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

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

SUBMITTER: Juan-Mateu J 

PROVIDER: S-EPMC5828453 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature