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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.

Author information

1
Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
2
Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium.
3
Department of Clinical and Experimental Medicine, Islet Laboratory, University of Pisa, Pisa, Italy.
4
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
5
Department of Medical Biology, University of Melbourne, Parkville, Australia.
6
Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium akupperc@ulb.ac.be.

Abstract

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.

PMID:
28667119
DOI:
10.2337/db16-1252
[Indexed for MEDLINE]
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