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
ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine
Varsha Venkatarangan, … , Si Houn Hahn, Ming Li
Varsha Venkatarangan, … , Si Houn Hahn, Ming Li
Published August 10, 2023
Citation Information: J Clin Invest. 2023;133(19):e169551. https://doi.org/10.1172/JCI169551.
View: Text | PDF
Research Article Cell biology Nephrology Article has an altmetric score of 87

ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

  • Text
  • PDF
Abstract

Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).

Authors

Varsha Venkatarangan, Weichao Zhang, Xi Yang, Jess Thoene, Si Houn Hahn, Ming Li

×

Figure 1

Identification of cystinosin(7Δ) as a rapidly degrading disease variant.

Options: View larger image (or click on image) Download as PowerPoint
Identification of cystinosin(7Δ) as a rapidly degrading disease variant....
(A) Topology map of cystinosin: cystinosin is a 7-transmembrane protein that contains a large lysosomal lumenal loop, 7 putative N-linked glycosylation sites (gold), an N-terminal signal peptide (red) and a C-terminal lysosome targeting motif (blue). The 7 amino acid deletion in Cystinosin(7Δ) is shown in black. (B) CHX chase was performed in cells stably expressing either cystinosin(7Δ)-GFP or WT cystinosin-GFP. Cystinosin-GFP appears predominantly as a band of apprpximately 100 kDa, which remains stable throughout the chase. Meanwhile, cystinosin(7Δ)-GFP is present as 4 bands and a free GFP band. Bands 1 and 3 degrade rapidly, whereas bands 2 and 4 are stable. (C) Quantification of the full-length cystinosin(7Δ)-GFP (band 1) and WT cystinosin-GFP in B. (D) Flow cytometry measurement of cystinosin(7Δ)-GFP fluorescence signal after 24 hours of CHX treatment. (E) CHX chase experiment in cells stably expressing untagged cystinosin(7Δ), probed with an endogenous cystinosin antibody. The bracket at approximately 75kDa highlights a small population of higher molecular weight species. (F) Quantification of band 1 in E. (G) CHX chase performed in patient fibroblasts homozygous for 7Δ. To ensure antibody specificity, a control fibroblast from a patient with CTNS deletion (57 kb genomic DNA deletion) was included. The bracket at approximately 75kDa highlights a small population of higher molecular weight species. Error bars indicate the SD. All quantifications and data analysis were performed based on 3 independent replicates.

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

Sign up for email alerts

Picked up by 11 news outlets
Blogged by 1
Posted by 9 X users
6 readers on Mendeley
See more details