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 ...
    • 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)
    • Vascular Malformations (Apr 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
Reversible cold-induced lens opacity in a hibernator reveals a molecular target for treating cataracts
Hao Yang, … , Wei Li, Xingchao Shentu
Hao Yang, … , Wei Li, Xingchao Shentu
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(18):e169666. https://doi.org/10.1172/JCI169666.
View: Text | PDF
Research Article Ophthalmology

Reversible cold-induced lens opacity in a hibernator reveals a molecular target for treating cataracts

  • Text
  • PDF
Abstract

Maintaining protein homeostasis (proteostasis) requires precise control of protein folding and degradation. Failure to properly respond to stresses disrupts proteostasis, which is a hallmark of many diseases, including cataracts. Hibernators are natural cold-stress adaptors; however, little is known about how they keep a balanced proteome under conditions of drastic temperature shift. Intriguingly, we identified a reversible lens opacity phenotype in ground squirrels (GSs) associated with their hibernation-rewarming process. To understand this “cataract-reversing” phenomenon, we first established induced lens epithelial cells differentiated from GS-derived induced pluripotent stem cells, which helped us explore the molecular mechanism preventing the accumulation of protein aggregates in GS lenses. We discovered that the ubiquitin-proteasome system (UPS) played a vital role in minimizing the aggregation of the lens protein αA-crystallin (CRYAA) during rewarming. Such function was, for the first time to our knowledge, associated with an E3 ubiquitin ligase, RNF114, which appears to be one of the key mechanisms mediating the turnover and homeostasis of lens proteins. Leveraging this knowledge gained from hibernators, we engineered a deliverable RNF114 complex and successfully reduced lens opacity in rats with cold-induced cataracts and zebrafish with oxidative stress–related cataracts. These data provide new insights into the critical role of the UPS in maintaining proteostasis in cold and possibly other forms of stresses. The newly identified E3 ubiquitin ligase RNF114, related to CRYAA, offers a promising avenue for treating cataracts with protein aggregates.

Authors

Hao Yang, Xiyuan Ping, Jiayue Zhou, Hailaiti Ailifeire, Jing Wu, Francisco M. Nadal-Nicolás, Kiyoharu J. Miyagishima, Jing Bao, Yuxin Huang, Yilei Cui, Xin Xing, Shiqiang Wang, Ke Yao, Wei Li, Xingchao Shentu

×

Figure 2

Efficient differentiation of GS iPSCs into GS iLECs.

Options: View larger image (or click on image) Download as PowerPoint
Efficient differentiation of GS iPSCs into GS iLECs.
(A) Schematic repre...
(A) Schematic representation of the 4-stage differentiation protocol from GS iPSCs to lens bodies (LBs). GS iLECs were obtained at the end of stage 3, and underwent 1 mechanical passaging during the transition from stage 3 to stage 4. (B) Cellular morphology at different stages of differentiation under a Leica optical microscope. Scale bar: 20 μm. Red arrows and dashed lines indicate LB-like structures during differentiation. (C) Immunofluorescence images showing the intracellular localization of fluorescently labeled characteristic proteins NANOG, CRYAA, SIX1, TFAP2A, PAX6, CRYAB, and CRYBB2 at different stages of differentiation. Scale bar: 60 μm. (D) qPCR analysis was conducted to assess the expression levels of stage-specific proteins and the impact of different differentiation protocols on the expression levels of each stage-specific protein (n = 3 independent experiments). (E) Proportion of CRYAA-positive cells detected by flow cytometry in GS iPSCs and GS iLECs (n = 3 independent experiments).

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

Sign up for email alerts