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J Biol Chem. 2016 Jun 3;291(23):12040-56. doi: 10.1074/jbc.M115.704619. Epub 2016 Apr 4.

Ubiquitin D Regulates IRE1α/c-Jun N-terminal Kinase (JNK) Protein-dependent Apoptosis in Pancreatic Beta Cells.

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From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
the Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology (VIB), 9000 Ghent, Belgium, the Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
the Laboratory of Clinical and Experimental Endocrinology, KULeuven, 3000 Leuven, Belgium, and.
the Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
From the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium,


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.


IRE1α; apoptosis; c-Jun N-terminal kinase (JNK); cytokinesis; endoplasmic reticulum stress (ER stress); type 1 diabetes; ubiquitin D

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