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Diabetes. 2018 Mar;67(3):423-436. doi: 10.2337/db17-0736. Epub 2017 Dec 15.

SRp55 Regulates a Splicing Network That Controls Human Pancreatic β-Cell Function and Survival.

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ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy.
WELBIO, Université Libre de Bruxelles, Brussels, Belgium.


Progressive failure of insulin-producing β-cells is the central event leading to diabetes, but the signaling networks controlling β-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 β-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 β-cell apoptosis. Furthermore, SRp55 depletion inhibits β-cell mitochondrial function, explaining the observed decrease in insulin release. These data unveil a novel layer of regulation of human β-cell function and survival, namely alternative splicing modulated by key splicing regulators such as SRp55, that may cross talk with candidate genes for diabetes.

[Available on 2019-03-01]
[Indexed for MEDLINE]
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