PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway.

ABSTRACT:

Objective

Loss-of-function mutations in Perk (EIF2AK3) result in permanent neonatal diabetes in humans (Wolcott-Rallison Syndrome) and mice. Previously, we found that diabetes associated with Perk deficiency resulted from insufficient proliferation of beta-cells and from defects in insulin secretion. A substantial fraction of PERK-deficient beta-cells display a highly abnormal cellular phenotype characterized by grossly distended endoplasmic reticulum (ER) and retention of proinsulin. We investigated over synthesis, lack of ER-associated degradation (ERAD), and defects in ER to Golgi trafficking as possible causes.

Research design and methods

ER functions of PERK were investigated in cell culture and mice in which Perk was impaired or gene dosage modulated. The Ins2(+/Akita)

SUBMITTER: Gupta S 

PROVIDER: S-EPMC2911049 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature