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MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes

Abstract

Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and strategies to prevent beta cell apoptosis and dysfunction are urgently needed. Here, we identified mammalian sterile 20–like kinase-1 (MST1) as a critical regulator of apoptotic beta cell death and function. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes.

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Figure 1: MST1 is activated in diabetes.
Figure 2: MST1 induces beta cell death.
Figure 3: MST1 impairs beta cell function by destabilizing PDX1.
Figure 4: MST1 deficiency improves beta cell survival and function.
Figure 5: Mst1 deletion protects from diabetes in vivo.
Figure 6: Beta cell–specific disruption of Mst1 prevents hyperglycemia and HFD-induced diabetes progression.

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Acknowledgements

This work was supported by the JDRF, the German Research Foundation (Emmy Noether Programm MA4172/1-1), the European Research Council, the German Federal Ministry of Science (Diabetes Competence Network), the European Federation for the Study of Diabetes and University of Bremen Research Funds (all to K.M.). We thank J. Bergemann for excellent technical assistance, G. Dharmadhikari and M. Panse for help with the analyses and G. Rutter and D. Schumann for critical discussion. Human islets were provided through the Juvenile Diabetes Research Foundation award 31-2008-413 (European Consortium for Islet Transplantation Islets for Basic Research Program) and by the Integrated Islet Distribution Program. Human pancreatic sections were obtained from the National Disease Research Interchange, which is supported by the US National Institutes of Health. MST1 and dn-MST1 plasmids and adenoviruses were provided by J. Sadoshima and Y. Maejima (Rutgers New Jersey Medical School), PDX1-WT plasmids and pGEX bacterial expression vector by R. Walther (University of Greifswald), INS-1E cells by C. Wollheim (Lund and Geneva Universities), RIP-Cre mice by P. Herrera (University of Geneva) and A. Mansouri (Max Planck Institute for Biophysical Chemistry), mouse pB.RSV.PDX1-GFP plasmid by I. Leibiger (Karolinska University) and rat insulin-2 promoter plasmid by R. Zinkernagel (University of Zurich). Adenovirus carrying eGFP as a control was provided by A.E. Karlsen (Novo Nordisk A/S).

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A.A. conceived of the project, designed all and performed most of the experiments, analyzed the data and wrote the paper. F. Paroni provided experimental and technical support and analyzed data. Z.A., S.K., V.K. and T.Y. performed experiments and analyzed data. T.F. provided mutated PDX1 plasmids, W.T. provided Mst1−/− and Mst1fl/fl mice and J.K.C., F. Pattou and J.O. isolated human islets. K.M. supervised the project and wrote the paper.

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Correspondence to Amin Ardestani or Kathrin Maedler.

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Ardestani, A., Paroni, F., Azizi, Z. et al. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nat Med 20, 385–397 (2014). https://doi.org/10.1038/nm.3482

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