Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis.

TitleOpposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsLu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, Paton AW, Paton JC, Walter P, Ashkenazi A
Date Published2014 Jul 4
KeywordsAnimals, Apoptosis, Caspases, Endoplasmic Reticulum Stress, Endoribonucleases, HCT116 Cells, Humans, Ligands, Mice, Mice, Inbred C57BL, Protein-Serine-Threonine Kinases, Receptors, TNF-Related Apoptosis-Inducing Ligand, RNA Stability, RNA, Messenger, Transcription Factor CHOP, Unfolded Protein Response

Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

Alternate JournalScience
PubMed ID24994655
PubMed Central IDPMC4284148
Grant ListR01 GM032384 / GM / NIGMS NIH HHS / United States
T32 GM064337 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States