Progressive failure of insulin-producing beta cells is the central event leading to diabetes, but the signalling 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 function and survival of human beta cells. RNA-seq analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion and JNK signalling. Specifically, SRp55-mediated splicing changes modulate the function of the pro-apoptotic proteins BIM and BAX, JNK signalling and endoplasmic reticulum stress, explaining why SRp55 depletion triggers beta cell apoptosis. Furthermore, SRp55 depletion inhibits beta cell mitochondrial 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 crosstalk with candidate genes for diabetes.

SRp55 Regulates a Splicing Network that Controls Human Pancreatic Beta Cell Function and Survival

Bugliani, Marco;Marchetti, Piero;
2018-01-01

Abstract

Progressive failure of insulin-producing beta cells is the central event leading to diabetes, but the signalling 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 function and survival of human beta cells. RNA-seq analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion and JNK signalling. Specifically, SRp55-mediated splicing changes modulate the function of the pro-apoptotic proteins BIM and BAX, JNK signalling and endoplasmic reticulum stress, explaining why SRp55 depletion triggers beta cell apoptosis. Furthermore, SRp55 depletion inhibits beta cell mitochondrial 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 crosstalk with candidate genes for diabetes.
2018
Juan-Mateu, Jonàs; Alvelos, Maria Inês; Turatsinze, Jean-Valéry; Villate, Olatz; Lizarraga-Mollinedo, Esther; Grieco, Fabio Arturo; Marroquí, Laura; Bugliani, Marco; Marchetti, Piero; Eizirik, Décio L.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/890521
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