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

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Progressive failure of insulin-producing beta-cells is central to diabetes pathogenesis.
• Signaling networks governing beta-cell fate and function are not fully understood.

Purpose of the Study:

• To investigate the role of the splicing factor SRp55 in human beta-cell function and survival.
• To elucidate the molecular mechanisms by which SRp55 influences beta-cell fate.

Main Methods:

• RNA sequencing to identify SRp55-regulated genes.
• Analysis of gene splicing patterns in human beta-cells.
• Functional assays assessing beta-cell apoptosis, insulin secretion, and mitochondrial function.

Main Results:

• SRp55 regulates splicing of genes critical for beta-cell survival, death, insulin secretion, and c-Jun N-terminal kinase (JNK) signaling.
• SRp55 depletion leads to beta-cell apoptosis via modulation of BIM, BAX, JNK signaling, and endoplasmic reticulum stress.
• SRp55 deficiency impairs beta-cell mitochondrial function, reducing insulin release.

Conclusions:

• Alternative splicing, modulated by SRp55, represents a novel regulatory layer for human beta-cell function and survival.
• SRp55's role links splicing regulation to diabetes susceptibility genes like GLIS3 and beta-cell dysfunction.