UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date


Document Type



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.

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Copyright © 2010, American Society for Clinical Investigation. Link to article on publisher's website

DOI of Published Version



Published in Volume 120, Issue 3 (March 1, 2010). J Clin Invest. 2010;120(3):744–755. doi:10.1172/JCI39678.

Journal/Book/Conference Title

The Journal of clinical investigation

Related Resources

Link to article in PubMed

PubMed ID