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 b-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 cytokinemediated killing of human b-cells, a process partially prevented by MCL-1 overexpression. By generating a b-cell-specific Mcl-1 knockout mouse strain (bMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. β-Cells from bMcl-1KO mice were, however, more susceptible to cytokineinduced apoptosis. Moreover, bMcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3b, the E3 ligases MULE and bTrCP, and the deubiquitinase USP9x regulate cytokinemediated MCL-1 protein turnover in rodent b-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.

MCL-1 is a key antiapoptotic protein in human and rodent pancreatic β-cells

Marselli, Lorella;Marchetti, Piero;
2017-01-01

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 b-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 cytokinemediated killing of human b-cells, a process partially prevented by MCL-1 overexpression. By generating a b-cell-specific Mcl-1 knockout mouse strain (bMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. β-Cells from bMcl-1KO mice were, however, more susceptible to cytokineinduced apoptosis. Moreover, bMcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3b, the E3 ligases MULE and bTrCP, and the deubiquitinase USP9x regulate cytokinemediated MCL-1 protein turnover in rodent b-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.
2017
Meyerovich, Kira; Violato, Natalia M.; Fukaya, Makiko; Dirix, Violette; Pachera, Nathalie; Marselli, Lorella; Marchetti, Piero; Strasser, Andreas; Eizirik, Decio L.; Cardozo, Alessandra K.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/879877
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