In a recent study published in the Genes & Diseases journal, researchers from Sun Yat-sen University, Tongji University, Shanghai Engineering Research Center of Precise Diagnosis and Treatment of Eye Diseases, and University of California elucidated the functional significance of SUMOylation in lens capsular fibrosis.
Initial investigations revealed elevated global SUMOylation (SUMO1/2/3 conjugates) in human ASC specimens. Gain-of-function models showed that transient overexpression of individual SUMO paralogs (SUMO1/2/3) drives epithelial-to-mesenchymal transition (EMT) in human lens epithelial cells (LECs), by inducing a reduction in tight junction proteins (occludin and claudin-1), an increase in fibronectin and collagen type I (Col1a), and up-regulation of EMT transcription factors SNAIL and SLUG; conversely, the knockdown of Sumo1, a SUMO isoform, was shown to partially mitigate TGFβ2-driven EMT and experimental ASC.
Subsequent experiments involving the overexpression and knockdown of SUMOylation E1 enzyme (SUMO E1) unravelled its critical role in facilitating the proliferation, invasion, and EMT of LECs. Treatment with ML792, a selective SUMO E1 inhibitor, was shown to effectively mitigate TGFβ2/injury-induced EMT in LECs through precise blockade of global SUMOylation.
Additionally, ML792 treatment abrogated SMAD4 SUMOylation, impairing its nuclear translocation, and subsequently suppressing the expression of genes that drive TGFβ2-induced EMT in human LECs, thus attenuating fibrotic plaque formation in experimental ASC models. Furthermore, site-directed mutation of predicted SUMOylation sites in SMAD4 abrogated TGFβ2-induced EMT in LECs, establishing SMAD4 SUMOylation as a critical checkpoint in ocular fibrotic pathology.
In conclusion, this study establishes SUMOylation as a critical driver of lens fibrosis, mediated by SUMO E1 enzyme activity, while its inhibition with ML792 disrupts SMAD4 SUMOylation and subsequent TGFβ2-induced fibrotic transformation, revealing a novel SUMOylation-SMAD4 regulatory axis in ocular fibrosis and establishing SUMO E1 inhibition as a promising new therapeutic strategy for treating fibrotic lens disorders.
Reference
Title of the original paper: Blockage of SUMO E1 enzyme inhibits ocular lens fibrosis by mediating SMAD4 SUMOylation
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101827
Funding Information:
- National Natural Science Foundation of China (No. 81970783)
- Science and Technology Program of Guangzhou, China (No. SL2024A03J00523)
- Youth Program of the National Natural Science Foundation of China (No. 82305319)
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