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MST1 Is a Key Regulator of Beta Cell Apoptosis and Dysfunction in Diabetes

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MST1 Is a Key Regulator of Beta Cell Apoptosis and Dysfunction in Diabetes ARTICLES MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes Amin Ardestani1, Federico Paroni1,6, Zahra Azizi1,6, Supreet Kaur1,6, Vrushali Khobragade1, Ting Yuan1, Thomas Frogne2, Wufan Tao3, Jose Oberholzer4, Francois Pattou5, Julie Kerr Conte5 & Kathrin Maedler1 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. Pancreatic beta cell death is the fundamental cause of type 1 diabetes of events, which makes the initiation of beta cell death complex and (T1D) and a contributing factor to the reduced beta cell mass in type 2 its blockade difficult to successfully achieve in vivo. Therefore, the diabetes (T2D)1–4. In both cases, the mechanisms of beta cell death identification of a common key regulator of beta cell apoptosis would are complex and as yet not fully defined. Thus, multiple triggering offer a new therapeutic target for the treatment of diabetes. factors have been identified; these factors initiate a variety of signal- The identification of the genes that regulate apoptosis has laid the ing cascades that affect the expression of apoptotic genes, leading foundation for the discovery of new drug targets. MST1 (also known Nature America, Inc. All rights reserved. America, Inc. Nature 4 to subsequent beta cell failure. In T1D, autoimmune destruction of as STK4 and KRS2) is a ubiquitously expressed serine-threonine kinase insulin-producing beta cells and critically diminished beta cell mass that is part of the Hippo signaling pathway and involved in multiple 2 © 201 are hallmarks of the disease . Beta cell destruction occurs through cellular processes such as morphogenesis, proliferation, stress response immune-mediated processes; mononuclear cell infiltration in the and apoptosis8,9. MST1 is a target and activator of caspases, serving pancreatic islets and interaction between antigen-presenting cells and to amplify the apoptotic signaling pathway10,11. Thr183 in subdomain T cells lead to high local concentrations of inflammatory cytokines, VIII of MST1 has been defined as a primary site for the phosphoactiva- npg chemokines, reactive oxygen species and other apoptotic triggers (for tion and the autophosphorylation of MST1 and is essential for kinase example, the perforin and Fas–Fas ligand systems)2. In T2D, beta cell activation. Both phosphorylation and caspase-mediated cleavage are dysfunction and reduced beta cell mass are the ultimate events leading required for full activation of MST1 during apoptosis. MST1 promotes to the development of clinically overt disease in insulin-resistant indi- cell death through regulation of multiple downstream targets such as viduals. Beta cell destruction is caused by multiple stimuli including LATS1 and LATS2, histone H2B and members of the FOXO family, glucotoxicity, lipotoxicity, proinflammatory cytokines, endoplasmic as well as through induction of stress kinase c-Jun-N-terminal kinase reticulum stress and oxidative stress5. Unfortunately, although it (JNK) and activation of caspase-3 (refs. 9,12,13). has been demonstrated that even a small amount of preserved Genetic mutations and/or metabolic disturbances can alter protein endogenous insulin secretion has great benefits in terms of clinical networks and thereby disrupt downstream signaling pathways that outcome6, none of the currently widely used antidiabetic agents are essential for beta cell survival and function. The transcription target the maintenance of endogenous beta cell mass. factor pancreatic duodenal homeobox-1 (PDX1, previously called Beta cells are highly sensitive to apoptotic damages induced by multi- IPF1, IDX1, STF1 or IUF1)14,15 is a key mediator of beta cell ple stressors such as inflammatory and oxidative assault, owing at least development and function16. In humans, mutations in the PDX1 in part to their low expression of cytoprotective enzymes7. The initial gene can predispose individuals to develop maturity onset diabetes of trigger of beta cell death still remains unclear; it follows an orchestra the young, type 4 (MODY 4)17, suggesting a critical role for PDX1 in 1Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany. 2Department of Incretin & Islet Biology, Novo Nordisk A/S, Denmark. 3State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China. 4Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA. 5INSERM U859 Biotherapies for Diabetes, European Genomic Institute for Diabetes, Lille Regional Hospital Center, University of Lille, Lille, France. 6These authors contributed equally to this work. Correspondence should be addressed to K.M. ([email protected]) or A.A. ([email protected]). Received 5 December 2013; accepted 21 January 2014; published online 16 March 2014; doi:10.1038/nm.3482 NATURE MEDICINE VOLUME 20 | NUMBER 4 | APRIL 2014 385 A RTICLES mature beta cells; reduced PDX1 expression affects insulin production were inhibited by LY294002, and triciribine (an AKT inhibitor) led and secretion and predisposes to beta cell apoptosis16,18. to lower levels of phosphorylation of Gsk3 and Foxo1, two well- Because MST1 acts as common mediator in multiple apoptotic characterized AKT substrates, and induced MST1 activation (Fig. 1g,h signaling pathways, we hypothesized that it is an initiating trigger of and Supplementary Fig. 2e). We further corroborated these find- apoptotic signaling in beta cells. MST1 depletion completely restored ings using siRNA against AKT, which led to a critical upregulation normogylcemia and insulin secretion and prevented diabetes progres- of MST1 activity and potentiated cytokine-induced phosphoryla- sion. These findings suggest that MST1 could be a fundamental target tion of MST1 and beta cell death (Supplementary Fig. 2f). MST1 for diabetes therapy. overexpression also diminished insulin-induced AKT phosphor- ylation and, conversely, there was higher AKT phosphorylation in RESULTS MST1-depleted beta cells (Fig. 1i). Knockdown of MST1 expression MST1 is activated in diabetes antagonized the apoptotic effect of AKT inactivation in INS-1E cells, To test whether MST1 activation is correlated with beta cell apopto- implicating endogenous MST1 in the apoptotic mechanism induced sis, we exposed isolated human and mouse islets and the rat beta cell by PI3K-AKT inhibition (Supplementary Fig. 2g,h). In summary, line INS-1E to a complex diabetogenic milieu. MST1 activity was these results suggest that MST1 is activated in prodiabetic conditions highly upregulated in these cells under these conditions (created in vitro and in vivo, antagonized by PI3K-AKT signaling and depend- through incubation with the cytokines interleukin-1β (IL-1β) and ent on the JNK- and caspase-induced apoptotic machinery. interferon-γ (IFN-γ) (IL/IF), upon chronic exposure to increasing glucose concentrations (22.2 and 33.3 mM) or palmitic acid, or upon MST1 induces beta cell death exposure to acute oxidative stress from hydrogen peroxide) (Fig. 1a–c MST1 overexpression alone was also sufficient to induce apoptosis and Supplementary Fig. 1a,b). The upregulation of MST1 occurred in human and rat beta cells (Fig. 2a–c). To investigate pathways that by both caspase-mediated cleavage and autophosphorylation (yield- potentially contribute to MST1-induced beta cell apoptosis, we over- ing MST1 phosphorylated on T183 (pMST1)). This was accompanied expressed MST1 in human islets and rat INS-1E cells through an by higher phosphorylation of histone H2B as well as induction of adenoviral system, which efficiently upregulated MST1, activated JNK signaling (Fig. 1a–c). In contrast, short-term culture with high JNK and induced beta cell apoptosis, as determined by an increased glucose concentrations (11.2, 22.2 and 33.3 mM) induced neither number of TUNEL-positive beta cells as well as caspase-3 activation apoptosis nor MST1 cleavage and phosphorylation (Supplementary and cleavage of poly-(ADP-ribose) polymerase (PARP), a down- Fig. 1d). MST1 was also activated in islets from subjects with T2D stream substrate of caspase-3 (Fig. 2a–c). Previous data proposed (Fig. 1d), obese diabetic Leprdb mice (db/db mice, Fig. 1e) and a role for the mitochondrial pathway in MST-dependent signal- hyperglycemic mice fed with a high-fat, high-sucrose diet (HFD) for ing26,27. Evaluation of established mitochondrial proteins in MST1- 16 weeks (Supplementary
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