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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.

Author information

1
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium deizirik@ulb.ac.be mjuanmat@ulb.ac.be.
2
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
3
Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, Pisa, Italy.
4
WELBIO, Université Libre de Bruxelles, Brussels, Belgium.

Abstract

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.

PMID:
29246973
PMCID:
PMC5828453
[Available on 2019-03-01]
DOI:
10.2337/db17-0736
[Indexed for MEDLINE]
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