1. Biochemistry and Chemical Biology
  2. Cell Biology

Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response

  1. Carmela Sidrauski  Is a corresponding author
  2. Jordan C Tsai
  3. Martin Kampmann
  4. Brian R Hearn
  5. Punitha Vedantham
  6. Priyadarshini Jaishankar
  7. Masaaki Sokabe
  8. Aaron S Mendez
  9. Billy W Newton
  10. Edward L Tang
  11. Erik Verschueren
  12. Jeffrey R Johnson
  13. Nevan J Krogan
  14. Christopher S Fraser
  15. Jonathan S Weissman
  16. Adam R Renslo
  17. Peter Walter
  1. University of California, San Francisco, United States
  2. Howard Hughes Medical Institution, University of California, San Francisco, United States
  3. University of California, Davis, United States
https://doi.org/10.7554/eLife.07314
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Cite this article
  1. Carmela Sidrauski
  2. Jordan C Tsai
  3. Martin Kampmann
  4. Brian R Hearn
  5. Punitha Vedantham
  6. Priyadarshini Jaishankar
  7. Masaaki Sokabe
  8. Aaron S Mendez
  9. Billy W Newton
  10. Edward L Tang
  11. Erik Verschueren
  12. Jeffrey R Johnson
  13. Nevan J Krogan
  14. Christopher S Fraser
  15. Jonathan S Weissman
  16. Adam R Renslo
  17. Peter Walter
(2015)
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
eLife 4:e07314.
https://doi.org/10.7554/eLife.07314
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Abstract

The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate eIF2 serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, a potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function in rodents by blocking long-term depression. ISRIB was identified in a phenotypic cell-based screen, and its mechanism of action remained unknown. We now report that ISRIB is an activator of eIF2B. Our reporter-based shRNA screen revealed an eIF2B requirement for ISRIB activity. Our results define ISRIB as a symmetric molecule, show ISRIB-mediated stabilization of activated eIF2B dimers, and suggest that eIF2B4 (δ-subunit) contributes to the ISRIB binding site. We also developed new ISRIB analogs, improving its EC50 to 600 pM in cell culture. By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases.

Article and author information

Author details

  1. Carmela Sidrauski

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    carmelas@me.com
    Competing interests
    CS: Inventors on UC patent application PCT/US2014/029568. Title: Modulators of the eIF2a pathway.

  2. Jordan C Tsai

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5202-722X

  3. Martin Kampmann

    Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3819-7019

  4. Brian R Hearn

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    BRH: Inventors on UC patent application PCT/US2014/029568. Title: Modulators of the eIF2a pathway.

  5. Punitha Vedantham

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    PV: Inventors on UC patent application PCT/US2014/029568. Title: Modulators of the eIF2a pathway.

  6. Priyadarshini Jaishankar

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  7. Masaaki Sokabe

    Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.

  8. Aaron S Mendez

    Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  9. Billy W Newton

    QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  10. Edward L Tang

    QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  11. Erik Verschueren

    QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5842-6344

  12. Jeffrey R Johnson

    QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  13. Nevan J Krogan

    QB3, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  14. Christopher S Fraser

    Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.

  15. Jonathan S Weissman

    Howard Hughes Medical Institution, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  16. Adam R Renslo

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    ARR: Inventors on UC patent application PCT/US2014/029568. Title: Modulators of the eIF2a pathway.

  17. Peter Walter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    PW: Inventors on UC patent application PCT/US2014/029568. Title: Modulators of the eIF2a pathway.

Funding

Howard Hughes Medical Institute (HHMI)

  • Carmela Sidrauski
  • Jordan C Tsai
  • Martin Kampmann
  • Aaron S Mendez
  • Jonathan S Weissman
  • Peter Walter

The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2015, Sidrauski et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Carmela Sidrauski
  2. Jordan C Tsai
  3. Martin Kampmann
  4. Brian R Hearn
  5. Punitha Vedantham
  6. Priyadarshini Jaishankar
  7. Masaaki Sokabe
  8. Aaron S Mendez
  9. Billy W Newton
  10. Edward L Tang
  11. Erik Verschueren
  12. Jeffrey R Johnson
  13. Nevan J Krogan
  14. Christopher S Fraser
  15. Jonathan S Weissman
  16. Adam R Renslo
  17. Peter Walter
(2015)
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
eLife 4:e07314.
https://doi.org/10.7554/eLife.07314

Share this article

https://doi.org/10.7554/eLife.07314

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Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes

    Yao Liang Wong, Lauren LeBon ... Carmela Sidrauski
    Research Advance

    eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (Sidrauski et al., 2015). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR.