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.