title: Opposing unfolded-protein-response signals converge on death receptor 5 to control 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.
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.affiliation: 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.
authors.forename: Diego
authors.initials: D
authors.lastname: Acosta-Alvear
authors.affiliation: 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.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kimmig
authors.affiliation: 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.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Mendez
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia.
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.affiliation: Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. peter@walterlab.ucsf.edu aa@gene.com.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D051742:Transcription Factor CHOP; D056811:Unfolded Protein Response
chemical_list: C497249:DDIT3 protein, human; D008024:Ligands; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C099217:CASP5 protein, human; D020169:Caspases