Publication Date:
2014-07-06
Description:
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 IRE1alpha 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284148/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284148/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Min -- Lawrence, David A -- Marsters, Scot -- Acosta-Alvear, Diego -- Kimmig, Philipp -- Mendez, Aaron S -- Paton, Adrienne W -- Paton, James C -- Walter, Peter -- Ashkenazi, Avi -- R01 GM032384/GM/NIGMS NIH HHS/ -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jul 4;345(6192):98-101. doi: 10.1126/science.1254312.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. ; 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. ; Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia. ; 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. ; Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. peter@walterlab.ucsf.edu aa@gene.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24994655" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
Caspases
;
Endoplasmic Reticulum Stress/genetics/*physiology
;
Endoribonucleases/metabolism
;
HCT116 Cells
;
Humans
;
Ligands
;
Mice
;
Mice, Inbred C57BL
;
Protein-Serine-Threonine Kinases/metabolism
;
RNA Stability
;
RNA, Messenger/metabolism
;
Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists/genetics/*physiology
;
Transcription Factor CHOP
;
*Unfolded Protein Response
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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