title: RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions.
abstract: Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)-a kinase at the crossroad between life and death downstream of various receptors-as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Estornes
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: M A
authors.initials: MA
authors.lastname: Aguileta
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Dubuisson
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: De Keyser
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Goossens
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Kersse
authors.affiliation: 1] Apoptosis Research Center, NUI Galway, Galway, Ireland [2] School of Natural Sciences, NUI Galway, Galway, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Samali
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: 1] VIB Inflammation Research Center, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: M J M
authors.initials: MJ
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics* / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; C507699:necrostatin-1; D014415:Tunicamycin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D004722:Endoribonucleases; D053181:Caspase 8; D004318:Doxycycline