0.41	B1501	GAGAALQI	0.57	B5801
GVYYPDKV	0.39	A0201	LPQGFSAL	0.47	B0702	APHGVVFL	0.61	B0702
SVLNDILSR	0.42	A0301	TRFQTLLA	0.49	B2705	NIDGYFKI	0.65	A0101
LPQGFSAL	0.47	B0702	YADSFVIR	0.49	A0101	ITGRLQSLQTY	0.68	A0101
KVTLADAGFIK	0.48	A0301	TPINLVRDL	0.50	B0702	TRGVYYPDKVF	0.78	B2705
YADSFVIR	0.49	A0101	APHGVVFL	0.61	B0702	QLTPTWRV	0.79	A0201
TPINLVRDL	0.50	B0702	DPLSETKCTL	0.66	B0702	YPDKVFRSSV	0.83	B0702
NYKLPDDF	0.56	A2402	ALGKLQDV	0.66	A0201	VLYENQKLI	0.84	A0201
NFYEPQII	0.57	A2402	ITGRLQSLQTY	0.68	A0101	NTLVKQLSSNF	0.89	A2601
NIDGYFKI	0.65	A0101	TRGVYYPDKVF	0.78	B2705	TTDNTFVS	0.96	A0101
DPLSETKCTL	0.66	B0702	QLTPTWRV	0.79	A0201	LPPAYTNSF	1.10	B0702
ALGKLQDV	0.66	A0201	GINITRFQTL	0.79	B0801	QRNFYEPQII	1.15	B2705
NESLIDLQEL	0.67	B4001	QPYRVVVLSF	0.82	B0702	QPRTFLLKY	1.16	A0101
FVIRGDEV	0.71	A0201	LYENQKLI	0.83	A2402	NVYADSFVIR	1.19	A0301
QLTPTWRV	0.79	A0201	YPDKVFRSSV	0.83	B0702	GEVFNATRF	1.21	B4001
QPYRVVVLSF	0.82	B0702	VLYENQKLI	0.84	A0201	EELDKYFKNH	1.24	A2601
LYENQKLI	0.83	A2402	GVLTESNKKF	0.87	A2601	YYPDKVFRSSV	1.24	A2402
YPDKVFRSSV	0.83	B0702	VRDLPQGFSAL	0.93	B2705	AEVQIDRLITG	1.29	B4001
KNIDGYFKI	0.84	A2402	DPLQPELDSF	1.09	B0702	EPLVDLPI	1.30	B0702
VLYENQKLI	0.84	A0201	LPPAYTNSF	1.10	B0702	TGRLQSLQTY	1.31	B1501
VYADSFVIR	0.85	A2402	DILSRLDKV	1.11	B0801	SVLHSTQDLFL	1.33	A0201
TVYDPLQP	0.88	A0301	NGIGVTQNVLY	1.12	A2601	YGVSPTKL	1.37	A2601
HFPREGVF	0.89	A2402	QRNFYEPQII	1.15	B2705	VTLADAGFIK	1.39	A0301
QDVVNQNAQAL	0.93	B4001	QPRTFLLKY	1.16	A0101	LPFQQFGRDIA	1.44	B0801
FEYVSQPF	0.96	B4001	EELDKYFKNH	1.24	A2601	QKFNGLTVLPP	1.45	B2705
SIIAYTMSL	1.04	B0801	LPFQQFGRDI	1.29	B0702	DGYFKIYSKH	1.55	A2601
KKFLPFQQFGR	1.11	B2705	EPLVDLPI	1.30	B0702	YENQKLIANQF	1.55	B1501
DILSRLDKV	1.11	B0801	TGRLQSLQTY	1.31	B1501	FPREGVFVSN	1.56	B0702
QPRTFLLKY	1.16	A0101	QKLIANQF	1.31	B1501	GNYNYLYRL	1.63	B2705
NVYADSFVIR	1.19	A0301	TTEILPVSM	1.32	A0101	NATRFASVY	1.82	A2601
GEVFNATRF	1.21	B4001	SPDVDLGDISG	1.33	B0702	YRLFRKSNLKP	1.83	B2705
EELDKYFKNH	1.24	A2601	DVVIGIVNN	1.42	A2601	HADQLTPTWRV	1.98	A0101
QKLIANQF	1.31	B1501	LPFQQFGRDIA	1.44	B0801	YVTQQLIRA	2.00	A0201
TTEILPVSM	1.32	A0101	QKFNGLTVLPP	1.45	B2705
SLLIVNNA	1.37	A0201	DIADTTDAVRD	1.52	A2601
YGVSPTKL	1.37	A2601	DGYFKIYSKH	1.55	A2601
VTLADAGFIK	1.39	A0301	GNYNYLYRL	1.63	B2705
VGYQPYRV	1.42	A0201	SRLDKVEAEV	1.64	B2705
DIADTTDAVRD	1.52	A2601	NATRFASVY	1.82	A2601
DGYFKIYSKH	1.55	A2601	YRLFRKSNLKP	1.83	B2705
RDLPQGFSAL	1.55	B4001	HADQLTPTWRV	1.98	A0101
LEPLVDLPI	1.64	B4001	YVTQQLIRA	2.00	A0201
SRLDKVEAEV	1.64	B2705
NATRFASVY	1.82	A2601
YVTQQLIRA	2.00	A0201

^{^a}

HLA-A01:01, HLA-A02:01, HLA-A03:01, HLA-A24:02, HLA-A26:01, HLA-B07:02, HLA-B08:01, HLA-B27:05, HLA-B39:01, HLA-B40:01, HLA-B58:01, and HLA-B15:01. Scores indicated are percentile ranks corresponding to the predicted affinity score for each allele (range 0–100, 0 is best, ranks below 2 are considered binders). In bold are peptides reported to be antigenic for SARS-CoV-1 found in the immune epitope database (http://www.iedb.org/).

Figure 4. (A) Scatter plot showing the predicted affinity of produced peptides for common HLA alleles as calculated by HLAthena. Color region encompasses peptides that are predicted to bind to at least one of the common HLA alleles used in the analysis. (B) Schematic representation of relative locations in the S1 protein sequence where the generated peptides are found. (C) Venn diagrams depicting overlap between peptides of S1 protein predicted to bind to common HLA alleles and peptides produced experimentally by ERAP1, ERAP2, IRAP, or ERAP1/ERAP2 mixture. Numerals indicate number of peptides in each separate segment.

In a recent publication, the authors proposed that different HLA alleles can have significant variability in their ability to present SARS-CoV-2 epitopes, with HLA-B46:01 having the capability to present the fewest and HLA-B15:03 being able to present the most. (31) We thus used the NetMHCpan 4.1 server to predict potential epitopes form the S1 spike glycoprotein sequence that could be presented by HLA-B46:01 and HLA-B15:03 (Supplemental Table S3) and compared them to the experimentally produced peptides. ERAP1 was found to produce 15 potential ligands for HLA-B15:03 but only 6 for HLA-B46:01, consistent with the proposed trend. In contrast, ERAP2 produced 8 potential ligands for both alleles and IRAP produced 6 for HLA-B15:03 and 4 for HLA-B46:01. Strikingly, the mixture of ERAP1 with ERAP2 produced 3 peptides that could bind onto HLA-B15:03, but no peptides predicted to bind onto HLA-B46:01 (Table 2). Thus, our findings appear to validate the hypothesis that HLA-B15:03 is likely to present more SARS-CoV-2 epitopes than HLA-B46:01, but only for ERAP1, which however is considered the dominant aminopeptidase activity in the cell for generating antigenic peptides.

Table 2. Peptides Generated by Each Aminopeptidase That Are Predicted to Bind to HLA-B15:03 and HLA-B46:01^a

ERAP1		ERAP2		IRAP		ERAP1/ERAP2
sequence	score	sequence	score	sequence	score	sequence	score
HLA-B15:03		HLA-B15:03		HLA-B15:03		HLA-B15:03
ATRFASVY	0.37	VGYLQPRTF	0.53	VGYLQPRTF	0.53	VGYLQPRTF	0.54
VGYLQPRTF	0.53	NQKLIANQF	0.58	LKYNENGTITD	1.40	NQKLIANQF	0.58
NQKLIANQF	0.58	GRLQSLQTY	0.65	GYLQPRTF	1.59	LKYNENGTITD	1.41
GRLQSLQTY	0.65	LGAENSVAY	0.84	GEVFNATRF	1.63
FEYVSQPF	0.83	QKLIANQF	0.91	GVYYPDKVF	1.71
QKLIANQF	0.91	LKYNENGTITD	1.40	AGAALQIPF	1.91
KAHFPREGVF	1.34	SLGAENSVAY	1.48
LKYNENGTITD	1.40	NGIGVTQNVLY	1.89
AQYTSALLA	1.42
KRFDNPVLPFN	1.58
GYLQPRTF	1.59
SVASQSIIAY	1.59
GEVFNATRF	1.63
GVYYPDKVF	1.71
VYYPDKVF	1.80
HLA-B46:01		HLA-B46:01		HLA-B46:01		HLA-B46:01
FEYVSQPF	0.62	LGAENSVAY	0.037	TLADAGFIKQY	0.08	–
SIIAYTMSL	0.64	LPIGINITRF	0.71	YVGYLQPRTF	1.66
ATRFASVY	0.65	SLGAENSVAY	0.72	GVYYPDKVF	1.75
SVASQSIIAY	0.91	GVLTESNKKF	1.34	TGRLQSLQTY	1.98
IANQFNSAI	1.25	YVGYLQPRTF	1.65
GVYYPDKVF	1.75	NGIGVTQNVLY	1.84
		FKEELDKY	1.90
		TGRLQSLQTY	1.98

^{^a}

Scores indicated are percentile ranks corresponding to the predicted score for each allele (range 0–100, 0 is best, ranks below 2 are considered binders).

Bioinformatic epitope predictions based on antigen sequence are often used as a tool to study the potential antigenicity of a particular epitope or pathogen. The power of those predictions is constantly evolving and primarily relies on predictions of binding affinity on HLA. To compare such predictions to our experimentally generated peptides, we used the full sequence of the S1 spike glycoprotein and the NetMHCpan 4.1 server (32) to predict potential epitopes that could be presented by the common HLA alleles indicated in the previous paragraph. The server predicted 929 potential epitopes with lengths of 8–12 residues (Supplemental Table S4). Of those potential epitopes, however, less than 7% were found to be produced experimentally by one of the enzymes tested and more specifically 58 by ERAP1, 52 by ERAP2, 4 for the ERAP1/2 mixture, and 53 by IRAP (Figure 4C). This finding suggests that intracellular antigen processing by aminopeptidases can significantly limit which peptides can be presented by MHCI. Indeed, it has been recently proposed that the main function of ERAP1 is to limit the peptide pool available for MHCI. (33) In this context, this experimental approach could be useful in optimizing bioinformatic predictions of potential MHCI epitopes.

Our findings provide new information on both the general biological functions of intracellular aminopeptidases that generate antigenic peptides as well as on specific processing of a key antigen from SARS-CoV-2. Specifically, our results highlight that each enzyme bears a unique trimming fingerprint to antigen processing. Although this has been suggested before on the basis of differences in specificity toward specific peptide substrates, (23,27,34,35) it has not been observed in the context of peptide ensembles. This is potentially important since competition of different peptides for the cavity in these enzymes could result in complex substrate interactions. At first glance, major differences in trimming fingerprints between each or the three enzymes, may appear to impose an unnecessary complication to antigenic peptide generation. It is conceivable, however, that this trimming variability is desirable for the immune system, since it can expand the breadth of possible antigenic peptides detected in different immunological settings and cell types. Our results also highlight a previously proposed property of ERAP1: the specialization in trimming large peptides and producing peptides that have the ideal length for MHCI binding—most of the ERAP1 products fall well within that range. (26) In contrast, both ERAP2 and IRAP appear to be less optimized for length selection. However, they are still able to produce many peptides that are potential cargo for MHCI, casting some doubt on whether the unique trimming properties of ERAP1 are absolutely necessary for this basic function. Furthermore, the combination of ERAP1 with ERAP2 appears to provide significant synergism in trimming, to the point of overtrimming peptides and limiting available sequences. Synergism between ERAP1 and ERAP2 has been demonstrated before in trimming isolated peptides and these two enzymes have been proposed to also form functional dimers. (23,24) According to our observations, their combination is especially efficient in trimming. While the biological repercussions of this are not fully clear yet, it is conceivable that the strong associations between ERAP2 activity and predisposition to autoimmunity may be related to this effect. (36)

Despite the current importance in understanding immune reactions in COVID-19, very little is known about the cellular adaptive immune responses against SARS-CoV-2. Cellular immune responses are emerging as a central player in clearing the infection and as targets for vaccine efforts. (37,38) Furthermore, HLA polymorphic variation has been suggested to underlie the large variability in virus clearance that has been observed among individuals. (39) Our analysis of the largest antigen of SARS-CoV-2, S1 spike glycoprotein, suggests that aminopeptidase trimming can be a significant filter that helps shape which peptides will be presented by HLA. Thus, we propose a short list of candidate peptides that could be prioritized in downstream antigenic analysis as well as in vaccine design and efficacy studies (Tables 1 and 2).

While the functions of ERAP1, ERAP2, and IRAP have been studied in both in vitro and in vivo contexts during the past decade, their relative functional differences have only been compared in processing specific substrates at a time. However, all these enzymes have a broad substrate specificity and can normally encounter thousands of different peptides in the ER or endosomal compartments. On the other hand, studies focusing on the presented immunopeptidome have revealed effects attributed to ERAP1 and ERAP2 trimming, but direct comparisons have been difficult because of the dominant effect of MHCI affinity on presentation. (40) Our approach stands in-between these two types of studies. It mimics the multiple-substrate situation that is likely normal in vivo but focuses on antigenic peptide precursor trimming. In this context, our approach may have broader application for the quick prediction of potential antigenic epitopes as an additional filter on bioinformatic predictions. Indeed, bioinformatic predictions result in many candidate peptides, very few of which will provoke an immune response; adding more filters can increase the usefulness of these rapid approaches. However, our approach also has limitations that need to be taken into account when interpreting results. Due to differences in ionization and detection by the LC-MS/MS some peptides may not be detected or may be under-represented compared to other sequences, making comparisons between different peptides less reliable. Furthermore, it is an in vitro approach that is limited to the peptide pool used and cannot take into account the dynamics of MHCI binding that can protect peptides from further aminopeptidase degradation (41) or peptide proofreading by chaperone components or the peptide loading complex. (42) Due to those limitations, we restricted our analysis to statistical comparisons and avoided drawing conclusions regarding particular peptide sequences. Recent studies have also suggested that ERAP1 may trim peptides while they are bound onto MHCI. (43) Further systematic analysis of this phenomenon however, suggested that it is either very rare or misinterpreted in the case of rapid-dissociating peptides. (44) We therefore did not attempt to characterize trimming of prebound peptides in this study.

In summary, we analyzed the trimming of a peptide ensemble spanning the sequence of the S1 spike glycoprotein of SARS-CoV-2, the pathogen responsible for the recent COVID-19 pandemic. Our analysis provided novel insight into the function of antigen trimming enzymes and suggested that aminopeptidase trimming may be a significant filter in determining which peptides can be presented by MHCI. Furthermore, we have identified a limited set of peptides that were experimentally produced by elongated precursors which could be prioritized in future studies aiming to investigate the antigenicity of SARS-CoV-2 infected cells and assist in the design of highly effective vaccines that aim to produce adaptive cytotoxic responses. We propose that our experimental approach may also be useful as a general tool for enhancing bioinformatic predictions of antigenic epitopes.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00457.

Table S1: List of generated peptides after digestion by each enzyme (XLSX)
Table S2: List of generated 8–11mers from each enzyme with best predicted binding score based on the HLAthena server (XLSX)
Table S3: Predicted binding score of peptides from the S1 spike glycoprotein of SARS-CoV-2 for HLA-B15:03 and HLA-B46:01, based on the HLAthena prediction server; in red, the peptides that are predicted to be binders (XLSX)
Table S4: List of potential epitopes from the sequence of the S1 spike glycoprotein of SARS-CoV-2 predicted using the NetMHCpan 4.1 server (XLSX)

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Author Information

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Corresponding Author
- Efstratios Stratikos - National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece; http://orcid.org/0000-0002-3566-2309; Email: [email protected] [email protected]
Authors
- George Stamatakis - Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
- Martina Samiotaki - Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
- Anastasia Mpakali - National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece; http://orcid.org/0000-0003-0869-9680
- George Panayotou - Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
Funding
This research was supported by NCSR Demokritos and by “InfrafrontierGR/Phenotypos” (MIS 5002135) and by “The Greek Research Infrastructure for Personalised Medicine (pMED-GR)” (MIS 5002802), both funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and cofinanced by Greece and the EU (ERDF).
Notes
The authors declare no competing financial interest.
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (45) partner repository with the data set identifier PXD019901 (http://www.ebi.ac.uk/pride/archive/).

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Rock, K. L.; Goldberg, A. L. Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu. Rev. Immunol. 1999, 17, 739– 79, DOI: 10.1146/annurev.immunol.17.1.739
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Degradation of cell proteins and the generation of MHC class I-presented peptides
Rock, Kenneth L.; Goldberg, Alfred L.
Annual Review of Immunology (1999), 17 (), 739-779CODEN: ARIMDU; ISSN:0732-0582. (Annual Reviews Inc.)
A review with 211 refs. Major histocompatibility complex (MHC) class I mols. display on the cell surface 8- to 10-residue peptides derived from the spectrum of proteins expressed in the cells. By screening for non-self MHC-bound peptides, the immune system identifies and then can eliminate cells that are producing viral or mutant proteins. These antigenic peptides are generated as side products in the continual turnover of intracellular proteins, which occurs primarily by the ubiquitin-proteasome pathway. Most of the oligopeptides generated by the proteasome are further degraded by distinct endopeptidases and aminopeptidases into amino acids, which are used for new protein synthesis or energy prodn. However, a fraction of these peptides escape complete destruction and after transport into the endoplasmic reticulum are bound by MHC class I mols. and delivered to the cell surface. Herein we review recent discoveries about the proteolytic systems that degrade cell proteins, how the ubiquitin-proteasome pathway generates the peptides presented on MHC-class I mols., and how this process is stimulated by immune modifiers to enhance antigen presentation.
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Weimershaus, M.; Evnouchidou, I.; Saveanu, L.; van Endert, P. Peptidases trimming MHC class I ligands. Curr. Opin. Immunol. 2013, 25 (1), 90– 6, DOI: 10.1016/j.coi.2012.10.001
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Peptidases trimming MHC class I ligands
Weimershaus, Mirjana; Evnouchidou, Irini; Saveanu, Loredana; van Endert, Peter
Current Opinion in Immunology (2013), 25 (1), 90-96CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
A review. Peptides presented by MHC class I mols. are typically produced through antigen degrdn. by the proteasome followed by trimming by exopeptidases. According to recent results, these include both aminopeptidases and carboxypeptidases in the cytosol and the endoplasmic reticulum. While cytosolic peptidases have a net neutral or destructive effect on MHC ligands, endoplasmic reticulum aminopeptidases are required for efficient class I loading and have a strong effect on the repertoire of peptide/MHC complexes. Cells lacking these enzymes can be eliminated both by NK cells and by CD8+ T cells recognizing complexes formed between an MHC class Ib mol. and a conserved peptide. Cross-presented peptides derived from internalized antigens can be processed by insulin-regulated aminopeptidase, the only endosomal trimming peptidase.
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Hammer, G. E.; Kanaseki, T.; Shastri, N. The final touches make perfect the peptide-MHC class I repertoire. Immunity 2007, 26 (4), 397– 406, DOI: 10.1016/j.immuni.2007.04.003
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The final touches make perfect the peptide-MHC class I repertoire
Hammer, Gianna Elena; Kanaseki, Takayuki; Shastri, Nilabh
Immunity (2007), 26 (4), 397-406CODEN: IUNIEH; ISSN:1074-7613. (Cell Press)
A review. Major histocompatibility complex (MHC) class I mols. present short, perfectly cleaved peptides on the cell surface for immune surveillance by CD8+ T cells. The pathway for generating these peptides begins in the cytoplasm, and the peptide-MHC I (pMHC I) repertoire is finalized in the endoplasmic reticulum. Recent studies show that the peptides for MHC I are customized by the ER aminopeptidase assocd. with antigen processing and by dynamic interactions within the MHC peptide-loading complex. Failure to customize the pMHC I repertoire has profound immunol. consequences.
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Giastas, P.; Mpakali, A.; Papakyriakou, A.; Lelis, A.; Kokkala, P.; Neu, M.; Rowland, P.; Liddle, J.; Georgiadis, D.; Stratikos, E. Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (52), 26709– 26716, DOI: 10.1073/pnas.1912070116
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Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1
Giastas, Petros; Mpakali, Anastasia; Papakyriakou, Athanasios; Lelis, Aggelos; Kokkala, Paraskevi; Neu, Margarete; Rowland, Paul; Liddle, John; Georgiadis, Dimitris; Stratikos, Efstratios
Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (52), 26709-26716CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that optimizes the peptide cargo of major histocompatibility class I (MHC-I) mols. and regulates adaptive immunity. It has unusual substrate selectivity for length and sequence, resulting in poorly understood effects on the cellular immunopeptidome. To understand substrate selection by ERAP1, we solved 2 crystal structures of the enzyme with bound transition-state pseudopeptide analogs at 1.68 Å and 1.72 Å. Both peptides have their N terminus bound at the active site and extend away along a large internal cavity, interacting with shallow pockets that can influence selectivity. The longer peptide is disordered through the central region of the cavity and has its C terminus bound in an allosteric pocket of domain IV that features a carboxypeptidase-like structural motif. These structures, along with enzymic and computational analyses, explain how ERAP1 can select peptides based on length while retaining the broad sequence-specificity necessary for its biol. function.
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Stratikos, E.; Stern, L. J. Antigenic peptide trimming by ER aminopeptidases--insights from structural studies. Mol. Immunol. 2013, 55 (3–4), 212– 9, DOI: 10.1016/j.molimm.2013.03.002
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Antigenic peptide trimming by ER aminopeptidases - Insights from structural studies
Stratikos, Efstratios; Stern, Lawrence J.
Molecular Immunology (2013), 55 (3-4), 212-219CODEN: MOIMD5; ISSN:0161-5890. (Elsevier)
A review. Generation and destruction of antigenic peptides by ER resident aminopeptidases ERAP1 and ERAP2 have been shown in the last few years to be important for the correct functioning and regulation of the adaptive immune response. These two highly homologous aminopeptidases appear to have evolved complex mechanisms well suited for their biol. role in antigen presentation. Furthermore, polymorphic variability in these enzymes appears to affect their function and predispose individuals to disease. This review discusses our current understanding of the mol. mechanisms behind ERAP1/2 function as suggested by several recently detd. crystallog. structures of these enzymes.
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Evnouchidou, I.; Kamal, R. P.; Seregin, S. S.; Goto, Y.; Tsujimoto, M.; Hattori, A.; Voulgari, P. V.; Drosos, A. A.; Amalfitano, A.; York, I. A.; Stratikos, E. Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J. Immunol. 2011, 186 (4), 1909– 13, DOI: 10.4049/jimmunol.1003337
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Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme
Evnouchidou, Irini; Kamal, Ram P.; Seregin, Sergey S.; Goto, Yoshikuni; Tsujimoto, Masafumi; Hattori, Akira; Voulgari, Paraskevi V.; Drosos, Alexandros A.; Amalfitano, Andrea; York, Ian A.; Stratikos, Efstratios
Journal of Immunology (2011), 186 (4), 1909-1913CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, the authors analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis-Menten anal. revealed that the presence of SNPs affects the Michaelis const. and turnover no. of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from std. Michaelis-Menten behavior, demonstrating substrate-inhibition kinetics; to the authors' knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation anal. was consistent with changes in the substrate inhibition const. Ki, further supporting that ERAP1 allelic compn. may affect Ag processing in vivo. The authors propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity.
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Stamogiannos, A.; Maben, Z.; Papakyriakou, A.; Mpakali, A.; Kokkala, P.; Georgiadis, D.; Stern, L. J.; Stratikos, E. Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1. Biochemistry 2017, 56 (10), 1546– 1558, DOI: 10.1021/acs.biochem.6b01170
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Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1
Stamogiannos, Athanasios; Maben, Zachary; Papakyriakou, Athanasios; Mpakali, Anastasia; Kokkala, Paraskevi; Georgiadis, Dimitris; Stern, Lawrence J.; Stratikos, Efstratios
Biochemistry (2017), 56 (10), 1546-1558CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular enzyme important for the generation of antigenic epitopes and class I MHC-restricted adaptive immune responses. ERAP1 processes a vast variety of different peptides but still shows length and sequence selectivity although the mechanism behind these properties is poorly understood. X-ray crystallog. anal. has revealed that ERAP1 can assume at least two distinct conformations in which the C-terminal domain IV is either proximal or distal to the active site domain II. To help understand the role of this conformational change in the catalytic mechanism of ERAP1 we used site-directed mutagenesis to perturb key salt-bridges between domains II and IV. Enzymic anal. revealed that these mutations, although located away from the catalytic site, greatly reduce catalytic efficiency and shift allosteric kinetic behavior. The variants were more efficiently activated by small peptides, and bound a competitive inhibitor with weaker affinity and faster dissocn. kinetics. Mol. dynamics anal. suggested that the mutations affect the conformational distribution of ERAP1, reducing the population of closed states. Small-angle x-ray scattering indicated that both wild-type and the ERAP1 variants are predominantly in an open conformational state in soln. Overall, our findings suggest that electrostatic interactions between domains II and IV in ERAP1 are crucial for driving a conformational change that regulates the structural integrity of the catalytic site. The extent of domain opening in ERAP1 probably underlies its specialization for antigenic peptide precursors and should be taken into account for inhibitor development efforts.
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Mpakali, A.; Giastas, P.; Mathioudakis, N.; Mavridis, I. M.; Saridakis, E.; Stratikos, E. Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2. J. Biol. Chem. 2015, 290 (43), 26021– 32, DOI: 10.1074/jbc.M115.685909
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Structural basis for antigenic peptide recognition and processing by endoplasmic reticulum (ER) aminopeptidase 2
Mpakali, Anastasia; Giastas, Petros; Mathioudakis, Nikolas; Mavridis, Irene M.; Saridakis, Emmanuel; Stratikos, Efstratios
Journal of Biological Chemistry (2015), 290 (43), 26021-26032CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Endoplasmic reticulum (ER) aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I mols. and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we detd. crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analog and a peptidic product to 2.5 and 2.7 Å, resp., and compared them to the apo-form structure detd. to 3.0 Å. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analog extends away from the catalytic center toward the distal end of the internal cavity, making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product, although decreasing electron d. toward its C terminus indicated progressive disorder. Enzymic anal. confirmed that visualized interactions can either pos. or neg. impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to det. trimming rates, thus combining substrate permissiveness with sequence bias.
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Mpakali, A.; Saridakis, E.; Harlos, K.; Zhao, Y.; Papakyriakou, A.; Kokkala, P.; Georgiadis, D.; Stratikos, E. Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing. J. Immunol. 2015, 195 (6), 2842– 2851, DOI: 10.4049/jimmunol.1501103
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Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing
Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl; Zhao, Yuguang; Papakyriakou, Athanasios; Kokkala, Paraskevi; Georgiadis, Dimitris; Stratikos, Efstratios
Journal of Immunology (2015), 195 (6), 2842-2851CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast no. of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that preps. antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes.
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Saveanu, L.; Carroll, O.; Lindo, V.; Del Val, M.; Lopez, D.; Lepelletier, Y.; Greer, F.; Schomburg, L.; Fruci, D.; Niedermann, G.; van Endert, P. M. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat. Immunol. 2005, 6 (7), 689– 97, DOI: 10.1038/ni1208
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Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum
Saveanu, Loredana; Carroll, Oliver; Lindo, Vivian; Del Val, Margarita; Lopez, Daniel; Lepelletier, Yves; Greer, Fiona; Schomburg, Lutz; Fruci, Doriana; Niedermann, Gabriele; van Endert, Peter M.
Nature Immunology (2005), 6 (7), 689-697CODEN: NIAMCZ; ISSN:1529-2908. (Nature Publishing Group)
The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases. The authors show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. This trimming of a longer peptide required the concerted action of both ERAP1 and ERAP2, both for in vitro digestion and in vivo for cellular antigen presentation. ERAP1 and ERAP2 localized together in vivo and assocd. phys. in complexes that were most likely heterodimeric. Thus, the human endoplasmic reticulum is equipped with a pair of trimming aminopeptidases that have complementary functions in HLA class I peptide presentation.
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Evnouchidou, I.; Weimershaus, M.; Saveanu, L.; van Endert, P. ERAP1-ERAP2 dimerization increases peptide-trimming efficiency. J. Immunol. 2014, 193 (2), 901– 8, DOI: 10.4049/jimmunol.1302855
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ERAP1-ERAP2 Dimerization Increases Peptide-Trimming Efficiency
Evnouchidou, Irini; Weimershaus, Mirjana; Saveanu, Loredana; van Endert, Peter
Journal of Immunology (2014), 193 (2), 901-908CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
The endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 play a crit. role in the prodn. of final epitopes presented by MHC class I mols. Formation of heterodimers by ERAP1 and ERAP2 has been proposed to facilitate trimming of epitope precursor peptides, but the effects of dimerization on ERAP function remain unknown. In this study, we produced stabilized ERAP1-ERAP2 heterodimers and found that they produced several mature epitopes more efficiently than a mix of the two enzymes unable to dimerize. Phys. interaction with ERAP2 changes basic enzymic parameters of ERAP1 and improves its substrate-binding affinity. Thus, by bringing the two enzymes in proximity and by producing allosteric effects on ERAP1, dimerization of ERAP1/2 creates complexes with superior peptide-trimming efficacy. Such complexes are likely to enhance Ag presentation by cells displaying coordinated expression of the two enzymes.
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Zervoudi, E.; Papakyriakou, A.; Georgiadou, D.; Evnouchidou, I.; Gajda, A.; Poreba, M.; Salvesen, G. S.; Drag, M.; Hattori, A.; Swevers, L.; Vourloumis, D.; Stratikos, E. Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides. Biochem. J. 2011, 435 (2), 411– 20, DOI: 10.1042/BJ20102049
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Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides
Zervoudi, Efthalia; Papakyriakou, Athanasios; Georgiadou, Dimitra; Evnouchidou, Irini; Gajda, Anna; Poreba, Marcin; Salvesen, Guy S.; Drag, Marcin; Hattori, Akira; Swevers, Luc; Vourloumis, Dionisios; Stratikos, Efstratios
Biochemical Journal (2011), 435 (2), 411-420CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play crit. roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I mols. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorogenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Mol. modeling of the three S1 pockets reveals substrate-enzyme interactions that are crit. determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biol. function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes.
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Chang, S. C.; Momburg, F.; Bhutani, N.; Goldberg, A. L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (47), 17107– 12, DOI: 10.1073/pnas.0500721102
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The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism
Chang, Shih-Chung; Momburg, Frank; Bhutani, Nidhi; Goldberg, Alfred L.
Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (47), 17107-17112CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-γ-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I mols. The authors recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8-9 residues, the length required for binding to MHC class I mols. Here, the authors show another remarkable property of ERAP1: that it strongly prefers substrates 9-16 residues long, the lengths of peptides transported efficiently into the ER by the transporter assocd. with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N- and C-terminal sequences. No other aminopeptidase, including the closely related ER-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I mols., prefers peptides with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to peptides that can serve as MHC class I epitopes. Its "mol. ruler" mechanism involves binding the hydrophobic C terminus of the substrate 9-16 residues away from the active site.
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Lorente, E.; Barriga, A.; Johnstone, C.; Mir, C.; Jimenez, M.; Lopez, D. Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases. PLoS One 2013, 8 (11), e79596 DOI: 10.1371/journal.pone.0079596
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Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases
Lorente, Elena; Barriga, Alejandro; Johnstone, Carolina; Mir, Carmen; Jimenez, Mercedes; Lopez, Daniel
PLoS One (2013), 8 (11), e79596CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
In the classical human leukocyte antigen (HLA) class I antigen processing and presentation pathway, the antigenic peptides are generated from viral proteins by multiple proteolytic cleavages of the proteasome (and in some cases other cytosolic proteases) and transported to the endoplasmic reticulum (ER) lumen where they are exposed to aminopeptidase activity. In human cells, two different ER-resident enzymes, ERAP1 and ERAP2, can trim the N-terminally extended residues of peptide precursors. In this study, the possible cooperative effect of generating five naturally processed HLA-B27 ligands by both proteases was analyzed. We identified differences in the products obtained with increased detection of natural HLA-B27 ligands by comparing double vs. single enzyme digestions by mass spectrometry anal. These in vitro data suggest that each enzyme can use the degrdn. products of the other as a substrate for new N-terminal trimming, indicating concerted aminoproteolytic activity of ERAP1 and ERAP2.
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Hulsen, T.; de Vlieg, J.; Alkema, W. BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 2008, 9, 488, DOI: 10.1186/1471-2164-9-488
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BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams
Hulsen Tim; de Vlieg Jacob; Alkema Wynand
BMC genomics (2008), 9 (), 488 ISSN:.
BACKGROUND: In many genomics projects, numerous lists containing biological identifiers are produced. Often it is useful to see the overlap between different lists, enabling researchers to quickly observe similarities and differences between the data sets they are analyzing. One of the most popular methods to visualize the overlap and differences between data sets is the Venn diagram: a diagram consisting of two or more circles in which each circle corresponds to a data set, and the overlap between the circles corresponds to the overlap between the data sets. Venn diagrams are especially useful when they are 'area-proportional' i.e. the sizes of the circles and the overlaps correspond to the sizes of the data sets. Currently there are no programs available that can create area-proportional Venn diagrams connected to a wide range of biological databases. RESULTS: We designed a web application named BioVenn to summarize the overlap between two or three lists of identifiers, using area-proportional Venn diagrams. The user only needs to input these lists of identifiers in the textboxes and push the submit button. Parameters like colors and text size can be adjusted easily through the web interface. The position of the text can be adjusted by 'drag-and-drop' principle. The output Venn diagram can be shown as an SVG or PNG image embedded in the web application, or as a standalone SVG or PNG image. The latter option is useful for batch queries. Besides the Venn diagram, BioVenn outputs lists of identifiers for each of the resulting subsets. If an identifier is recognized as belonging to one of the supported biological databases, the output is linked to that database. Finally, BioVenn can map Affymetrix and EntrezGene identifiers to Ensembl genes. CONCLUSION: BioVenn is an easy-to-use web application to generate area-proportional Venn diagrams from lists of biological identifiers. It supports a wide range of identifiers from the most used biological databases currently available. Its implementation on the World Wide Web makes it available for use on any computer with internet connection, independent of operating system and without the need to install programs locally. BioVenn is freely accessible at http://www.cmbi.ru.nl/cdd/biovenn/.
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Sarkizova, S.; Klaeger, S.; Le, P. M.; Li, L. W.; Oliveira, G.; Keshishian, H.; Hartigan, C. R.; Zhang, W.; Braun, D. A.; Ligon, K. L.; Bachireddy, P.; Zervantonakis, I. K.; Rosenbluth, J. M.; Ouspenskaia, T.; Law, T.; Justesen, S.; Stevens, J.; Lane, W. J.; Eisenhaure, T.; Lan Zhang, G.; Clauser, K. R.; Hacohen, N.; Carr, S. A.; Wu, C. J.; Keskin, D. B. A large peptidome dataset improves HLA class I epitope prediction across most of the human population. Nat. Biotechnol. 2020, 38 (2), 199– 209, DOI: 10.1038/s41587-019-0322-9
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A large peptidome dataset improves HLA class I epitope prediction across most of the human population
Sarkizova, Siranush; Klaeger, Susan; Le, Phuong M.; Li, Letitia W.; Oliveira, Giacomo; Keshishian, Hasmik; Hartigan, Christina R.; Zhang, Wandi; Braun, David A.; Ligon, Keith L.; Bachireddy, Pavan; Zervantonakis, Ioannis K.; Rosenbluth, Jennifer M.; Ouspenskaia, Tamara; Law, Travis; Justesen, Sune; Stevens, Jonathan; Lane, William J.; Eisenhaure, Thomas; Lan Zhang, Guang; Clauser, Karl R.; Hacohen, Nir; Carr, Steven A.; Wu, Catherine J.; Keskin, Derin B.
Nature Biotechnology (2020), 38 (2), 199-209CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-assocd. peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs assocd. with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-assocd. ligands with 1.5-fold improvement in pos. predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were obsd. exptl. in 11 patient-derived tumor cell lines.
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Vita, R.; Zarebski, L.; Greenbaum, J. A.; Emami, H.; Hoof, I.; Salimi, N.; Damle, R.; Sette, A.; Peters, B. The immune epitope database 2.0. Nucleic Acids Res. 2010, 38 (Database issue), D854– D862, DOI: 10.1093/nar/gkp1004
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The Immune Epitope Database 2.0
Vita, Randi; Zarebski, Laura; Greenbaum, Jason A.; Emami, Hussein; Hoof, Ilka; Salimi, Nima; Damle, Rohini; Sette, Alessandro; Peters, Bjoern
Nucleic Acids Research (2010), 38 (Database Iss), D854-D862CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
The Immune Epitope Database (IEDB, www.iedb.org) provides a catalog of exptl. characterized B and T cell epitopes, as well as data on Major Histocompatibility Complex (MHC) binding and MHC ligand elution expts. The database represents the mol. structures recognized by adaptive immune receptors and the exptl. contexts in which these mols. were detd. to be immune epitopes. Epitopes recognized in humans, nonhuman primates, rodents, pigs, cats and all other tested species are included. Both pos. and neg. exptl. results are captured. Over the course of 4 years, the data from 180 978 expts. were curated manually from the literature, which covers ∼99% of all publicly available information on peptide epitopes mapped in infectious agents (excluding HIV) and 93% of those mapped in allergens. In addn., data that would otherwise be unavailable to the public from 129 186 expts. were submitted directly by investigators. The curation of epitopes related to autoimmunity is expected to be completed by the end of 2010. The database can be queried by epitope structure, source organism, MHC restriction, assay type or host organism, among other criteria. The database structure, as well as its querying, browsing and reporting interfaces, was completely redesigned for the IEDB 2.0 release, which became publicly available in early 2009.
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Nguyen, A.; David, J. K.; Maden, S. K.; Wood, M. A.; Weeder, B. R.; Nellore, A.; Thompson, R. F. Human leukocyte antigen susceptibility map for SARS-CoV-2. J. Virol. 2020, DOI: 10.1128/JVI.00510-20
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Reynisson, B.; Alvarez, B.; Paul, S.; Peters, B.; Nielsen, M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 2020, 48 (W1), W449– W454, DOI: 10.1093/nar/gkaa379
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NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data
Reynisson, Birkir; Alvarez, Bruno; Paul, Sinu; Peters, Bjoern; Nielsen, Morten
Nucleic Acids Research (2020), 48 (W1), W449-W454CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
Major histocompatibility complex (MHC) mols. are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the development of T-cell immune responses. MHC mols. come in two main variants: MHC Class I (MHC-I) and MHC Class II (MHC-II). MHC-I predominantly present peptides derived from intracellular proteins, whereas MHC-II predominantly presents peptides from extracellular proteins. In both cases, the binding between MHC and antigenic peptides is the most selective step in the antigen presentation pathway. Therefore, the prediction of peptide binding to MHC is a powerful utility to predict the possible specificity of a T-cell immune response. Commonly MHC binding prediction tools are trained on binding affinity or mass spectrometry-eluted ligands. Recent studies have however demonstrated how the integration of both data types can boost predictive performances. Inspired by this, we here present NetMHCpan-4.1 and NetMHCIIpan-4.0, two web servers created to predict binding between peptides and MHC-I and MHC-II, resp. Both methods exploit tailored machine learning strategies to integrate different training data types, resulting in state-of-the-art performance and outperforming their competitors.
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Komov, L.; Kadosh, D. M.; Barnea, E.; Milner, E.; Hendler, A.; Admon, A. Cell Surface MHC Class I Expression Is Limited by the Availability of Peptide-Receptive “Empty” Molecules Rather than by the Supply of Peptide Ligands. Proteomics 2018, 18 (12), e1700248 DOI: 10.1002/pmic.201700248
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Hearn, A.; York, I. A.; Rock, K. L. The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum. J. Immunol. 2009, 183 (9), 5526– 36, DOI: 10.4049/jimmunol.0803663
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The Specificity of Trimming of MHC Class I-Presented Peptides in the Endoplasmic Reticulum
Hearn, Arron; York, Ian A.; Rock, Kenneth L.
Journal of Immunology (2009), 183 (9), 5526-5536CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
Aminopeptidases in the endoplasmic reticulum (ER) can cleave antigenic peptides and in so doing either create or destroy MHC class I-presented epitopes. However, the specificity of this trimming process overall and of the major ER aminopeptidase ERAP1 in particular is not well understood. This issue is important because peptide trimming influences the magnitude and specificity of CD8 T cell responses. By systematically varying the N-terminal flanking sequences of peptides in a cell-free biochem. system and in intact cells, the authors elucidated the specificity of ERAP1 and of ER trimming overall. ERAP1 can cleave after many amino acids on the N terminus of epitope precursors but does so at markedly different rates. The specificity seen with purified ERAP1 is similar to that obsd. for trimming and presentation of epitopes in the ER of intact cells. The authors define N-terminal sequences that are favorable or unfavorable for Ag presentation in ways that are independent from the epitopes core sequence. When databases of known presented peptides were analyzed, the residues that were preferred for the trimming of model peptide precursors were overrepresented in N-terminal flanking sequences of epitopes generally. These data define key determinants in the specificity of Ag processing.
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Georgiadou, D.; Hearn, A.; Evnouchidou, I.; Chroni, A.; Leondiadis, L.; York, I. A.; Rock, K. L.; Stratikos, E. Placental leucine aminopeptidase efficiently generates mature antigenic peptides in vitro but in patterns distinct from endoplasmic reticulum aminopeptidase 1. J. Immunol. 2010, 185 (3), 1584– 92, DOI: 10.4049/jimmunol.0902502
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Placental Leucine Aminopeptidase Efficiently Generates Mature Antigenic Peptides In Vitro but in Patterns Distinct from Endoplasmic Reticulum Aminopeptidase 1
Georgiadou, Dimitra; Hearn, Arron; Evnouchidou, Irini; Chroni, Angeliki; Leondiadis, Leondios; York, Ian A.; Rock, Kenneth L.; Stratikos, Efstratios
Journal of Immunology (2010), 185 (3), 1584-1592CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
All three members of the oxytocinase subfamily of M1 aminopeptidases, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and placental leucine aminopeptidase (PLAP), also known as insulin-regulated aminopeptidase, have been implicated in the generation of MHC class I-presented peptides. ERAP1 and 2 trim peptides in the endoplasmic reticulum for direct presentation, whereas PLAP has been recently implicated in cross-presentation. The best characterized member of the family, ERAP1, has unique enzymic properties that fit well with its role in Ag processing. ERAP1 can trim a large variety of long peptide sequences and efficiently accumulate mature antigenic epitopes of 8-9 aa long. In this study, the authors evaluate the ability of PLAP to process antigenic peptide precursors in vitro and compare it with ERAP1. The authors find that, similar to ERAP1, PLAP can trim a variety of long peptide sequences efficiently and, in most cases, accumulates appreciable amts. of correct length mature antigenic epitope. Again, similar to ERAP1, PLAP continued trimming some of the epitopes tested and accumulated smaller products effectively destroying the epitope. However, the intermediate accumulation properties of ERAP1 and PLAP are distinct and epitope dependent, suggesting that these two enzymes may impose different selective pressures on epitope generation. Overall, although PLAP has the necessary enzymic properties to participate in generating or destroying MHC class I-presented peptides, its trimming behavior is distinct from that of ERAP1, something that supports a sep. role for these two enzymes in Ag processing.
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Kuiper, J. J.; Van Setten, J.; Ripke, S.; Van, T. S. R.; Mulder, F.; Missotten, T.; Baarsma, G. S.; Francioli, L. C.; Pulit, S. L.; De Kovel, C. G.; Ten Dam-Van Loon, N.; Den Hollander, A. I.; Huis in het Veld, P.; Hoyng, C. B.; Cordero-Coma, M.; Martin, J.; Llorenc, V.; Arya, B.; Thomas, D.; Bakker, S. C.; Ophoff, R. A.; Rothova, A.; De Bakker, P. I.; Mutis, T.; Koeleman, B. P. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Hum. Mol. Genet. 2014, 23 (22), 6081– 6087, DOI: 10.1093/hmg/ddu307
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A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
Kuiper, Jonas J. W.; Van Setten, Jessica; Ripke, Stephan; Slot, Ruben Van 'T.; Mulder, Flip; Missotten, Tom; Baarsma, G. Seerp; Francioli, Laurent C.; Pulit, Sara L.; Kovel, Carolien G. F. De; Loon, Ninette Ten Dam-Van; Hollander, Anneke I. Den; Veld, Paulien Huis in het; Hoyng, Carel B.; Cordero-Coma, Miguel; Martin, Javier; Llorenc, Victor; Arya, Bharti; Thomas, Dhanes; Bakker, Steven C.; Ophoff, Roel A.; Rothova, Aniki; Bakker, Paul I. W. De; Mutis, Tuna; Koeleman, Bobby P. C.
Human Molecular Genetics (2014), 23 (22), 6081-6087CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA assocn. for a human disease. We have conducted a genome-wide assocn. study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC assocn. through high-resoln. imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC assocn. (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10-74). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093;OR = 2.3,95%CI 1.7-3.1, for the T allele, P = 8.6 × 10-8) and at 14q32.31 in the TECPR2 gene (rs150571175;OR = 6.1,95%CI 3.2-11.7, for the A allele, P = 3.2 × 10-8). The assocn. near ERAP2 was confirmed in an independent British case-control samples (combined meta-anal. P = 1.7 × 10-9). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly assocd. with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.
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Grifoni, A.; Weiskopf, D.; Ramirez, S. I.; Mateus, J.; Dan, J. M.; Moderbacher, C. R.; Rawlings, S. A.; Sutherland, A.; Premkumar, L.; Jadi, R. S.; Marrama, D.; de Silva, A. M.; Frazier, A.; Carlin, A. F.; Greenbaum, J. A.; Peters, B.; Krammer, F.; Smith, D. M.; Crotty, S.; Sette, A. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020, 181 (7), 1489– 1501, DOI: 10.1016/j.cell.2020.05.015
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Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals
Grifoni, Alba; Weiskopf, Daniela; Ramirez, Sydney I.; Mateus, Jose; Dan, Jennifer M.; Moderbacher, Carolyn Rydyznski; Rawlings, Stephen A.; Sutherland, Aaron; Premkumar, Lakshmanane; Jadi, Ramesh S.; Marrama, Daniel; de Silva, Aravinda M.; Frazier, April; Carlin, Aaron F.; Greenbaum, Jason A.; Peters, Bjoern; Krammer, Florian; Smith, Davey M.; Crotty, Shane; Sette, Alessandro
Cell (Cambridge, MA, United States) (2020), 181 (7), 1489-1501.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, resp. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with addnl. responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
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Wilk, A. J.; Rustagi, A.; Zhao, N. Q.; Roque, J.; Martinez-Colon, G. J.; McKechnie, J. L.; Ivison, G. T.; Ranganath, T.; Vergara, R.; Hollis, T.; Simpson, L. J.; Grant, P.; Subramanian, A.; Rogers, A. J.; Blish, C. A. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 2020, 26 (7), 1070– 1076, DOI: 10.1038/s41591-020-0944-y
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A single-cell atlas of the peripheral immune response in patients with severe COVID-19
Wilk, Aaron J.; Rustagi, Arjun; Zhao, Nancy Q.; Roque, Jonasel; Martinez-Colon, Giovanny J.; McKechnie, Julia L.; Ivison, Geoffrey T.; Ranganath, Thanmayi; Vergara, Rosemary; Hollis, Taylor; Simpson, Laura J.; Grant, Philip; Subramanian, Aruna; Rogers, Angela J.; Blish, Catherine A.
Nature Medicine (New York, NY, United States) (2020), 26 (7), 1070-1076CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
Abstr.: There is an urgent need to better understand the pathophysiol. of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approx. 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been assocd. with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines that may be produced by a subset of inflammatory monocytes , lymphopenia and T cell exhaustion . To elucidate pathways in peripheral immune cells that might lead to immunopathol. or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mech. ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amts. of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.
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Wang, W.; Zhang, W.; Zhang, J.; He, J.; Zhu, F. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19). HLA 2020, 96 (2), 194– 196, DOI: 10.1111/tan.13941
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Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19)
Wang, Wei; Zhang, Wei; Zhang, Jingjing; He, Ji; Zhu, Faming
HLA (2020), 96 (2), 194-196CODEN: HLAAAK; ISSN:2059-2310. (John Wiley & Sons Ltd.)
COVID-19 is a respiratory disease caused by a novel coronavirus and is currently a global pandemic. HLA variation is assocd. with COVID-19 because HLA plays a pivotal role in the immune response to pathogens. Here, 82 individuals with COVID-19 were genotyped for HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 loci using next-generation sequencing (NGS). Frequencies of the HLA-C*07:29, C*08:01G, B*15:27, B*40:06, DRB1*04:06, and DPB1*36:01 alleles were higher, while the frequencies of the DRB1*12:02 and DPB1*04:01 alleles were lower in COVID-19 patients than in the control population, with uncorrected statistical significance. Only HLA-C*07:29 and B*15:27 were significant when the cor. P-value was considered. These data suggested that some HLA alleles may be assocd. with the occurrence of COVID-19.
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de Castro, J. A. L. How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. Front. Immunol. 2018, 9, 2463, DOI: 10.3389/fimmu.2018.02463
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How ERAP1 and ERAP2 shape the peptidomes of disease-associated MHC-I proteins
de Castro, Jose A. Lopez
Frontiers in Immunology (2018), 9 (), 2463/1-2463/17CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
A review. Four inflammatory diseases are strongly assocd. with Major Histocompatibility Complex class I (MHC-I) mols birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behcet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-assocd. MHC-I mols. in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic assocn. with various diseases, the role of polymorphisms detg. changes in enzymic activity or expression levels, and the distinct peptidomes of disease-assocd. MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely sep. roles in their processing of MHC-I ligands. The studies reviewed here provide a mol. basis for the distinct patterns of genetic assocn. of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint assocn. of both enzymes and unrelated MHC-I alleles influence different pathol. outcomes.
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Infantes, S.; Samino, Y.; Lorente, E.; Jimenez, M.; Garcia, R.; Del Val, M.; Lopez, D. Cutting Edge: H-2L(d) Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing. J. Immunol. 2010, 184 (7), 3351– 3355, DOI: 10.4049/jimmunol.0901560
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Cutting Edge: H-2Ld Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing
Infantes, Susana; Samino, Yolanda; Lorente, Elena; Jimenez, Mercedes; Garcia, Ruth; Del Val, Margarita; Lopez, Daniel
Journal of Immunology (2010), 184 (7), 3351-3355CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
In the classical MHC class I Ag presentation pathway, antigenic peptides derived from viral proteins by multiple proteolytic cleavages are transported to the endoplasmic reticulum lumen and are then exposed to aminopeptidase activity. In the current study, a long MHC class I natural ligand recognized by cytotoxic T lymphocytes was used to study the kinetics of degrdn. by aminopeptidase. The in vitro data indicate that this N-extended peptide is efficiently trimmed to a 9-mer, unless its binding to the MHC mols. protects the full-length peptide.
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Thomas, C.; Tampe, R. MHC I chaperone complexes shaping immunity. Curr. Opin. Immunol. 2019, 58, 9– 15, DOI: 10.1016/j.coi.2019.01.001
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MHC I chaperone complexes shaping immunity
Thomas, Christoph; Tampe, Robert
Current Opinion in Immunology (2019), 58 (), 9-15CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
Major histocompatibility complex class I (MHC I) mols. present peptides on the surface of most nucleated cells and allow the immune system to detect and eliminate infected or malignantly transformed cells. The peptides are derived from endogenous proteins by proteasomal degrdn. or aberrant translation, and are translocated from the cytosol into the endoplasmic reticulum (ER) by the transporter assocd. with antigen processing (TAP), a central component of the peptide-loading complex (PLC). The peptides are subsequently processed by ER-resident aminopeptidases (ERAP1/2) and loaded onto MHC I. This loading, however, does not happen indiscriminately: in a process called peptide editing or peptide proofreading, the MHC I-specific chaperones tapasin and TAPBPR (TAP-binding protein-related) catalyze the selection of high-affinity peptides and stable peptide-MHC I (pMHC I) complexes. Once correctly loaded with a high-affinity peptide, pMHC I complexes travel to the cell surface where they are recognized by T lymphocytes to control their differentiation in the thymus, their priming in the lymph node, and their final long-term surveillance of target cells in the periphery. Recent structural studies of the PLC and of TAPBPR-MHC I complexes by single-particle cryo-electron microscopy, X-ray crystallog., and NMR spectroscopy have provided fundamental insights into the mechanisms of MHC I peptide loading and proofreading, highlighting the dynamic nature of the involved complexes and the conformational plasticity of the individual proteins.
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Chen, H.; Li, L.; Weimershaus, M.; Evnouchidou, I.; van Endert, P.; Bouvier, M. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Sci. Rep. 2016, 6, 28902, DOI: 10.1038/srep28902
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ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing
Chen, Hanna; Li, Lenong; Weimershaus, Mirjana; Evnouchidou, Irini; van Endert, Peter; Bouvier, Marlene
Scientific Reports (2016), 6 (), 28902CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biol. of antigen presentation. To date, the mol. context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a mol. mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens.
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Mavridis, G.; Arya, R.; Domnick, A.; Zoidakis, J.; Makridakis, M.; Vlahou, A.; Mpakali, A.; Lelis, A.; Georgiadis, D.; Tampe, R.; Papakyriakou, A.; Stern, L. J.; Stratikos, E. A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1. J. Biol. Chem. 2020, 295 (21), 7193– 7210, DOI: 10.1074/jbc.RA120.012976
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A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1
Mavridis, George; Arya, Richa; Domnick, Alexander; Zoidakis, Jerome; Makridakis, Manousos; Vlahou, Antonia; Mpakali, Anastasia; Lelis, Angelos; Georgiadis, Dimitris; Tampe, Robert; Papakyriakou, Athanasios; Stern, Lawrence J.; Stratikos, Efstratios
Journal of Biological Chemistry (2020), 295 (21), 7193-7211CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) mols. and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in soln. and in preformed MHCI-peptide complexes, but which mode is more relevant to its biol. function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in soln. or when bound to three MHCI alleles, HLA-B*58, HLA-B*08, and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12-mer progressed at a considerable rate, albeit still slower than in soln. Results from thermodn., kinetic, and computational analyses suggested that this 12-mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissocn. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from preformed MHCI complexes as efficiently as ERAP1. A pseudopeptide analog with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1/MHCI/peptide complex. Similarly, no interactions between ERAP1 and purified peptide-loading complex were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degrdn. and that trimming in soln. along with the dynamic nature of peptide binding to MHCI are sufficient to explain ERAP1 processing of antigenic peptide precursors.
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Nucleic Acids Research (2019), 47 (D1), D442-D450CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
A review. The PRoteomics IDEntifications (PRIDE) database is the world's largest data repository of mass spectrometry-based proteomics data, and is one of the founding members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data vols. and addnl. data types. A new scalable and fault tolerant storage backed, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Addnl., we emphasize the improved support for quant. proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and vol. of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas.
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Abstract
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Figure 1
Figure 1. (A) Heatmap showing trimming of 15mers by aminopeptidases for each biological replicate. (B) Average label-free quantification (LFQ) signal of 15mers in the sample before and after incubation with the indicated enzyme. (C) Heatmap showing LFQ signal for 8–11mers produced after digestion. (D) Average signal of 8–11mers.
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Figure 2
Figure 2. Venn diagrams indicating overlap between peptide sequences produced by each enzyme. Numerals indicate number of peptides in each segment. Analysis was performed using BioVenn. (28) (A) Comparison of all peptides produced by each enzyme. (B) Comparison of 8–11mers produced by each enzyme. (C) Comparison of 8–11mers produced by ERAP1, ERAP2, as well as their mixture (ERAP1/2).
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Figure 3
Figure 3. Length distribution of peptides detected by LC-MS/MS after enzymatic digestion. (A) Number of peptides detected of each length. (B) Relative fraction of each length compared to the total number of peptides detected.
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Figure 4
Figure 4. (A) Scatter plot showing the predicted affinity of produced peptides for common HLA alleles as calculated by HLAthena. Color region encompasses peptides that are predicted to bind to at least one of the common HLA alleles used in the analysis. (B) Schematic representation of relative locations in the S1 protein sequence where the generated peptides are found. (C) Venn diagrams depicting overlap between peptides of S1 protein predicted to bind to common HLA alleles and peptides produced experimentally by ERAP1, ERAP2, IRAP, or ERAP1/ERAP2 mixture. Numerals indicate number of peptides in each separate segment.
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References
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  Journal of Immunology (2020), 205 (3), 555-564CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  A review. Coronavirus disease-2019 (COVID-19) is caused by the newly emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was recently declared as a pandemic by the World Health Organization. In its severe form, the disease is characterized by acute respiratory distress syndrome, and there are no targeted intervention strategies to treat or prevent it. The immune response is thought to both contribute to the pathogenesis of disease and provide protection during its resoln. Thus, understanding the immune response to SARS-CoV-2 is of the utmost importance for developing and testing vaccines and therapeutics. In this review, we discuss the earliest knowledge and hypotheses of the mechanisms of immune pathol. in the lung during acute infection as well at the later stages of disease resoln., recovery, and immune memory formation.
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8. 8
  Song, P.; Li, W.; Xie, J.; Hou, Y.; You, C. Cytokine storm induced by SARS-CoV-2. Clin. Chim. Acta 2020, 509, 280– 287, DOI: 10.1016/j.cca.2020.06.017
  8
  Cytokine storm induced by SARS-CoV-2
  Song, Peipei; Li, Wei; Xie, Jianqin; Hou, Yanlong; You, Chongge
  Clinica Chimica Acta (2020), 509 (), 280-287CODEN: CCATAR; ISSN:0009-8981. (Elsevier B.V.)
  A review. Coronavirus disease 2019 (COVID-19), caused by the virus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely throughout the world. Despite the strict global outbreak management and quarantine measures that have been implemented, the incidence of COVID-19 continues to rise, resulting in more than 290,000 deaths and representing an extremely serious threat to human life and health. The clin. symptoms of the affected patients are heterogeneous, ranging from mild upper respiratory symptoms to severe pneumonitis and even acute respiratory distress syndrome (ARDS) or death. Systemic immune over activation due to SARS-CoV-2 infection causes the cytokine storm, which is esp. noteworthy in severely ill patients with COVID-19. Pieces of evidence from current studies have shown that the cytokine storm may be an important factor in disease progression, even leading to multiple organ failure and death. This review provides an overview of the knowledge on the COVID-19 epidemiol. profile, the mol. mechanisms of the SARS-CoV-2-induced cytokine storm and immune responses, the pathophysiol. changes that occur during infection, the main antiviral compds. used in treatment strategies and the potential drugs for targeting cytokines, this information is presented to provide valuable guidance for further studies and for a therapeutic redn. of this excessive immune response.
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9. 9
  Li, K.; Hao, Z.; Zhao, X.; Du, J.; Zhou, Y. SARS-CoV-2 infection-induced immune responses: Friends or foes?. Scand. J. Immunol. 2020, 92 (2), e12895 DOI: 10.1111/sji.12895
  9
  SARS-CoV-2 infection-induced immune responses: Friends or foes?
  Li, Keying; Hao, Zhenhua; Zhao, Xiaohui; Du, Jiying; Zhou, Yanlin
  Scandinavian Journal of Immunology (2020), 92 (2), e12895CODEN: SJIMAX; ISSN:1365-3083. (Wiley-Blackwell)
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that belongs to the β-genus, causing the outbreak of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection can stimulate a pronounced immune response in the host, which embodies in the decrease of lymphocytes and aberrant increase of cytokines in COVID-19 patients. SARS-CoV-2 RNA and proteins interact with various pattern recognition receptors that switch on antiviral immune responses to regulate viral replication and spreading within the host in vivo. However, overactive and impaired immune responses also cause immune damage and subsequent tissue inflammation. This article focuses on the dual roles of immune system during SARS-CoV-2 infection, providing a theor. basic for identifying therapeutic targets in a situation with an unfavorable immune reaction.
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10. 10
  Peeples, L. News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (15), 8218– 8221, DOI: 10.1073/pnas.2005456117
  10
  News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine
  Peeples, Lynne
  Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (15), 8218-8221CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  A review. As researchers scramble to develop a Covid-19 vaccine, they are debating which, if any, of the phenomena related to a virus infection-aiding immune "enhancement" such as antibody-dependent enhancement (ADE) or cell-based enhancement including allergic inflammation caused by Th2 immunopathol., could be at play in the case of Covid-19 and how these phenomena might affect the success of vaccine candidates. Vaccine experts have underscored the need to avoid past mistakes including the halting of SARS vaccine development. Ecol. disruption increases the odds that a future coronavirus will jump from other hosts to humans.
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11. 11
  Leslie, M. T cells found in coronavirus patients ‘bode well’ for long-term immunity. Science 2020, 368 (6493), 809– 810, DOI: 10.1126/science.368.6493.809
  11
  T cells found in coronavirus patients 'bode well' for long-term immunity
  Leslie, Mitch
  Science (Washington, DC, United States) (2020), 368 (6493), 809-810CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
  A review. Whether T cells join the immune system's fight against SARS-CoV-2, the virus that causes COVID-19, has been unclear. Two new studies have identified T cells that react to the virus in patients who had COVID-19 or were recovering from it. Both studies detected helper T cells, which orchestrate antiviral responses of other immune cells, and 1 of the studies also found killer T cells that eliminate virally infected cells. Both studies also discovered helper T cells that target the virus in blood samples from people who had never been infected. These people likely had the cells because they had been infected by similar coronaviruses that cause colds. The results suggest the virus induces a strong T cell response in patients, but they do not indicate whether people who have recovered from COVID-19 are immune to the virus.
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12. 12
  Manners, C.; Larios Bautista, E.; Sidoti, H.; Lopez, O. J. Protective Adaptive Immunity Against Severe Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2) and Implications for Vaccines. Cureus 2020, 12 (6), e8399 DOI: 10.7759/cureus.8399
  There is no corresponding record for this reference.
13. 13
  Mukherjee, S.; Tworowski, D.; Detroja, R.; Mukherjee, S. B.; Frenkel-Morgenstern, M. Immunoinformatics and Structural Analysis for Identification of Immunodominant Epitopes in SARS-CoV-2 as Potential Vaccine Targets. Vaccines (Basel, Switz.) 2020, 8 (2), 290, DOI: 10.3390/vaccines8020290
  There is no corresponding record for this reference.
14. 14
  Rock, K. L.; Goldberg, A. L. Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu. Rev. Immunol. 1999, 17, 739– 79, DOI: 10.1146/annurev.immunol.17.1.739
  14
  Degradation of cell proteins and the generation of MHC class I-presented peptides
  Rock, Kenneth L.; Goldberg, Alfred L.
  Annual Review of Immunology (1999), 17 (), 739-779CODEN: ARIMDU; ISSN:0732-0582. (Annual Reviews Inc.)
  A review with 211 refs. Major histocompatibility complex (MHC) class I mols. display on the cell surface 8- to 10-residue peptides derived from the spectrum of proteins expressed in the cells. By screening for non-self MHC-bound peptides, the immune system identifies and then can eliminate cells that are producing viral or mutant proteins. These antigenic peptides are generated as side products in the continual turnover of intracellular proteins, which occurs primarily by the ubiquitin-proteasome pathway. Most of the oligopeptides generated by the proteasome are further degraded by distinct endopeptidases and aminopeptidases into amino acids, which are used for new protein synthesis or energy prodn. However, a fraction of these peptides escape complete destruction and after transport into the endoplasmic reticulum are bound by MHC class I mols. and delivered to the cell surface. Herein we review recent discoveries about the proteolytic systems that degrade cell proteins, how the ubiquitin-proteasome pathway generates the peptides presented on MHC-class I mols., and how this process is stimulated by immune modifiers to enhance antigen presentation.
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15. 15
  Weimershaus, M.; Evnouchidou, I.; Saveanu, L.; van Endert, P. Peptidases trimming MHC class I ligands. Curr. Opin. Immunol. 2013, 25 (1), 90– 6, DOI: 10.1016/j.coi.2012.10.001
  15
  Peptidases trimming MHC class I ligands
  Weimershaus, Mirjana; Evnouchidou, Irini; Saveanu, Loredana; van Endert, Peter
  Current Opinion in Immunology (2013), 25 (1), 90-96CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
  A review. Peptides presented by MHC class I mols. are typically produced through antigen degrdn. by the proteasome followed by trimming by exopeptidases. According to recent results, these include both aminopeptidases and carboxypeptidases in the cytosol and the endoplasmic reticulum. While cytosolic peptidases have a net neutral or destructive effect on MHC ligands, endoplasmic reticulum aminopeptidases are required for efficient class I loading and have a strong effect on the repertoire of peptide/MHC complexes. Cells lacking these enzymes can be eliminated both by NK cells and by CD8+ T cells recognizing complexes formed between an MHC class Ib mol. and a conserved peptide. Cross-presented peptides derived from internalized antigens can be processed by insulin-regulated aminopeptidase, the only endosomal trimming peptidase.
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16. 16
  Hammer, G. E.; Kanaseki, T.; Shastri, N. The final touches make perfect the peptide-MHC class I repertoire. Immunity 2007, 26 (4), 397– 406, DOI: 10.1016/j.immuni.2007.04.003
  16
  The final touches make perfect the peptide-MHC class I repertoire
  Hammer, Gianna Elena; Kanaseki, Takayuki; Shastri, Nilabh
  Immunity (2007), 26 (4), 397-406CODEN: IUNIEH; ISSN:1074-7613. (Cell Press)
  A review. Major histocompatibility complex (MHC) class I mols. present short, perfectly cleaved peptides on the cell surface for immune surveillance by CD8+ T cells. The pathway for generating these peptides begins in the cytoplasm, and the peptide-MHC I (pMHC I) repertoire is finalized in the endoplasmic reticulum. Recent studies show that the peptides for MHC I are customized by the ER aminopeptidase assocd. with antigen processing and by dynamic interactions within the MHC peptide-loading complex. Failure to customize the pMHC I repertoire has profound immunol. consequences.
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17. 17
  Giastas, P.; Mpakali, A.; Papakyriakou, A.; Lelis, A.; Kokkala, P.; Neu, M.; Rowland, P.; Liddle, J.; Georgiadis, D.; Stratikos, E. Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (52), 26709– 26716, DOI: 10.1073/pnas.1912070116
  17
  Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1
  Giastas, Petros; Mpakali, Anastasia; Papakyriakou, Athanasios; Lelis, Aggelos; Kokkala, Paraskevi; Neu, Margarete; Rowland, Paul; Liddle, John; Georgiadis, Dimitris; Stratikos, Efstratios
  Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (52), 26709-26716CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that optimizes the peptide cargo of major histocompatibility class I (MHC-I) mols. and regulates adaptive immunity. It has unusual substrate selectivity for length and sequence, resulting in poorly understood effects on the cellular immunopeptidome. To understand substrate selection by ERAP1, we solved 2 crystal structures of the enzyme with bound transition-state pseudopeptide analogs at 1.68 Å and 1.72 Å. Both peptides have their N terminus bound at the active site and extend away along a large internal cavity, interacting with shallow pockets that can influence selectivity. The longer peptide is disordered through the central region of the cavity and has its C terminus bound in an allosteric pocket of domain IV that features a carboxypeptidase-like structural motif. These structures, along with enzymic and computational analyses, explain how ERAP1 can select peptides based on length while retaining the broad sequence-specificity necessary for its biol. function.
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18. 18
  Stratikos, E.; Stern, L. J. Antigenic peptide trimming by ER aminopeptidases--insights from structural studies. Mol. Immunol. 2013, 55 (3–4), 212– 9, DOI: 10.1016/j.molimm.2013.03.002
  18
  Antigenic peptide trimming by ER aminopeptidases - Insights from structural studies
  Stratikos, Efstratios; Stern, Lawrence J.
  Molecular Immunology (2013), 55 (3-4), 212-219CODEN: MOIMD5; ISSN:0161-5890. (Elsevier)
  A review. Generation and destruction of antigenic peptides by ER resident aminopeptidases ERAP1 and ERAP2 have been shown in the last few years to be important for the correct functioning and regulation of the adaptive immune response. These two highly homologous aminopeptidases appear to have evolved complex mechanisms well suited for their biol. role in antigen presentation. Furthermore, polymorphic variability in these enzymes appears to affect their function and predispose individuals to disease. This review discusses our current understanding of the mol. mechanisms behind ERAP1/2 function as suggested by several recently detd. crystallog. structures of these enzymes.
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19. 19
  Evnouchidou, I.; Kamal, R. P.; Seregin, S. S.; Goto, Y.; Tsujimoto, M.; Hattori, A.; Voulgari, P. V.; Drosos, A. A.; Amalfitano, A.; York, I. A.; Stratikos, E. Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J. Immunol. 2011, 186 (4), 1909– 13, DOI: 10.4049/jimmunol.1003337
  19
  Cutting Edge: Coding Single Nucleotide Polymorphisms of Endoplasmic Reticulum Aminopeptidase 1 Can Affect Antigenic Peptide Generation In Vitro by Influencing Basic Enzymatic Properties of the Enzyme
  Evnouchidou, Irini; Kamal, Ram P.; Seregin, Sergey S.; Goto, Yoshikuni; Tsujimoto, Masafumi; Hattori, Akira; Voulgari, Paraskevi V.; Drosos, Alexandros A.; Amalfitano, Andrea; York, Ian A.; Stratikos, Efstratios
  Journal of Immunology (2011), 186 (4), 1909-1913CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, the authors analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis-Menten anal. revealed that the presence of SNPs affects the Michaelis const. and turnover no. of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from std. Michaelis-Menten behavior, demonstrating substrate-inhibition kinetics; to the authors' knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation anal. was consistent with changes in the substrate inhibition const. Ki, further supporting that ERAP1 allelic compn. may affect Ag processing in vivo. The authors propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity.
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20. 20
  Stamogiannos, A.; Maben, Z.; Papakyriakou, A.; Mpakali, A.; Kokkala, P.; Georgiadis, D.; Stern, L. J.; Stratikos, E. Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1. Biochemistry 2017, 56 (10), 1546– 1558, DOI: 10.1021/acs.biochem.6b01170
  20
  Critical Role of Interdomain Interactions in the Conformational Change and Catalytic Mechanism of Endoplasmic Reticulum Aminopeptidase 1
  Stamogiannos, Athanasios; Maben, Zachary; Papakyriakou, Athanasios; Mpakali, Anastasia; Kokkala, Paraskevi; Georgiadis, Dimitris; Stern, Lawrence J.; Stratikos, Efstratios
  Biochemistry (2017), 56 (10), 1546-1558CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular enzyme important for the generation of antigenic epitopes and class I MHC-restricted adaptive immune responses. ERAP1 processes a vast variety of different peptides but still shows length and sequence selectivity although the mechanism behind these properties is poorly understood. X-ray crystallog. anal. has revealed that ERAP1 can assume at least two distinct conformations in which the C-terminal domain IV is either proximal or distal to the active site domain II. To help understand the role of this conformational change in the catalytic mechanism of ERAP1 we used site-directed mutagenesis to perturb key salt-bridges between domains II and IV. Enzymic anal. revealed that these mutations, although located away from the catalytic site, greatly reduce catalytic efficiency and shift allosteric kinetic behavior. The variants were more efficiently activated by small peptides, and bound a competitive inhibitor with weaker affinity and faster dissocn. kinetics. Mol. dynamics anal. suggested that the mutations affect the conformational distribution of ERAP1, reducing the population of closed states. Small-angle x-ray scattering indicated that both wild-type and the ERAP1 variants are predominantly in an open conformational state in soln. Overall, our findings suggest that electrostatic interactions between domains II and IV in ERAP1 are crucial for driving a conformational change that regulates the structural integrity of the catalytic site. The extent of domain opening in ERAP1 probably underlies its specialization for antigenic peptide precursors and should be taken into account for inhibitor development efforts.
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21. 21
  Mpakali, A.; Giastas, P.; Mathioudakis, N.; Mavridis, I. M.; Saridakis, E.; Stratikos, E. Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2. J. Biol. Chem. 2015, 290 (43), 26021– 32, DOI: 10.1074/jbc.M115.685909
  21
  Structural basis for antigenic peptide recognition and processing by endoplasmic reticulum (ER) aminopeptidase 2
  Mpakali, Anastasia; Giastas, Petros; Mathioudakis, Nikolas; Mavridis, Irene M.; Saridakis, Emmanuel; Stratikos, Efstratios
  Journal of Biological Chemistry (2015), 290 (43), 26021-26032CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Endoplasmic reticulum (ER) aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I mols. and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we detd. crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analog and a peptidic product to 2.5 and 2.7 Å, resp., and compared them to the apo-form structure detd. to 3.0 Å. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analog extends away from the catalytic center toward the distal end of the internal cavity, making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product, although decreasing electron d. toward its C terminus indicated progressive disorder. Enzymic anal. confirmed that visualized interactions can either pos. or neg. impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to det. trimming rates, thus combining substrate permissiveness with sequence bias.
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22. 22
  Mpakali, A.; Saridakis, E.; Harlos, K.; Zhao, Y.; Papakyriakou, A.; Kokkala, P.; Georgiadis, D.; Stratikos, E. Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing. J. Immunol. 2015, 195 (6), 2842– 2851, DOI: 10.4049/jimmunol.1501103
  22
  Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing
  Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl; Zhao, Yuguang; Papakyriakou, Athanasios; Kokkala, Paraskevi; Georgiadis, Dimitris; Stratikos, Efstratios
  Journal of Immunology (2015), 195 (6), 2842-2851CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast no. of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that preps. antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes.
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23. 23
  Saveanu, L.; Carroll, O.; Lindo, V.; Del Val, M.; Lopez, D.; Lepelletier, Y.; Greer, F.; Schomburg, L.; Fruci, D.; Niedermann, G.; van Endert, P. M. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat. Immunol. 2005, 6 (7), 689– 97, DOI: 10.1038/ni1208
  23
  Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum
  Saveanu, Loredana; Carroll, Oliver; Lindo, Vivian; Del Val, Margarita; Lopez, Daniel; Lepelletier, Yves; Greer, Fiona; Schomburg, Lutz; Fruci, Doriana; Niedermann, Gabriele; van Endert, Peter M.
  Nature Immunology (2005), 6 (7), 689-697CODEN: NIAMCZ; ISSN:1529-2908. (Nature Publishing Group)
  The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases. The authors show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. This trimming of a longer peptide required the concerted action of both ERAP1 and ERAP2, both for in vitro digestion and in vivo for cellular antigen presentation. ERAP1 and ERAP2 localized together in vivo and assocd. phys. in complexes that were most likely heterodimeric. Thus, the human endoplasmic reticulum is equipped with a pair of trimming aminopeptidases that have complementary functions in HLA class I peptide presentation.
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24. 24
  Evnouchidou, I.; Weimershaus, M.; Saveanu, L.; van Endert, P. ERAP1-ERAP2 dimerization increases peptide-trimming efficiency. J. Immunol. 2014, 193 (2), 901– 8, DOI: 10.4049/jimmunol.1302855
  24
  ERAP1-ERAP2 Dimerization Increases Peptide-Trimming Efficiency
  Evnouchidou, Irini; Weimershaus, Mirjana; Saveanu, Loredana; van Endert, Peter
  Journal of Immunology (2014), 193 (2), 901-908CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  The endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 play a crit. role in the prodn. of final epitopes presented by MHC class I mols. Formation of heterodimers by ERAP1 and ERAP2 has been proposed to facilitate trimming of epitope precursor peptides, but the effects of dimerization on ERAP function remain unknown. In this study, we produced stabilized ERAP1-ERAP2 heterodimers and found that they produced several mature epitopes more efficiently than a mix of the two enzymes unable to dimerize. Phys. interaction with ERAP2 changes basic enzymic parameters of ERAP1 and improves its substrate-binding affinity. Thus, by bringing the two enzymes in proximity and by producing allosteric effects on ERAP1, dimerization of ERAP1/2 creates complexes with superior peptide-trimming efficacy. Such complexes are likely to enhance Ag presentation by cells displaying coordinated expression of the two enzymes.
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25. 25
  Zervoudi, E.; Papakyriakou, A.; Georgiadou, D.; Evnouchidou, I.; Gajda, A.; Poreba, M.; Salvesen, G. S.; Drag, M.; Hattori, A.; Swevers, L.; Vourloumis, D.; Stratikos, E. Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides. Biochem. J. 2011, 435 (2), 411– 20, DOI: 10.1042/BJ20102049
  25
  Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides
  Zervoudi, Efthalia; Papakyriakou, Athanasios; Georgiadou, Dimitra; Evnouchidou, Irini; Gajda, Anna; Poreba, Marcin; Salvesen, Guy S.; Drag, Marcin; Hattori, Akira; Swevers, Luc; Vourloumis, Dionisios; Stratikos, Efstratios
  Biochemical Journal (2011), 435 (2), 411-420CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
  ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play crit. roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I mols. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorogenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Mol. modeling of the three S1 pockets reveals substrate-enzyme interactions that are crit. determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biol. function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes.
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26. 26
  Chang, S. C.; Momburg, F.; Bhutani, N.; Goldberg, A. L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (47), 17107– 12, DOI: 10.1073/pnas.0500721102
  26
  The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism
  Chang, Shih-Chung; Momburg, Frank; Bhutani, Nidhi; Goldberg, Alfred L.
  Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (47), 17107-17112CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-γ-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I mols. The authors recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8-9 residues, the length required for binding to MHC class I mols. Here, the authors show another remarkable property of ERAP1: that it strongly prefers substrates 9-16 residues long, the lengths of peptides transported efficiently into the ER by the transporter assocd. with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N- and C-terminal sequences. No other aminopeptidase, including the closely related ER-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I mols., prefers peptides with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to peptides that can serve as MHC class I epitopes. Its "mol. ruler" mechanism involves binding the hydrophobic C terminus of the substrate 9-16 residues away from the active site.
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27. 27
  Lorente, E.; Barriga, A.; Johnstone, C.; Mir, C.; Jimenez, M.; Lopez, D. Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases. PLoS One 2013, 8 (11), e79596 DOI: 10.1371/journal.pone.0079596
  27
  Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases
  Lorente, Elena; Barriga, Alejandro; Johnstone, Carolina; Mir, Carmen; Jimenez, Mercedes; Lopez, Daniel
  PLoS One (2013), 8 (11), e79596CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
  In the classical human leukocyte antigen (HLA) class I antigen processing and presentation pathway, the antigenic peptides are generated from viral proteins by multiple proteolytic cleavages of the proteasome (and in some cases other cytosolic proteases) and transported to the endoplasmic reticulum (ER) lumen where they are exposed to aminopeptidase activity. In human cells, two different ER-resident enzymes, ERAP1 and ERAP2, can trim the N-terminally extended residues of peptide precursors. In this study, the possible cooperative effect of generating five naturally processed HLA-B27 ligands by both proteases was analyzed. We identified differences in the products obtained with increased detection of natural HLA-B27 ligands by comparing double vs. single enzyme digestions by mass spectrometry anal. These in vitro data suggest that each enzyme can use the degrdn. products of the other as a substrate for new N-terminal trimming, indicating concerted aminoproteolytic activity of ERAP1 and ERAP2.
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28. 28
  Hulsen, T.; de Vlieg, J.; Alkema, W. BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 2008, 9, 488, DOI: 10.1186/1471-2164-9-488
  28
  BioVenn - a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams
  Hulsen Tim; de Vlieg Jacob; Alkema Wynand
  BMC genomics (2008), 9 (), 488 ISSN:.
  BACKGROUND: In many genomics projects, numerous lists containing biological identifiers are produced. Often it is useful to see the overlap between different lists, enabling researchers to quickly observe similarities and differences between the data sets they are analyzing. One of the most popular methods to visualize the overlap and differences between data sets is the Venn diagram: a diagram consisting of two or more circles in which each circle corresponds to a data set, and the overlap between the circles corresponds to the overlap between the data sets. Venn diagrams are especially useful when they are 'area-proportional' i.e. the sizes of the circles and the overlaps correspond to the sizes of the data sets. Currently there are no programs available that can create area-proportional Venn diagrams connected to a wide range of biological databases. RESULTS: We designed a web application named BioVenn to summarize the overlap between two or three lists of identifiers, using area-proportional Venn diagrams. The user only needs to input these lists of identifiers in the textboxes and push the submit button. Parameters like colors and text size can be adjusted easily through the web interface. The position of the text can be adjusted by 'drag-and-drop' principle. The output Venn diagram can be shown as an SVG or PNG image embedded in the web application, or as a standalone SVG or PNG image. The latter option is useful for batch queries. Besides the Venn diagram, BioVenn outputs lists of identifiers for each of the resulting subsets. If an identifier is recognized as belonging to one of the supported biological databases, the output is linked to that database. Finally, BioVenn can map Affymetrix and EntrezGene identifiers to Ensembl genes. CONCLUSION: BioVenn is an easy-to-use web application to generate area-proportional Venn diagrams from lists of biological identifiers. It supports a wide range of identifiers from the most used biological databases currently available. Its implementation on the World Wide Web makes it available for use on any computer with internet connection, independent of operating system and without the need to install programs locally. BioVenn is freely accessible at http://www.cmbi.ru.nl/cdd/biovenn/.
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29. 29
  Sarkizova, S.; Klaeger, S.; Le, P. M.; Li, L. W.; Oliveira, G.; Keshishian, H.; Hartigan, C. R.; Zhang, W.; Braun, D. A.; Ligon, K. L.; Bachireddy, P.; Zervantonakis, I. K.; Rosenbluth, J. M.; Ouspenskaia, T.; Law, T.; Justesen, S.; Stevens, J.; Lane, W. J.; Eisenhaure, T.; Lan Zhang, G.; Clauser, K. R.; Hacohen, N.; Carr, S. A.; Wu, C. J.; Keskin, D. B. A large peptidome dataset improves HLA class I epitope prediction across most of the human population. Nat. Biotechnol. 2020, 38 (2), 199– 209, DOI: 10.1038/s41587-019-0322-9
  29
  A large peptidome dataset improves HLA class I epitope prediction across most of the human population
  Sarkizova, Siranush; Klaeger, Susan; Le, Phuong M.; Li, Letitia W.; Oliveira, Giacomo; Keshishian, Hasmik; Hartigan, Christina R.; Zhang, Wandi; Braun, David A.; Ligon, Keith L.; Bachireddy, Pavan; Zervantonakis, Ioannis K.; Rosenbluth, Jennifer M.; Ouspenskaia, Tamara; Law, Travis; Justesen, Sune; Stevens, Jonathan; Lane, William J.; Eisenhaure, Thomas; Lan Zhang, Guang; Clauser, Karl R.; Hacohen, Nir; Carr, Steven A.; Wu, Catherine J.; Keskin, Derin B.
  Nature Biotechnology (2020), 38 (2), 199-209CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
  Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-assocd. peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs assocd. with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-assocd. ligands with 1.5-fold improvement in pos. predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were obsd. exptl. in 11 patient-derived tumor cell lines.
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30. 30
  Vita, R.; Zarebski, L.; Greenbaum, J. A.; Emami, H.; Hoof, I.; Salimi, N.; Damle, R.; Sette, A.; Peters, B. The immune epitope database 2.0. Nucleic Acids Res. 2010, 38 (Database issue), D854– D862, DOI: 10.1093/nar/gkp1004
  30
  The Immune Epitope Database 2.0
  Vita, Randi; Zarebski, Laura; Greenbaum, Jason A.; Emami, Hussein; Hoof, Ilka; Salimi, Nima; Damle, Rohini; Sette, Alessandro; Peters, Bjoern
  Nucleic Acids Research (2010), 38 (Database Iss), D854-D862CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
  The Immune Epitope Database (IEDB, www.iedb.org) provides a catalog of exptl. characterized B and T cell epitopes, as well as data on Major Histocompatibility Complex (MHC) binding and MHC ligand elution expts. The database represents the mol. structures recognized by adaptive immune receptors and the exptl. contexts in which these mols. were detd. to be immune epitopes. Epitopes recognized in humans, nonhuman primates, rodents, pigs, cats and all other tested species are included. Both pos. and neg. exptl. results are captured. Over the course of 4 years, the data from 180 978 expts. were curated manually from the literature, which covers ∼99% of all publicly available information on peptide epitopes mapped in infectious agents (excluding HIV) and 93% of those mapped in allergens. In addn., data that would otherwise be unavailable to the public from 129 186 expts. were submitted directly by investigators. The curation of epitopes related to autoimmunity is expected to be completed by the end of 2010. The database can be queried by epitope structure, source organism, MHC restriction, assay type or host organism, among other criteria. The database structure, as well as its querying, browsing and reporting interfaces, was completely redesigned for the IEDB 2.0 release, which became publicly available in early 2009.
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31. 31
  Nguyen, A.; David, J. K.; Maden, S. K.; Wood, M. A.; Weeder, B. R.; Nellore, A.; Thompson, R. F. Human leukocyte antigen susceptibility map for SARS-CoV-2. J. Virol. 2020, DOI: 10.1128/JVI.00510-20
  There is no corresponding record for this reference.
32. 32
  Reynisson, B.; Alvarez, B.; Paul, S.; Peters, B.; Nielsen, M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 2020, 48 (W1), W449– W454, DOI: 10.1093/nar/gkaa379
  32
  NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data
  Reynisson, Birkir; Alvarez, Bruno; Paul, Sinu; Peters, Bjoern; Nielsen, Morten
  Nucleic Acids Research (2020), 48 (W1), W449-W454CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
  Major histocompatibility complex (MHC) mols. are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the development of T-cell immune responses. MHC mols. come in two main variants: MHC Class I (MHC-I) and MHC Class II (MHC-II). MHC-I predominantly present peptides derived from intracellular proteins, whereas MHC-II predominantly presents peptides from extracellular proteins. In both cases, the binding between MHC and antigenic peptides is the most selective step in the antigen presentation pathway. Therefore, the prediction of peptide binding to MHC is a powerful utility to predict the possible specificity of a T-cell immune response. Commonly MHC binding prediction tools are trained on binding affinity or mass spectrometry-eluted ligands. Recent studies have however demonstrated how the integration of both data types can boost predictive performances. Inspired by this, we here present NetMHCpan-4.1 and NetMHCIIpan-4.0, two web servers created to predict binding between peptides and MHC-I and MHC-II, resp. Both methods exploit tailored machine learning strategies to integrate different training data types, resulting in state-of-the-art performance and outperforming their competitors.
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33. 33
  Komov, L.; Kadosh, D. M.; Barnea, E.; Milner, E.; Hendler, A.; Admon, A. Cell Surface MHC Class I Expression Is Limited by the Availability of Peptide-Receptive “Empty” Molecules Rather than by the Supply of Peptide Ligands. Proteomics 2018, 18 (12), e1700248 DOI: 10.1002/pmic.201700248
  There is no corresponding record for this reference.
34. 34
  Hearn, A.; York, I. A.; Rock, K. L. The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum. J. Immunol. 2009, 183 (9), 5526– 36, DOI: 10.4049/jimmunol.0803663
  34
  The Specificity of Trimming of MHC Class I-Presented Peptides in the Endoplasmic Reticulum
  Hearn, Arron; York, Ian A.; Rock, Kenneth L.
  Journal of Immunology (2009), 183 (9), 5526-5536CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  Aminopeptidases in the endoplasmic reticulum (ER) can cleave antigenic peptides and in so doing either create or destroy MHC class I-presented epitopes. However, the specificity of this trimming process overall and of the major ER aminopeptidase ERAP1 in particular is not well understood. This issue is important because peptide trimming influences the magnitude and specificity of CD8 T cell responses. By systematically varying the N-terminal flanking sequences of peptides in a cell-free biochem. system and in intact cells, the authors elucidated the specificity of ERAP1 and of ER trimming overall. ERAP1 can cleave after many amino acids on the N terminus of epitope precursors but does so at markedly different rates. The specificity seen with purified ERAP1 is similar to that obsd. for trimming and presentation of epitopes in the ER of intact cells. The authors define N-terminal sequences that are favorable or unfavorable for Ag presentation in ways that are independent from the epitopes core sequence. When databases of known presented peptides were analyzed, the residues that were preferred for the trimming of model peptide precursors were overrepresented in N-terminal flanking sequences of epitopes generally. These data define key determinants in the specificity of Ag processing.
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35. 35
  Georgiadou, D.; Hearn, A.; Evnouchidou, I.; Chroni, A.; Leondiadis, L.; York, I. A.; Rock, K. L.; Stratikos, E. Placental leucine aminopeptidase efficiently generates mature antigenic peptides in vitro but in patterns distinct from endoplasmic reticulum aminopeptidase 1. J. Immunol. 2010, 185 (3), 1584– 92, DOI: 10.4049/jimmunol.0902502
  35
  Placental Leucine Aminopeptidase Efficiently Generates Mature Antigenic Peptides In Vitro but in Patterns Distinct from Endoplasmic Reticulum Aminopeptidase 1
  Georgiadou, Dimitra; Hearn, Arron; Evnouchidou, Irini; Chroni, Angeliki; Leondiadis, Leondios; York, Ian A.; Rock, Kenneth L.; Stratikos, Efstratios
  Journal of Immunology (2010), 185 (3), 1584-1592CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  All three members of the oxytocinase subfamily of M1 aminopeptidases, endoplasmic reticulum aminopeptidase 1 (ERAP1), ERAP2, and placental leucine aminopeptidase (PLAP), also known as insulin-regulated aminopeptidase, have been implicated in the generation of MHC class I-presented peptides. ERAP1 and 2 trim peptides in the endoplasmic reticulum for direct presentation, whereas PLAP has been recently implicated in cross-presentation. The best characterized member of the family, ERAP1, has unique enzymic properties that fit well with its role in Ag processing. ERAP1 can trim a large variety of long peptide sequences and efficiently accumulate mature antigenic epitopes of 8-9 aa long. In this study, the authors evaluate the ability of PLAP to process antigenic peptide precursors in vitro and compare it with ERAP1. The authors find that, similar to ERAP1, PLAP can trim a variety of long peptide sequences efficiently and, in most cases, accumulates appreciable amts. of correct length mature antigenic epitope. Again, similar to ERAP1, PLAP continued trimming some of the epitopes tested and accumulated smaller products effectively destroying the epitope. However, the intermediate accumulation properties of ERAP1 and PLAP are distinct and epitope dependent, suggesting that these two enzymes may impose different selective pressures on epitope generation. Overall, although PLAP has the necessary enzymic properties to participate in generating or destroying MHC class I-presented peptides, its trimming behavior is distinct from that of ERAP1, something that supports a sep. role for these two enzymes in Ag processing.
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36. 36
  Kuiper, J. J.; Van Setten, J.; Ripke, S.; Van, T. S. R.; Mulder, F.; Missotten, T.; Baarsma, G. S.; Francioli, L. C.; Pulit, S. L.; De Kovel, C. G.; Ten Dam-Van Loon, N.; Den Hollander, A. I.; Huis in het Veld, P.; Hoyng, C. B.; Cordero-Coma, M.; Martin, J.; Llorenc, V.; Arya, B.; Thomas, D.; Bakker, S. C.; Ophoff, R. A.; Rothova, A.; De Bakker, P. I.; Mutis, T.; Koeleman, B. P. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Hum. Mol. Genet. 2014, 23 (22), 6081– 6087, DOI: 10.1093/hmg/ddu307
  36
  A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy
  Kuiper, Jonas J. W.; Van Setten, Jessica; Ripke, Stephan; Slot, Ruben Van 'T.; Mulder, Flip; Missotten, Tom; Baarsma, G. Seerp; Francioli, Laurent C.; Pulit, Sara L.; Kovel, Carolien G. F. De; Loon, Ninette Ten Dam-Van; Hollander, Anneke I. Den; Veld, Paulien Huis in het; Hoyng, Carel B.; Cordero-Coma, Miguel; Martin, Javier; Llorenc, Victor; Arya, Bharti; Thomas, Dhanes; Bakker, Steven C.; Ophoff, Roel A.; Rothova, Aniki; Bakker, Paul I. W. De; Mutis, Tuna; Koeleman, Bobby P. C.
  Human Molecular Genetics (2014), 23 (22), 6081-6087CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
  Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA assocn. for a human disease. We have conducted a genome-wide assocn. study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC assocn. through high-resoln. imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC assocn. (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10-74). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093;OR = 2.3,95%CI 1.7-3.1, for the T allele, P = 8.6 × 10-8) and at 14q32.31 in the TECPR2 gene (rs150571175;OR = 6.1,95%CI 3.2-11.7, for the A allele, P = 3.2 × 10-8). The assocn. near ERAP2 was confirmed in an independent British case-control samples (combined meta-anal. P = 1.7 × 10-9). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly assocd. with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.
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37. 37
  Grifoni, A.; Weiskopf, D.; Ramirez, S. I.; Mateus, J.; Dan, J. M.; Moderbacher, C. R.; Rawlings, S. A.; Sutherland, A.; Premkumar, L.; Jadi, R. S.; Marrama, D.; de Silva, A. M.; Frazier, A.; Carlin, A. F.; Greenbaum, J. A.; Peters, B.; Krammer, F.; Smith, D. M.; Crotty, S.; Sette, A. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020, 181 (7), 1489– 1501, DOI: 10.1016/j.cell.2020.05.015
  37
  Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals
  Grifoni, Alba; Weiskopf, Daniela; Ramirez, Sydney I.; Mateus, Jose; Dan, Jennifer M.; Moderbacher, Carolyn Rydyznski; Rawlings, Stephen A.; Sutherland, Aaron; Premkumar, Lakshmanane; Jadi, Ramesh S.; Marrama, Daniel; de Silva, Aravinda M.; Frazier, April; Carlin, Aaron F.; Greenbaum, Jason A.; Peters, Bjoern; Krammer, Florian; Smith, Davey M.; Crotty, Shane; Sette, Alessandro
  Cell (Cambridge, MA, United States) (2020), 181 (7), 1489-1501.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, resp. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with addnl. responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
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38. 38
  Wilk, A. J.; Rustagi, A.; Zhao, N. Q.; Roque, J.; Martinez-Colon, G. J.; McKechnie, J. L.; Ivison, G. T.; Ranganath, T.; Vergara, R.; Hollis, T.; Simpson, L. J.; Grant, P.; Subramanian, A.; Rogers, A. J.; Blish, C. A. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 2020, 26 (7), 1070– 1076, DOI: 10.1038/s41591-020-0944-y
  38
  A single-cell atlas of the peripheral immune response in patients with severe COVID-19
  Wilk, Aaron J.; Rustagi, Arjun; Zhao, Nancy Q.; Roque, Jonasel; Martinez-Colon, Giovanny J.; McKechnie, Julia L.; Ivison, Geoffrey T.; Ranganath, Thanmayi; Vergara, Rosemary; Hollis, Taylor; Simpson, Laura J.; Grant, Philip; Subramanian, Aruna; Rogers, Angela J.; Blish, Catherine A.
  Nature Medicine (New York, NY, United States) (2020), 26 (7), 1070-1076CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
  Abstr.: There is an urgent need to better understand the pathophysiol. of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approx. 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been assocd. with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines that may be produced by a subset of inflammatory monocytes , lymphopenia and T cell exhaustion . To elucidate pathways in peripheral immune cells that might lead to immunopathol. or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mech. ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amts. of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.
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39. 39
  Wang, W.; Zhang, W.; Zhang, J.; He, J.; Zhu, F. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19). HLA 2020, 96 (2), 194– 196, DOI: 10.1111/tan.13941
  39
  Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19)
  Wang, Wei; Zhang, Wei; Zhang, Jingjing; He, Ji; Zhu, Faming
  HLA (2020), 96 (2), 194-196CODEN: HLAAAK; ISSN:2059-2310. (John Wiley & Sons Ltd.)
  COVID-19 is a respiratory disease caused by a novel coronavirus and is currently a global pandemic. HLA variation is assocd. with COVID-19 because HLA plays a pivotal role in the immune response to pathogens. Here, 82 individuals with COVID-19 were genotyped for HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 loci using next-generation sequencing (NGS). Frequencies of the HLA-C*07:29, C*08:01G, B*15:27, B*40:06, DRB1*04:06, and DPB1*36:01 alleles were higher, while the frequencies of the DRB1*12:02 and DPB1*04:01 alleles were lower in COVID-19 patients than in the control population, with uncorrected statistical significance. Only HLA-C*07:29 and B*15:27 were significant when the cor. P-value was considered. These data suggested that some HLA alleles may be assocd. with the occurrence of COVID-19.
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40. 40
  de Castro, J. A. L. How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. Front. Immunol. 2018, 9, 2463, DOI: 10.3389/fimmu.2018.02463
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  How ERAP1 and ERAP2 shape the peptidomes of disease-associated MHC-I proteins
  de Castro, Jose A. Lopez
  Frontiers in Immunology (2018), 9 (), 2463/1-2463/17CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
  A review. Four inflammatory diseases are strongly assocd. with Major Histocompatibility Complex class I (MHC-I) mols birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behcet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-assocd. MHC-I mols. in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic assocn. with various diseases, the role of polymorphisms detg. changes in enzymic activity or expression levels, and the distinct peptidomes of disease-assocd. MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely sep. roles in their processing of MHC-I ligands. The studies reviewed here provide a mol. basis for the distinct patterns of genetic assocn. of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint assocn. of both enzymes and unrelated MHC-I alleles influence different pathol. outcomes.
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41. 41
  Infantes, S.; Samino, Y.; Lorente, E.; Jimenez, M.; Garcia, R.; Del Val, M.; Lopez, D. Cutting Edge: H-2L(d) Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing. J. Immunol. 2010, 184 (7), 3351– 3355, DOI: 10.4049/jimmunol.0901560
  41
  Cutting Edge: H-2Ld Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing
  Infantes, Susana; Samino, Yolanda; Lorente, Elena; Jimenez, Mercedes; Garcia, Ruth; Del Val, Margarita; Lopez, Daniel
  Journal of Immunology (2010), 184 (7), 3351-3355CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
  In the classical MHC class I Ag presentation pathway, antigenic peptides derived from viral proteins by multiple proteolytic cleavages are transported to the endoplasmic reticulum lumen and are then exposed to aminopeptidase activity. In the current study, a long MHC class I natural ligand recognized by cytotoxic T lymphocytes was used to study the kinetics of degrdn. by aminopeptidase. The in vitro data indicate that this N-extended peptide is efficiently trimmed to a 9-mer, unless its binding to the MHC mols. protects the full-length peptide.
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42. 42
  Thomas, C.; Tampe, R. MHC I chaperone complexes shaping immunity. Curr. Opin. Immunol. 2019, 58, 9– 15, DOI: 10.1016/j.coi.2019.01.001
  42
  MHC I chaperone complexes shaping immunity
  Thomas, Christoph; Tampe, Robert
  Current Opinion in Immunology (2019), 58 (), 9-15CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
  Major histocompatibility complex class I (MHC I) mols. present peptides on the surface of most nucleated cells and allow the immune system to detect and eliminate infected or malignantly transformed cells. The peptides are derived from endogenous proteins by proteasomal degrdn. or aberrant translation, and are translocated from the cytosol into the endoplasmic reticulum (ER) by the transporter assocd. with antigen processing (TAP), a central component of the peptide-loading complex (PLC). The peptides are subsequently processed by ER-resident aminopeptidases (ERAP1/2) and loaded onto MHC I. This loading, however, does not happen indiscriminately: in a process called peptide editing or peptide proofreading, the MHC I-specific chaperones tapasin and TAPBPR (TAP-binding protein-related) catalyze the selection of high-affinity peptides and stable peptide-MHC I (pMHC I) complexes. Once correctly loaded with a high-affinity peptide, pMHC I complexes travel to the cell surface where they are recognized by T lymphocytes to control their differentiation in the thymus, their priming in the lymph node, and their final long-term surveillance of target cells in the periphery. Recent structural studies of the PLC and of TAPBPR-MHC I complexes by single-particle cryo-electron microscopy, X-ray crystallog., and NMR spectroscopy have provided fundamental insights into the mechanisms of MHC I peptide loading and proofreading, highlighting the dynamic nature of the involved complexes and the conformational plasticity of the individual proteins.
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43. 43
  Chen, H.; Li, L.; Weimershaus, M.; Evnouchidou, I.; van Endert, P.; Bouvier, M. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Sci. Rep. 2016, 6, 28902, DOI: 10.1038/srep28902
  43
  ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing
  Chen, Hanna; Li, Lenong; Weimershaus, Mirjana; Evnouchidou, Irini; van Endert, Peter; Bouvier, Marlene
  Scientific Reports (2016), 6 (), 28902CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
  The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biol. of antigen presentation. To date, the mol. context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a mol. mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens.
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44. 44
  Mavridis, G.; Arya, R.; Domnick, A.; Zoidakis, J.; Makridakis, M.; Vlahou, A.; Mpakali, A.; Lelis, A.; Georgiadis, D.; Tampe, R.; Papakyriakou, A.; Stern, L. J.; Stratikos, E. A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1. J. Biol. Chem. 2020, 295 (21), 7193– 7210, DOI: 10.1074/jbc.RA120.012976
  44
  A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1
  Mavridis, George; Arya, Richa; Domnick, Alexander; Zoidakis, Jerome; Makridakis, Manousos; Vlahou, Antonia; Mpakali, Anastasia; Lelis, Angelos; Georgiadis, Dimitris; Tampe, Robert; Papakyriakou, Athanasios; Stern, Lawrence J.; Stratikos, Efstratios
  Journal of Biological Chemistry (2020), 295 (21), 7193-7211CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
  Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) mols. and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in soln. and in preformed MHCI-peptide complexes, but which mode is more relevant to its biol. function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in soln. or when bound to three MHCI alleles, HLA-B*58, HLA-B*08, and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12-mer progressed at a considerable rate, albeit still slower than in soln. Results from thermodn., kinetic, and computational analyses suggested that this 12-mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissocn. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from preformed MHCI complexes as efficiently as ERAP1. A pseudopeptide analog with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1/MHCI/peptide complex. Similarly, no interactions between ERAP1 and purified peptide-loading complex were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degrdn. and that trimming in soln. along with the dynamic nature of peptide binding to MHCI are sufficient to explain ERAP1 processing of antigenic peptide precursors.
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  Perez-Riverol, Y.; Csordas, A.; Bai, J.; Bernal-Llinares, M.; Hewapathirana, S.; Kundu, D. J.; Inuganti, A.; Griss, J.; Mayer, G.; Eisenacher, M.; Perez, E.; Uszkoreit, J.; Pfeuffer, J.; Sachsenberg, T.; Yilmaz, S.; Tiwary, S.; Cox, J.; Audain, E.; Walzer, M.; Jarnuczak, A. F.; Ternent, T.; Brazma, A.; Vizcaino, J. A. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 2019, 47 (D1), D442– D450, DOI: 10.1093/nar/gky1106
  45
  The PRIDE database and related tools and resources in 2019: improving support for quantification data
  Perez-Riverol, Yasset; Csordas, Attila; Bai, Jingwen; Bernal-Llinare, Manuel; Hewapathirana, Suresh; Kundu, Deepti J.; Iuganti, Avinash; Griss, Johannes; Mayer, Gerhard; Eisenacher, Martin; Perez, Enrique; Uszkoreit, Julian; Pfeuffer, Julianus; Sachsenberg, Timo; Yilmaz, Sule; Tiwary, Shivani; Cox, Jurgen; Audain, Enrique; Walzer, Mathias; Jarnuczak, Andrew F.; Ternent, Tobias; Brazma, Alvis; Vizcaino, Juan Antonio
  Nucleic Acids Research (2019), 47 (D1), D442-D450CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
  A review. The PRoteomics IDEntifications (PRIDE) database is the world's largest data repository of mass spectrometry-based proteomics data, and is one of the founding members of the global ProteomeXchange (PX) consortium. In this manuscript, we summarize the developments in PRIDE resources and related tools since the previous update manuscript was published in Nucleic Acids Research in 2016. In the last 3 years, public data sharing through PRIDE (as part of PX) has definitely become the norm in the field. In parallel, data re-use of public proteomics data has increased enormously, with multiple applications. We first describe the new architecture of PRIDE Archive, the archival component of PRIDE. PRIDE Archive and the related data submission framework have been further developed to support the increase in submitted data vols. and addnl. data types. A new scalable and fault tolerant storage backed, Application Programming Interface and web interface have been implemented, as a part of an ongoing process. Addnl., we emphasize the improved support for quant. proteomics data through the mzTab format. At last, we outline key statistics on the current data contents and vol. of downloads, and how PRIDE data are starting to be disseminated to added-value resources including Ensembl, UniProt and Expression Atlas.
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Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00457.
- Table S1: List of generated peptides after digestion by each enzyme (XLSX)
- Table S2: List of generated 8–11mers from each enzyme with best predicted binding score based on the HLAthena server (XLSX)
- Table S3: Predicted binding score of peptides from the S1 spike glycoprotein of SARS-CoV-2 for HLA-B15:03 and HLA-B46:01, based on the HLAthena prediction server; in red, the peptides that are predicted to be binders (XLSX)
- Table S4: List of potential epitopes from the sequence of the S1 spike glycoprotein of SARS-CoV-2 predicted using the NetMHCpan 4.1 server (XLSX)
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Generation of SARS-CoV-2 S1 Spike Glycoprotein Putative Antigenic Epitopes in Vitro by Intracellular Aminopeptidases
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