RGD Reference Report - Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. - Rat Genome Database

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Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells.

Authors: Fonseca, SG  Ishigaki, S  Oslowski, CM  Lu, S  Lipson, KL  Ghosh, R  Hayashi, E  Ishihara, H  Oka, Y  Permutt, MA  Urano, F 
Citation: Fonseca SG, etal., J Clin Invest. 2010 Mar;120(3):744-55. doi: 10.1172/JCI39678. Epub 2010 Feb 15.
RGD ID: 10047363
Pubmed: PMID:20160352   (View Abstract at PubMed)
PMCID: PMC2827948   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI39678   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of ATF6-mediated unfolded protein response involved_inIGIUniProtKB:G3V90910047363PMID:20160352ParkinsonsUK-UCL 
negative regulation of transcription by RNA polymerase II involved_inIMP 10047363PMID:20160352ParkinsonsUK-UCL 
protein stabilization involved_inIMP 10047363PMID:20160352ParkinsonsUK-UCL 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
DNA-binding transcription factor binding enablesIPIUniProtKB:G3V90910047363PMID:20160352ParkinsonsUK-UCL 
proteasome binding enablesIDA 10047363PMID:20160352ParkinsonsUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Wfs1  (wolframin ER transmembrane glycoprotein)

Objects referenced in this article
Gene Atf6 activating transcription factor 6 Rattus norvegicus

Additional Information