Journal
DIABETES
Volume 67, Issue 3, Pages 423-436Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0736
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Funding
- Fonds National de la Recherche Scientifique Belgique (FNRS) [CR-2015A-06]
- Horizon Framework Programme [GA667191]
- National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases
- Human Islet Research Network Consortium [1UC4DK104166-01]
- H Marie Sklodowska-Curie Actions fellowship [660449]
- FNRS [26410496]
- Innovative Medicines Initiative 2 Joint Undertaking [115797]
- European Union's Horizon research and innovation programme
- European Federation of Pharmaceutical Industries and Associations
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [UC4DK104166] Funding Source: NIH RePORTER
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Progressive failure of insulin-producing beta-cells is the central event leading to diabetes, but the signaling networks controlling beta-cell fate remain poorly understood. Here we show that SRp55, a splicing factor regulated by the diabetes susceptibility gene GLIS3, has a major role in maintaining the function and survival of human beta-cells. RNA sequencing analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion, and c-Jun N-terminal kinase (JNK) signaling. In particular, SRp55-mediated splicing changes modulate the function of the proapoptotic proteins BIM and BAX, JNK signaling, and endoplasmic reticulum stress, explaining why SRp55 depletion triggers beta-cell apoptosis. Furthermore, SRp55 depletion inhibits beta-cellmitochondrial function, explaining the observed decrease in insulin release. These data unveil a novel layer of regulation of human beta-cell function and survival, namely alternative splicing modulated by key splicing regulators such as SRp55, that may cross talk with candidate genes for diabetes.
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