title: A siRNA screen reveals the prosurvival effect of protein kinase A activation in conditions of unresolved endoplasmic reticulum stress.
abstract: The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis- or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear. We performed a siRNA-based screen to identify new regulators of ER stress-induced death and found that repression of the Carney complex-associated protein PRKAR1A specifically protected the cells from ER stress-induced apoptosis, and not from apoptosis induced by etoposide or TNF. We demonstrate that the protection results from PKA activation and associate it, at least in part, with the phosphorylation-mediated inhibition of the PKA substrate Drp1 (dynamin-related protein 1). Our results therefore provide new information on the complex regulation of cellular death under ER stress conditions and bring new insights on the conditions that regulate the pro- versus anti-death functions of PKA.
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: M A
authors.initials: MA
authors.lastname: Aguileta
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Rojas-Rivera
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Goossens
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Estornes
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: G
authors.identifier: 0000-0001-6626-1316
authors.initials: G
authors.lastname: Van Isterdael
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: P
authors.identifier: 0000-0002-6669-8822
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Inflammation Research Center, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.|Department of Biomedical Molecular Biology, VIB, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
authors.forename: M J M
authors.initials: MJ
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005820:Genetic Testing; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D034741:RNA, Small Interfering; D017868:Cyclic AMP-Dependent Protein Kinases; C486391:Dnm1l protein, mouse; D034281:Dynamins