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Science. 2014 Jul 4;345(6192):98-101. doi: 10.1126/science.1254312.

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

Author information

1
Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2
Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
3
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia.
4
Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA. peter@walterlab.ucsf.edu aa@gene.com.
5
Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. peter@walterlab.ucsf.edu aa@gene.com.

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.

Comment in

PMID:
24994655
PMCID:
PMC4284148
DOI:
10.1126/science.1254312
[Indexed for MEDLINE]
Free PMC Article
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