Program in Gene Function and Expression; Program in Molecular Medicine
Medical Subject Headings
Activating Transcription Factor 6; Animals; COS Cells; Calmodulin-Binding Proteins; Cell Line, Tumor; Cercopithecus aethiops; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Insulin-Secreting Cells; Membrane Proteins; Mice; Proteasome Endopeptidase Complex; Rats; Signal Transduction; Trans-Activators; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Unfolded Protein Response; Wolfram Syndrome
Genetics and Genomics
Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.
Rights and Permissions
Published in Volume 120, Issue 3 (March 1, 2010) J Clin Invest. 2010;120(3):744–755. doi:10.1172/JCI39678. Copyright © 2010, American Society for Clinical Investigation. Link to article on publisher's website