1. Biochemistry and Chemical Biology
  2. Cell Biology

Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether

  1. Sandra Elizabeth Torres
  2. Ciara M Gallagher
  3. Lars Plate
  4. Meghna Gupta
  5. Christina R Liem
  6. Xiaoyan Guo
  7. Ruilin Tian
  8. Robert M Stroud
  9. Martin Kampmann
  10. Jonathan S Weissman  Is a corresponding author
  11. Peter Walter  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Vanderbilt University, United States
https://doi.org/10.7554/eLife.46595
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Cite this article
  1. Sandra Elizabeth Torres
  2. Ciara M Gallagher
  3. Lars Plate
  4. Meghna Gupta
  5. Christina R Liem
  6. Xiaoyan Guo
  7. Ruilin Tian
  8. Robert M Stroud
  9. Martin Kampmann
  10. Jonathan S Weissman
  11. Peter Walter
(2019)
Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether
eLife 8:e46595.
https://doi.org/10.7554/eLife.46595
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  3. Download .RIS

Abstract

The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity. Ceapins specifically inhibit the UPR sensor ATF6α, an ER-tethered transcription factor, by retaining it at the ER through an unknown mechanism. Our genome-wide CRISPR interference (CRISPRi) screen reveals that Ceapins function is completely dependent on the ABCD3 peroxisomal transporter. Proteomics studies establish that ABCD3 physically associates with ER-resident ATF6α in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6α to ABCD3's transmembrane regions without inhibiting or depending on ABCD3 transporter activity. Thus, our studies reveal that Ceapins function by chemical-induced misdirection which explains their remarkable specificity and opens up new mechanistic routes for drug development and synthetic biology.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

  1. Sandra Elizabeth Torres

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Ciara M Gallagher

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Lars Plate

    Department of Chemistry, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Meghna Gupta

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Christina R Liem

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Xiaoyan Guo

    Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ruilin Tian

    Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Robert M Stroud

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Martin Kampmann

    Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3819-7019

  10. Jonathan S Weissman

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    For correspondence
    Jonathan.Weissman@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2445-670X

  11. Peter Walter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    peter@walterlab.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

Funding

Howard Hughes Medical Institute

  • Jonathan S Weissman
  • Peter Walter

National Institutes of Health (GM111126)

  • Robert M Stroud

National Institutes of Health (DP2 OD021007)

  • Martin Kampmann

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

Copyright

© 2019, Torres 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. Sandra Elizabeth Torres
  2. Ciara M Gallagher
  3. Lars Plate
  4. Meghna Gupta
  5. Christina R Liem
  6. Xiaoyan Guo
  7. Ruilin Tian
  8. Robert M Stroud
  9. Martin Kampmann
  10. Jonathan S Weissman
  11. Peter Walter
(2019)
Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether
eLife 8:e46595.
https://doi.org/10.7554/eLife.46595

Share this article

https://doi.org/10.7554/eLife.46595

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