Misfolded proteins bind and activate death receptor 5 to induce apoptosis during unresolved endoplasmic reticulum stress

  1. Mable Lam
  2. Scot A Marsters
  3. Avi Ashkenazi  Is a corresponding author
  4. Peter Walter  Is a corresponding author
  1. Howard Hughes Medical Institute , University of California, San Francisco, United States
  2. Genentech, Inc, United States

Abstract

Disruption of protein folding in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)—a signaling network that ultimately determines cell fate. Initially, UPR signaling aims at cytoprotection and restoration of ER homeostasis; that failing, it drives apoptotic cell death. ER stress initiates apoptosis through intracellular activation of death receptor 5 (DR5) independent of its canonical extracellular ligand TRAIL; however, the mechanism underlying DR5 activation is unknown. In cultured human cells, we find that misfolded proteins can directly engage with DR5 in the ER-Golgi intermediate compartment, where DR5 assembles pro-apoptotic caspase 8-activating complexes. Moreover, peptides used as a proxy for exposed misfolded protein chains selectively bind to the purified DR5 ectodomain and induce its oligomerization. These findings indicate that misfolded proteins can act as ligands to activate DR5 intracellularly and promote apoptosis. We propose a model in which cells use DR5 as a terminal protein-folding checkpoint before committing to a terminal apoptotic fate.

Data availability

All data have been reported in the manuscript and supporting files. Source data files have been provided in all figures.

Article and author information

Author details

  1. Mable Lam

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute , 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:" 0000-0001-7016-2257
  2. Scot A Marsters

    Cancer Immunology, Genentech, Inc, South San Francisco, United States
    Competing interests
    Scot A Marsters, is affiliated with Genentech Inc. The author has no other competing interests to declare.
  3. Avi Ashkenazi

    Cancer Immunology, Genentech, Inc, South San Francisco, United States
    For correspondence
    ashkenazi.avi@gene.com
    Competing interests
    Avi Ashkenazi, is affiliated with Genentech Inc. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6890-4589
  4. Peter Walter

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute , University of California, San Francisco, San Francisco, United States
    For correspondence
    peter@walterlab.ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

Funding

National Science Foundation (Graduate Research Fellowship)

  • Mable Lam

Howard Hughes Medical Institute

  • Peter Walter

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

Reviewing Editor

  1. D Thomas Rutkowski, University of Iowa Carver College of Medicine, United States

Publication history

  1. Received: September 28, 2019
  2. Accepted: January 3, 2020
  3. Accepted Manuscript published: January 6, 2020 (version 1)
  4. Version of Record published: February 25, 2020 (version 2)

Copyright

© 2020, Lam 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. Mable Lam
  2. Scot A Marsters
  3. Avi Ashkenazi
  4. Peter Walter
(2020)
Misfolded proteins bind and activate death receptor 5 to induce apoptosis during unresolved endoplasmic reticulum stress
eLife 9:e52291.
https://doi.org/10.7554/eLife.52291

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