Walter Lab

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    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
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Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis.

Lu M, Lawrence D, Marsters S, Acosta-Alvear D, Kimmig P, Mendez A, Paton A, Paton J, Walter P, Ashkenazi A. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 345:98-101, 2014
(PMCID : PMC4163648) (PMID : 24994655) (PDF)

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.


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