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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Alternative Splicing*
  • Apoptosis*
  • Bcl-2-Like Protein 11 / genetics
  • Bcl-2-Like Protein 11 / metabolism*
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • Endoplasmic Reticulum Stress
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • MAP Kinase Signaling System
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • RNA Interference
  • Serine-Arginine Splicing Factors / antagonists & inhibitors
  • Serine-Arginine Splicing Factors / chemistry
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*


  • BAX protein, human
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Insulin
  • Phosphoproteins
  • SRSF6 protein, human
  • bcl-2-Associated X Protein
  • Serine-Arginine Splicing Factors