title: Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells.
abstract: 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.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Fonseca
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oslowski
authors.forename: Simin
authors.initials: S
authors.lastname: Lu
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lipson
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Ghosh
authors.forename: Emiko
authors.initials: E
authors.lastname: Hayashi
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D056811:Unfolded Protein Response; D014929:Wolfram Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D002148:Calmodulin-Binding Proteins; D008565:Membrane Proteins; D015534:Trans-Activators; D025801:Ubiquitin; C541096:WFS1 protein, rat; C114987:wolframin protein; C482345:SYVN1 protein, human; C498235:Syvn1 protein, mouse; C544172:Syvn1 protein, rat; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex