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https://hdl.handle.net/2440/87066
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Type: | Journal article |
Title: | Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis |
Author: | Lu, M. Lawrence, D. Marsters, S. Acosta-Alvear, D. Kimmig, P. Mendez, A. Paton, A. Paton, J. Walter, P. Ashkenazi, A. |
Citation: | Science, 2014; 345(6192):98-101 |
Publisher: | American Association for the Advancement of Science |
Issue Date: | 2014 |
ISSN: | 0036-8075 1095-9203 |
Statement of Responsibility: | Min Lu, David A. Lawrence, Scot Marsters, Diego Acosta-Alvear, Philipp Kimmig, Aaron S. Mendez, Adrienne W. Paton, James C. Paton, Peter Walter, Avi Ashkenazi |
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. |
Keywords: | HCT116 Cells Animals Mice, Inbred C57BL Humans Mice Endoribonucleases Caspases RNA, Messenger Ligands Apoptosis RNA Stability Transcription Factor CHOP Receptors, TNF-Related Apoptosis-Inducing Ligand Unfolded Protein Response Endoplasmic Reticulum Stress Protein Serine-Threonine Kinases |
Rights: | © 2014 American Association for the Advancement of Science. All Rights Reserved. |
DOI: | 10.1126/science.1254312 |
Published version: | http://dx.doi.org/10.1126/science.1254312 |
Appears in Collections: | Aurora harvest 7 Molecular and Biomedical Science publications |
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