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Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells
Sonya G. Fonseca, … , M. Alan Permutt, Fumihiko Urano
Sonya G. Fonseca, … , M. Alan Permutt, Fumihiko Urano
Published February 15, 2010
Citation Information: J Clin Invest. 2010;120(3):744-755. https://doi.org/10.1172/JCI39678.
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Research Article Metabolism

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

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Abstract

Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of β 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 6α (ATF6α), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6α target genes and repressed ATF6α-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6α to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, β cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6α 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 β cell death in diabetes.

Authors

Sonya G. Fonseca, Shinsuke Ishigaki, Christine M. Oslowski, Simin Lu, Kathryn L. Lipson, Rajarshi Ghosh, Emiko Hayashi, Hisamitsu Ishihara, Yoshitomo Oka, M. Alan Permutt, Fumihiko Urano

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Figure 2

WFS1 regulates ATF6α protein levels.

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WFS1 regulates ATF6α protein levels.
(A) IB analysis measured ATF6α and ...
(A) IB analysis measured ATF6α and WFS1 levels in MIN6 cells expressing shGFP (control) or shWFS1, as well as in MIN6 cells expressing shWFS1 or expressing shWFS1 and rescued with WFS1 (n = 3). (B) IB analysis measuring ATF6α, WFS1, IRE1α, and PERK levels in INS1 832/13 cells (treated with 2 mM DTT for 3 hours) overexpressing GFP (control) or WFS1 (n = 3). (C) Quantitative real-time PCR analysis of BiP, total Xbp-1, Chop, Ero1-α, Glut2, and Ins2 mRNA levels in INS1 832/13 cells overexpressing GFP (control) or WFS1 (n = 3). (D) IB analysis of ATF6α and WFS1 in COS7 cells transfected with ATF6α-HA or ATF6α-HA and WFS1-FLAG at 2 different ratios, and in INS1 832/13 cells expressing inducible WFS1 and treated with or without MG132. (E) IB analysis of ATF6α and WFS1 in MIN6 cells expressing shWFS1 and transfected with WT WFS1-FLAG or mutant P724L WFS1-FLAG and G695V WFS1-FLAG (n = 3). (F) IB analysis measuring ATF6α and WFS1 levels in INS1 832/13 cells expressing WT WFS1 or P724L WFS1 (n = 3). (G) WFS1 was subjected to IP from COS7 cells expressing ATF6α-HA or ATF6α-HA with WT, P724L, or G695V WFS1-Flag using an anti-Flag antibody. IPs and input proteins were analyzed using anti-HA and anti-Flag antibodies. **P < 0.01.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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