MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic β-Cells

Meyerovich, Kira; Violato, Natalia Moretti; Fukaya, Makiko; Dirix, Violette; Pachera, Nathalie; Marselli, Lorella; Marchetti, Piero; Strasser, Andreas; Eizirik, Décio L.; Cardozo, Alessandra K

doi:10.2337/db16-1252

Cited by 24 publications

(22 citation statements)

References 45 publications

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“…7c). Control experiments with the same cytokine concentrations and combinations as by 36 reduced significantly MCL-1 protein expression (data not shown), thus confirming earlier observations. Thus, a moderate expression of MCPIP1 correlated with a strong expression of the antiapoptotic protein MCL-1.…”

Section: Resultssupporting

confidence: 89%

“…Protein expression was estimated by Western blotting ( n = 4). Cytokine-mediated cell death was analyzed by PI staining, a well-established method of human beta-cell death measurement 35,36 . NFκB activation was measured by a SEAP-reporter gene assay.…”

Section: Resultsmentioning

confidence: 99%

“…MCL-1 is one of the most important antiapoptotic proteins in beta-cells 36 . The gene expression of Mcl1 was increased by IL-1β alone and the cytokine mixture in insulin-secreting INS1E cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity

et al. 2019

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The autoimmune-mediated beta-cell death in type 1 diabetes (T1DM) is associated with local inflammation (insulitis). We examined the role of MCPIP1 (monocyte chemotactic protein–induced protein 1), a novel cytokine-induced antiinflammatory protein, in this process. Basal MCPIP1 expression was lower in rat vs. human islets and beta-cells. Proinflammatory cytokines stimulated MCPIP1 expression in rat and human islets and in insulin-secreting cells. Moderate overexpression of MCPIP1 protected insulin-secreting INS1E cells against cytokine toxicity by a mechanism dependent on the presence of the PIN/DUB domain in MCPIP1. It also reduced cytokine-induced Chop and C/ebpβ expression and maintained MCL-1 expression. The shRNA-mediated suppression of MCPIP1 led to the potentiation of cytokine-mediated NFκB activation and cytokine toxicity in human EndoC-βH1 beta-cells. MCPIP1 expression was very high in infiltrated beta-cells before and after diabetes manifestation in the LEW.1AR1-iddm rat model of human T1DM. The extremely high expression of MCPIP1 in clonal beta-cells was associated with a failure of the regulatory feedback-loop mechanism, ER stress induction and high cytokine toxicity. In conclusion, our data indicate that the expression level of MCPIP1 affects the susceptibility of insulin-secreting cells to cytokines and regulates the mechanism of beta-cell death in T1DM.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity

et al. 2019

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“…The deubiquitinase USP9X stabilizes both MCL-1 [ 140 , 141 , 142 ] and BECLIN 1 [ 140 ] and protects them against polyubiquitiation and proteasomal degradation. MCL-1 is ubiquitinated with a Lys48-linked chain by the E3 enzyme MUEL25 [ 143 , 144 ].…”

Section: Regulation Of Beclin 1 Via Distinct Ubiquitination Machinmentioning

confidence: 99%

Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades

Boutouja

Brinkmeier

Mastalski

et al. 2017

IJMS

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Autophagy contributes to cellular homeostasis through the degradation of various intracellular targets such as proteins, organelles and microbes. This relates autophagy to various diseases such as infections, neurodegenerative diseases and cancer. A central component of the autophagy machinery is the class III phosphatidylinositol 3-kinase (PI3K-III) complex, which generates the signaling lipid phosphatidylinositol 3-phosphate (PtdIns3P). The catalytic subunit of this complex is the lipid-kinase VPS34, which associates with the membrane-targeting factor VPS15 as well as the multivalent adaptor protein BECLIN 1. A growing list of regulatory proteins binds to BECLIN 1 and modulates the activity of the PI3K-III complex. Here we discuss the regulation of BECLIN 1 by several different types of ubiquitination, resulting in distinct polyubiquitin chain linkages catalyzed by a set of E3 ligases. This contribution is part of the Special Issue “Ubiquitin System”.

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“…The most promising gene associated with regulatory function of the lead SNP rs111776337 in the 1q21.3 locus is MCL1, a key anti-apoptotic protein in human beta-cells 15,16 . Apoptosis is one mechanism the host utilizes to eliminate virus-infected cells and is the main form of cell death in type 1 diabetes 17 .…”

Section: Discussionmentioning

confidence: 99%

Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

Önengüt-Gümüşcü

Paila

Chen

et al. 2020

Sci Rep

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Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10–8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.

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MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic β-Cells

Cited by 24 publications

References 45 publications

MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity

MCPIP1 regulates the sensitivity of pancreatic beta-cells to cytokine toxicity

Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades

Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

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