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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-09, Vol.134 (18), p.1-14
Main Authors: Yang, Hao, Ping, Xiyuan, Zhou, Jiayue, Ailifeire, Hailaiti, Wu, Jing, Nadal-Nicolás, Francisco M, Miyagishima, Kiyoharu J, Bao, Jing, Huang, Yuxin, Cui, Yilei, Xing, Xin, Wang, Shiqiang, Yao, Ke, Li, Wei, Shentu, Xingchao
Format: Article
Language:English
Subjects:
Cataracts
Cell differentiation
Cold
Crystallin
Epithelial cells
Hibernation
Homeostasis
Hypothermia
Metabolism
Molecular modelling
Oxidative stress
Phenotypes
Pluripotency
Proteasomes
Protein folding
Proteomes
Quality control
Stem cells
Temperature requirements
Ubiquitin-protein ligase
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Summary: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 aA-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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI169666.