Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress.
Mable LamScot A MarstersAvi AshkenaziPeter WalterPublished in: eLife (2020)
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 Apo2L/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 that cells can use DR5 as a late protein-folding checkpoint before committing to a terminal apoptotic fate.
Keyphrases
- cell death
- endoplasmic reticulum stress
- cell cycle arrest
- endoplasmic reticulum
- induced apoptosis
- editorial comment
- oxidative stress
- amino acid
- protein protein
- binding protein
- cell fate
- anti inflammatory
- single molecule
- estrogen receptor
- molecular dynamics simulations
- breast cancer cells
- dna damage
- cell cycle
- endothelial cells
- small molecule
- reactive oxygen species