Misfolded proteins bind and activate death receptor 5 to induce apoptosis during unresolved endoplasmic reticulum stress
- Howard Hughes Medical Institute , University of California, San Francisco, United States
- 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.
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All data have been reported in the manuscript and supporting files. Source data files have been provided in all figures.
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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.
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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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
