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Diabetes. 2017 Sep;66(9):2446-2458. doi: 10.2337/db16-1252. Epub 2017 Jun 30.

MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic β-Cells.

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Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium.
Department of Clinical and Experimental Medicine, Islet Laboratory, University of Pisa, Pisa, Italy.
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Australia.
Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium


Induction of endoplasmic reticulum stress and activation of the intrinsic apoptotic pathway is widely believed to contribute to β-cell death in type 1 diabetes (T1D). MCL-1 is an antiapoptotic member of the BCL-2 protein family, whose depletion causes apoptosis in rodent β-cells in vitro. Importantly, decreased MCL-1 expression was observed in islets from patients with T1D. We report here that MCL-1 downregulation is associated with cytokine-mediated killing of human β-cells, a process partially prevented by MCL-1 overexpression. By generating a β-cell-specific Mcl-1 knockout mouse strain (βMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. β-Cells from βMcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, βMcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3β, the E3 ligases MULE and βTrCP, and the deubiquitinase USP9x regulate cytokine-mediated MCL-1 protein turnover in rodent β-cells. Our results identify MCL-1 as a critical prosurvival protein for preventing β-cell death and clarify the mechanisms behind its downregulation by proinflammatory cytokines. Development of strategies to prevent MCL-1 loss in the early stages of T1D may enhance β-cell survival and thereby delay or prevent disease progression.

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