Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival.

ABSTRACT: Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding ?-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal ?-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to ?-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM ?-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control ?-cell survival and function primarily through preservation of ER homeostasis.

SUBMITTER: Abreu D 

PROVIDER: S-EPMC7286786 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature