Title
WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells
GSBS Program
Biochemistry & Molecular Pharmacology
UMMS Affiliation
Graduate School of Biomedical Sciences; Program in Gene Function and Expression; Program in Molecular Medicine
Date
10-1-2005
Document Type
Article
Medical Subject Headings
Animals; COS Cells; Cell Line; Cercopithecus aethiops; Endoplasmic Reticulum; Endoribonucleases; Homeostasis; Humans; Insulin-Secreting Cells; Membrane Proteins; Mice; Models, Biological; Mutation; Protein Folding; Protein-Serine-Threonine Kinases; RNA, Messenger; Rats; Signal Transduction; Wolfram Syndrome
Disciplines
Life Sciences | Medicine and Health Sciences
Abstract
In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic beta-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying beta-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1.
Rights and Permissions
Citation: J Biol Chem. 2005 Nov 25;280(47):39609-15. Epub 2005 Sep 29. Link to article on publisher's site