Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Sorin V. Fedeles, … , Stefan Somlo, Ann-Hwee Lee
Sorin V. Fedeles, … , Stefan Somlo, Ann-Hwee Lee
Published April 6, 2015
Citation Information: J Clin Invest. 2015;125(5):1955-1967. https://doi.org/10.1172/JCI78863.
View: Text | PDF
Research Article Nephrology

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

  • Text
  • PDF
Abstract

The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.

Authors

Sorin V. Fedeles, Jae-Seon So, Amol Shrikhande, Seung Hun Lee, Anna-Rachel Gallagher, Christina E. Barkauskas, Stefan Somlo, Ann-Hwee Lee

×

Figure 5

SEC63 and XBP1 regulate autoproteolysis of EMR2 and CL1 adhesion GPCRs.

Options: View larger image (or click on image) Download as PowerPoint
SEC63 and XBP1 regulate autoproteolysis of EMR2 and CL1 adhesion GPCRs.
...
(A) WT and DKO cells were transfected with WT EMR2 and the cleavage-deficient S518A mutant, both with COOH-terminal myc epitope tags. (B) WT and DKO cells were transfected with CL1 and the ΔGPS cleavage–deficient mutant expression vectors with HA-epitope tags in the COOH terminus. Cell lysates were analyzed by immunoblotting. *Cell lines contained the Pkd1F/H-BAC and HA immunoblotting detected the PC1-CTF expressed in WT cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts