Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Metabolism

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

  • Text
  • PDF
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

×

Figure 7

WFS1 controls steady-state levels of ATF6α protein and activation.

Options: View larger image (or click on image) Download as PowerPoint
WFS1 controls steady-state levels of ATF6α protein and activation.
(A) I...
(A) In normal cells, WFS1 recruits the ER transcription factor ATF6α to the E3 ligase Hrd1 under non–ER stress conditions. Hrd1 marks ATF6α with ubiquitin for proteasomal degradation. Under ER stress, ATF6α dissociates from WFS1 and undergoes proteolysis, and its soluble aminoportion, p60ATF6α, translocates to the nucleus, where it upregulates ER stress target genes, such as BiP, CHOP, and XBP-1. At later time points, WFS1 is induced by ER stress, which causes the eventual degradation of ATF6α. (B) In patients with Wolfram syndrome or Wfs1–/– mice, ATF6α escapes from the proteasome-dependent degradation, leading to chronic hyperactivation of ATF6α signaling. This ATF6α hyperactivation is involved in apoptosis through apoptotic effectors of the UPR, such as CHOP.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts