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

Induction of endoplasmic reticulum stress and activation of the intrinsic apoptotic pathway is widely believed to contribute to beta-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 beta-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 beta-cells, a process partially prevented by MCL-1 overexpression. By generating a beta-cell-specific Mcl-1 knockout mouse strain (beta Mcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. beta-Cells from beta Mcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, beta Mcl-1KO mice displayed higher hyperglycemia and lower pancreatic insulin content after multiple low-dose streptozotocin treatment. We found that the kinase GSK3 beta, the E3 ligases MULE and bTrCP, and the deubiquitinase USP9x regulate cytokine-mediated MCL-1 protein turnover in rodent beta-cells. Our results identify MCL-1 as a critical prosurvival protein for preventing beta-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 beta-cell survival and thereby delay or prevent disease progression.