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

Ardestani, Amin; Paroni, Federico; Azizi, Zahra; Kaur, Supreet; Khobragade, Vrushali; Yuan, Ting; Frogne, Thomas; Tao, Wufan; Oberholzer, Jose; Pattou, Francois; Kerr Conte, Julie; Maedler, Kathrin

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. © 2014 Nature America, Inc. All rights reserved.

Citation

Ardestani, A., Paroni, F., Azizi, Z., Kaur, S., Khobragade, V., Yuan, T., Frogne, T., Tao, W., Oberholzer, J., Pattou, F., Kerr Conte, J., & Maedler, K. (2014). MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nature Medicine, 20(4), 385-397. https://doi.org/10.1038/nm.3482

• Journal Article Type: Article
• Acceptance Date: Jan 21, 2014
• Online Publication Date: Mar 16, 2014
• Publication Date: Apr 1, 2014
• Deposit Date: Jan 4, 2024
• Journal: Nature Medicine
• Print ISSN: 1078-8956
• Electronic ISSN: 1546-170X
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 20
• Issue: 4
• Pages: 385-397
• DOI: https://doi.org/10.1038/nm.3482
• Public URL: https://hull-repository.worktribe.com/output/4461724