Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Deconvoluting Stress-Responsive Proteostasis Signaling Pathways for Pharmacologic Activation Using Targeted RNA Sequencing

  • Julia M. D. Grandjean
    Julia M. D. Grandjean
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States
  • Lars Plate
    Lars Plate
    Department of Molecular Medicine  and  Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
    More by Lars Plate
  • Richard I. Morimoto
    Richard I. Morimoto
    Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, United States
  • Michael J. Bollong
    Michael J. Bollong
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
  • Evan T. Powers
    Evan T. Powers
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
  • , and 
  • R. Luke Wiseman*
    R. Luke Wiseman
    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, United States
    *Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037. E-mail: [email protected]. Phone: (858) 784-8820.
Cite this: ACS Chem. Biol. 2019, 14, 4, 784–795
Publication Date (Web):March 1, 2019
https://doi.org/10.1021/acschembio.9b00134
Copyright © 2019 American Chemical Society

    Article Views

    1914

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (5)»

    Abstract

    Abstract Image

    Cellular proteostasis is maintained by stress-responsive signaling pathways such as the heat shock response (HSR), the oxidative stress response (OSR), and the unfolded protein response (UPR). Activation of these pathways results in the transcriptional upregulation of select subsets of stress-responsive genes that restore proteostasis and adapt cellular physiology to promote recovery following various types of acute insult. The capacity for these pathways to regulate cellular proteostasis makes them attractive therapeutic targets for correcting proteostasis defects associated with diverse diseases. High-throughput screening (HTS) using cell-based reporter assays is highly effective for identifying putative activators of stress-responsive signaling pathways. However, the development of these compounds is hampered by the lack of medium-throughput assays to define compound potency and selectivity for a given pathway. Here, we describe a targeted RNA sequencing (RNAseq) assay that allows cost-effective, medium-throughput screening of stress-responsive signaling pathway activation. We demonstrate that this assay allows deconvolution of stress-responsive signaling activated by chemical genetic or pharmacologic agents. Furthermore, we use this assay to define the selectivity of putative OSR and HSR activating compounds previously identified by HTS. Our results demonstrate the potential for integrating this adaptable targeted RNAseq assay into screening programs focused on developing pharmacologic activators of stress-responsive signaling pathways.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.9b00134.

    • Supplemental experimental procedures, figure legends for Figures S1–S7, Figures S1–S7, supplemental table legends for Tables S1–S5, and Table S3 (PDF)

    • Table S1 (XLSX)

    • Table S2 (XLSX)

    • Table S4 (XLSX)

    • Table S5 (XLSX)

    Terms & Conditions

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

    Cited By

    This article is cited by 27 publications.

    1. Jonathan P. Davies, Athira Sivadas, Katherine R. Keller, Brynn K. Roman, Richard J.H. Wojcikiewicz, Lars Plate. Expression of SARS-CoV-2 Nonstructural Proteins 3 and 4 Can Tune the Unfolded Protein Response in Cell Culture. Journal of Proteome Research 2024, 23 (1) , 356-367. https://doi.org/10.1021/acs.jproteome.3c00600
    2. Gabriel M. Kline, Ryan J. Paxman, Chung-Yon Lin, Nicole Madrazo, Leonard Yoon, Julia M. D. Grandjean, Kyunga Lee, Karina Nugroho, Evan T. Powers, R. Luke Wiseman, Jeffery W. Kelly. Divergent Proteome Reactivity Influences Arm-Selective Activation of the Unfolded Protein Response by Pharmacological Endoplasmic Reticulum Proteostasis Regulators. ACS Chemical Biology 2023, 18 (8) , 1719-1729. https://doi.org/10.1021/acschembio.3c00042
    3. Jessica D. Rosarda, Kelsey R. Baron, Kayla Nutsch, Gabriel M. Kline, Caroline Stanton, Jeffery W. Kelly, Michael J. Bollong, R. Luke Wiseman. Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2. ACS Chemical Biology 2021, 16 (12) , 2852-2863. https://doi.org/10.1021/acschembio.1c00810
    4. Nicole Madrazo, Zinia Khattar, Evan T. Powers, Jessica D. Rosarda, R. Luke Wiseman, . Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations. Molecular Biology of the Cell 2024, https://doi.org/10.1091/mbc.E24-01-0041
    5. Jessica D. Rosarda, Sarah Giles, Sarah Harkins-Perry, Elizabeth A. Mills, Martin Friedlander, R. Luke Wiseman, Kevin T. Eade. Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-39775-w
    6. Eun-Jin Lee, Monica S. Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego A. Valdez Duran, Julia M. Grandjean, R. Luke Wiseman, Heike Kroeger, Jonathan H. Lin. Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss. The American Journal of Pathology 2023, 193 (11) , 1721-1739. https://doi.org/10.1016/j.ajpath.2022.12.002
    7. Valerie Perea, Kelsey R. Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D. Rosarda, Xiaoyan Guo, Martin Kampmann, R. Luke Wiseman. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells. Cell Chemical Biology 2023, 97 https://doi.org/10.1016/j.chembiol.2023.10.006
    8. Sabrina Ghosh, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Devin Kenney, Carly S. Golden, Camille V. Edwards, Vaishali Sanchorawala, Lawreen H. Connors, Richard M. Giadone, George J. Murphy. Mapping cellular response to destabilized transthyretin reveals cell- and amyloidogenic protein-specific signatures. Amyloid 2023, 30 (4) , 379-393. https://doi.org/10.1080/13506129.2023.2224494
    9. Joseph C. Genereux. Profiling protein targets of cellular toxicant exposure. Molecular Omics 2023, 19 (3) , 191-204. https://doi.org/10.1039/D2MO00246A
    10. Aparajita Madhavan, Bernard P. Kok, Bibiana Rius, Julia M. D. Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan T. Powers, Andrea Galmozzi, Enrique Saez, R. Luke Wiseman. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nature Communications 2022, 13 (1) https://doi.org/10.1038/s41467-022-28271-2
    11. Frédéric Anglès, Chao Wang, William E. Balch. Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03302-2
    12. Joseph E. Kaserman, Rhiannon B. Werder, Feiya Wang, Taylor Matte, Michelle I. Higgins, Mark Dodge, Jonathan Lindstrom-Vautrin, Pushpinder Bawa, Anne Hinds, Esther Bullitt, Ignacio S. Caballero, Xu Shi, Robert E. Gerszten, Nicola Brunetti-Pierri, Marc Liesa, Carlos Villacorta-Martin, Anthony N. Hollenberg, Darrell N. Kotton, Andrew A. Wilson. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity. Cell Reports 2022, 41 (10) , 111775. https://doi.org/10.1016/j.celrep.2022.111775
    13. Marie Pariollaud, Lara H. Ibrahim, Emanuel Irizarry, Rebecca M. Mello, Alanna B. Chan, Brian J. Altman, Reuben J. Shaw, Michael J. Bollong, R. Luke Wiseman, Katja A. Lamia. Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras -driven lung cancer. Science Advances 2022, 8 (39) https://doi.org/10.1126/sciadv.abo1123
    14. Chengcheng Shi, Faming Zhao, Tingting Zhang, Denghui Xu, Zhuangyu Hao, Fengzhen Cui, Ji‐Hua Shi, Yang Jin, Ningning Li, Caihong Yang, Yi Zhang, Xia Sheng. A novel prognostic signature in osteosarcoma characterised from the perspective of unfolded protein response. Clinical and Translational Medicine 2022, 12 (3) https://doi.org/10.1002/ctm2.750
    15. Jimin Yoon, Emmanuel E. Nekongo, Jessica E. Patrick, Tiffani Hui, Angela M. Phillips, Anna I. Ponomarenko, Samuel J. Hendel, Rebecca M. Sebastian, Yu Meng Zhang, Vincent L. Butty, C. Brandon Ogbunugafor, Yu-Shan Lin, Matthew D. Shoulders, . The endoplasmic reticulum proteostasis network profoundly shapes the protein sequence space accessible to HIV envelope. PLOS Biology 2022, 20 (2) , e3001569. https://doi.org/10.1371/journal.pbio.3001569
    16. Heike Kroeger, Julia M. D. Grandjean, Wei-Chieh Jerry Chiang, Daphne D. Bindels, Rebecca Mastey, Jennifer Okalova, Amanda Nguyen, Evan T. Powers, Jeffery W. Kelly, Neil J. Grimsey, Michel Michaelides, Joseph Carroll, R. Luke Wiseman, Jonathan H. Lin. ATF6 is essential for human cone photoreceptor development. Proceedings of the National Academy of Sciences 2021, 118 (39) https://doi.org/10.1073/pnas.2103196118
    17. Kevin M. Tharp, Ryo Higuchi-Sanabria, Greg A. Timblin, Breanna Ford, Carlos Garzon-Coral, Catherine Schneider, Jonathon M. Muncie, Connor Stashko, Joseph R. Daniele, Andrew S. Moore, Phillip A. Frankino, Stefan Homentcovschi, Sagar S. Manoli, Hao Shao, Alicia L. Richards, Kuei-Ho Chen, Johanna ten Hoeve, Gregory M. Ku, Marc Hellerstein, Daniel K. Nomura, Karou Saijo, Jason Gestwicki, Alexander R. Dunn, Nevan J. Krogan, Danielle L. Swaney, Andrew Dillin, Valerie M. Weaver. Adhesion-mediated mechanosignaling forces mitohormesis. Cell Metabolism 2021, 33 (7) , 1322-1341.e13. https://doi.org/10.1016/j.cmet.2021.04.017
    18. Madison T. Wright, Lars Plate. Revealing functional insights into ER proteostasis through proteomics and interactomics. Experimental Cell Research 2021, 399 (1) , 112417. https://doi.org/10.1016/j.yexcr.2020.112417
    19. Katherine M. Almasy, Jonathan P. Davies, Samantha M. Lisy, Reyhaneh Tirgar, Sirena C. Tran, Lars Plate. Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections. Proceedings of the National Academy of Sciences 2021, 118 (3) https://doi.org/10.1073/pnas.2012209118
    20. Sybil C.L. Hrstka, Soneela Ankam, Busranur Agac, Jon P. Klein, Raymond A. Moore, Bhavya Narapureddy, Isabella Schneider, Ronald F. Hrstka, Surendra Dasari, Nathan P. Staff. Proteomic analysis of human iPSC-derived sensory neurons implicates cell stress and microtubule dynamics dysfunction in bortezomib-induced peripheral neurotoxicity. Experimental Neurology 2021, 335 , 113520. https://doi.org/10.1016/j.expneurol.2020.113520
    21. Katherine M. Almasy, Jonathan P. Davies, Lars Plate. Comparative Host Interactomes of the SARS-CoV-2 Nonstructural Protein 3 and Human Coronavirus Homologs. Molecular & Cellular Proteomics 2021, 20 , 100120. https://doi.org/10.1016/j.mcpro.2021.100120
    22. Julia M.D. Grandjean, R.Luke Wiseman. Small molecule strategies to harness the unfolded protein response: where do we go from here?. Journal of Biological Chemistry 2020, 295 (46) , 15692-15711. https://doi.org/10.1074/jbc.REV120.010218
    23. Julia M. D. Grandjean, Aparajita Madhavan, Lauren Cech, Bryan O. Seguinot, Ryan J. Paxman, Emery Smith, Louis Scampavia, Evan T. Powers, Christina B. Cooley, Lars Plate, Timothy P. Spicer, Jeffery W. Kelly, R. Luke Wiseman. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nature Chemical Biology 2020, 16 (10) , 1052-1061. https://doi.org/10.1038/s41589-020-0584-z
    24. Lara Ibrahim, Jaleh Mesgarzadeh, Ian Xu, Evan T. Powers, R. Luke Wiseman, Michael J. Bollong. Defining the Functional Targets of Cap‘n’collar Transcription Factors NRF1, NRF2, and NRF3. Antioxidants 2020, 9 (10) , 1025. https://doi.org/10.3390/antiox9101025
    25. Kanagaraj Subramanian, Darren M. Hutt, Samantha M. Scott, Vijay Gupta, Shu Mao, William E. Balch. Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid. Journal of Biological Chemistry 2020, 295 (23) , 8017-8035. https://doi.org/10.1074/jbc.RA119.010524
    26. Eun-Jin Lee, Wei-Chieh Jerry Chiang, Heike Kroeger, Chloe Xiaoke Bi, Daniel L. Chao, Dorota Skowronska-Krawczyk, Rebecca R. Mastey, Stephen H. Tsang, Leon Chea, Kyle Kim, Scott R. Lambert, Julia M.D. Grandjean, Britta Baumann, Isabelle Audo, Susanne Kohl, Anthony T. Moore, R. Luke Wiseman, Joseph Carroll, Jonathan H. Lin. Multiexon deletion alleles of ATF6 linked to achromatopsia. JCI Insight 2020, 5 (7) https://doi.org/10.1172/jci.insight.136041
    27. Colin D. Gottlieb, Airlia C.S. Thompson, Alban Ordureau, J. Wade Harper, Ron R. Kopito. Acute unfolding of a single protein immediately stimulates recruitment of ubiquitin protein ligase E3C (UBE3C) to 26S proteasomes. Journal of Biological Chemistry 2019, 294 (45) , 16511-16524. https://doi.org/10.1074/jbc.RA119.009654