title: Ubiquitin D Regulates IRE1α/c-Jun N-terminal Kinase (JNK) Protein-dependent Apoptosis in Pancreatic Beta Cells.
abstract: Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1α is critical for this transition. IRE1α activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1α-interacting protein ubiquitin D (UBD) on the regulation of IRE1α and its downstream targets. UBD was identified by use of a MAPPIT (mammalian protein-protein interaction trap)-based IRE1α interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knockdown of UBD in human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/IRE1α activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1β and interferon (IFN)-γ in rat and human pancreatic beta cells, and it is also up-regulated in beta cells of inflamed islets from non-obese diabetic mice. UBD interacts with IRE1α in human and rodent beta cells, modulating IRE1α-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1α/JNK pro-apoptotic pathway in cytokine-exposed beta cells.
authors.affiliation: From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
authors.forename: Flora
authors.initials: F
authors.lastname: Brozzi
authors.affiliation: the Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), 9000 Ghent, Belgium, the Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
authors.affiliation: From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
authors.forename: Fabio Arturo
authors.initials: FA
authors.lastname: Grieco
authors.affiliation: From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
authors.forename: Matilda
authors.initials: M
authors.lastname: Juusola
authors.affiliation: From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
authors.forename: Alexander
authors.initials: A
authors.lastname: Balhuizen
authors.affiliation: the Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), 9000 Ghent, Belgium, the Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Lievens
authors.affiliation: the Laboratory of Clinical and Experimental Endocrinology, KULeuven, 3000 Leuven, Belgium, and.
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: the Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.affiliation: the Laboratory of Clinical and Experimental Endocrinology, KULeuven, 3000 Leuven, Belgium, and.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: the Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: the Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), 9000 Ghent, Belgium, the Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.affiliation: From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium, deizirik@ulb.ac.be.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; C109184:UBD protein, human; D014452:Ubiquitins; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
keywords: IRE1α; apoptosis; c-Jun N-terminal kinase (JNK); cytokinesis; endoplasmic reticulum stress (ER stress); type 1 diabetes; ubiquitin D