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Published on: May 2, 2019
MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic β-Cells
Kira Meyerovich1, Natalia M Violato1, Makiko Fukaya1
1Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
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.
Insights
MCL-1 protein is crucial for preventing beta-cell death in type 1 diabetes (T1D). Lowering MCL-1 levels makes beta-cells vulnerable to inflammatory cytokines, highlighting potential therapeutic targets.
Area of Science:
- Cell Biology
- Immunology
- Endocrinology
Background:
- Endoplasmic reticulum stress and apoptosis contribute to beta-cell death in type 1 diabetes (T1D).
- MCL-1, an antiapoptotic protein, is downregulated in T1D patient islets and its depletion induces apoptosis in rodent beta-cells.
- Cytokine-mediated killing of human beta-cells involves MCL-1 downregulation.
Purpose of the Study:
- To investigate the role of MCL-1 in beta-cell survival and its regulation by proinflammatory cytokines.
- To elucidate the mechanisms controlling MCL-1 protein turnover in beta-cells.
- To assess the therapeutic potential of maintaining MCL-1 levels in T1D.
Main Methods:
- Generation of a beta-cell-specific Mcl-1 knockout mouse model (βMcl-1KO).
- Assessment of beta-cell apoptosis, islet function, and hyperglycemia in βMcl-1KO mice.
- Investigation of MCL-1 regulation by GSK3β, MULE, βTrCP, and USP9x in rodent beta-cells.
Main Results:
- MCL-1 ablation in beta-cells did not affect islet development or function but increased susceptibility to cytokine-induced apoptosis.
- βMcl-1KO mice exhibited exacerbated hyperglycemia and reduced insulin content post-streptozotocin treatment.
- Cytokine-mediated MCL-1 downregulation is regulated by the kinase GSK3β, E3 ligases MULE and βTrCP, and deubiquitinase USP9x.
Conclusions:
- MCL-1 is a critical prosurvival protein essential for protecting beta-cells from inflammatory damage in T1D.
- Understanding MCL-1 regulation by cytokines provides insights into beta-cell death mechanisms.
- Strategies to prevent MCL-1 loss could be beneficial for enhancing beta-cell survival and managing T1D progression.
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