FADD phosphorylation impaired islet morphology and function.

Abstract

Previous studies have indicated that Fas-FasL pathway and its downstream caspase-8 can regulate islet mass and insulin secretion. As a classical adaptor in Fas-FasL signaling, Fas-associated death domain-containing protein (FADD) takes part in many non-apoptosis processes regulated by its phosphorylation. However, its role in islets has not been evaluated to date. Here, through comparative proteomics and bioinformatic analysis on FADD phosphorylated (FADD-D) and wild-type (WT) MEFs, we found three proteins involved in islet differentiation and function were dysregulated due to FADD phosphorylation. The mouse model of FADD-D, which mimics constitutive phosphorylated FADD expression in mice, was further analyzed to address this issue. We confirmed the proteomic results by immunohistological analyses on pancreatic islets. In addition, we found that FADD-D mice displayed decreased islet area, and the glucose stimulated insulin secretion (GSIS) of FADD-D islets was impaired. These data suggest a novel role of FADD in islet development and insulin secretion.