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

TLDR

ER stress activates the unfolded protein response to restore homeostasis, but when it persists, it can trigger apoptosis, although the precise mechanisms are not fully understood. The study aimed to determine whether persistent ER stress induces apoptosis through UPR‑controlled activation of death receptor 5. ER stress upregulates DR5 transcription via CHOP, while IRE1α transiently degrades DR5 mRNA to allow a period of adaptation. The authors found that sustained ER stress accumulates DR5 protein, leading to ligand‑independent DR5 activation and caspase‑8–mediated apoptosis.

Abstract

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.