MCL-1 is a key anti-apoptotic protein in human and rodent pancreatic beta-cells
Meyerovich, K; Violato, NM; Fukaya, M; Dirix, V; Pachera, N; Marselli, L; Marchetti, P; Strasser, A; Eizirik, DL; Cardozo, AK
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 anti-apoptotic 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 T1D patients. 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 (betaMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. beta-cells from betaMcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, betaMcl-1KO mice displayed higher hyperglycaemia and lower pancreatic insulin content after multiple low dose streptozotocin treatment. We found that the kinase GSK3beta, the E3 ligases MULE and betaTrCP and the deubiquitinase USP9x, regulate cytokine-mediated MCL-1 protein turnover in rodent beta-cells. Our results identify MCL-1 as a critical pro-survival protein for preventing beta-cell death and clarify the mechanisms behind its downregulation by pro-inflammatory 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.