期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 23, 页码 12040-12056出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.704619
关键词
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资金
- Juvenile Diabetes Research Foundation International Grant [17-2013-515]
- NIDDK, Human Islet Research, National Institutes of Health Network Consortium [1UC4DK104166-01]
- Fund for Scientific Research Flanders (FWO) [1522313N]
- European Union
- Actions de Recherche Concertee de la Communaute Francaise
- Fonds National de la Recherche Scientifique, Belgium
- Ghent University GROUP-ID Multidisciplinary Research Platform
- Katholieke Universiteit Leuven
- Seventh Framework Program of the European Union NAIMIT
- Innovative Medicines Initiative 2 Joint Undertaking [115797]
- Union's Horizon research and innovation program
- EFPIA
- JDRF
- The Leona M. and Harry B. Helmsley Charitable Trust
- ERC
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 IRE1 alpha is critical for this transition. IRE1 alpha activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1 alpha-interacting protein ubiquitin D (UBD) on the regulation of IRE1 alpha and its downstream targets. UBD was identified by use of a MAPPIT (mammalian protein-protein interaction trap)-based IRE1 alpha interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knockdown ofUBDin human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/IRE1 alpha activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma 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 IRE1 alpha in human and rodent beta cells, modulating IRE1 alpha-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1 alpha/JNK pro-apoptotic pathway in cytokine-exposed beta cells.
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