title: 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.
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Amin
authors.initials: A
authors.lastname: Ardestani
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Paroni
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Azizi
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Supreet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Vrushali
authors.initials: V
authors.lastname: Khobragade
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Ting
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Beta-cell Regeneration, Hagedorn Research Institute, Gentofte, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Frogne
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China.
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
authors.affiliation: Division of Transplantation, University of Illinois at Chicago, IL, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Thérapie Cellulaire du Diabète, INSERM /Université de Lille Nord de France, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Thérapie Cellulaire du Diabète, INSERM /Université de Lille Nord de France, France.
authors.forename: Julie Kerr
authors.initials: JK
authors.lastname: Conte
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D003920:Diabetes Mellitus / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D000099317:Hippo Kinases
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D018398:Homeodomain Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C095566:STK4 protein, human