image: (A) Representative anterior segment photographs of transparent capsules and ASC plaques in human patients. Scale bar: 2 mm.
(B) Immunofluorescence staining of lens epithelium from ASC patients and controls. SUMO1 (red), α-SMA (green), and DAPI (nuclear counterstain, blue). Scale bar: 50 μm.
(C) Quantification analysis of SUMO1 and α-SMA fluorescence intensity from (B). Two random regions per capsule were analyzed (n = 3 capsules/group). Statistical significance was determined by an unpaired Student's t-test. ***P < 0.001.
(D) Immunofluorescence co-staining of SUMO2/3 (red), α-SMA (green), and DAPI (nuclear, blue) in lens epithelium. Scale bar: 50 μm.
(E) Quantification of SUMO2/3 and α-SMA fluorescence intensity from (D). Data were analyzed as in (C). *P < 0.05 and **P < 0.01.
(F) Western blotting analysis of EMT markers in FHL124 LECs transfected with HA-tagged vector and SUMO isoforms. Cells were harvested 24 h post-transfection.
(G) Densitometric quantification of (F). Data were normalized to β-actin loading control. Statistical analysis was performed by one-way ANOVA with Bonferroni post-hoc test. **P < 0.01 and ***P < 0.001.
Credit: Min Hou, Yujie Ding, Xuan Bao, Liangping Liu, Yulan Wang, Mingxing Wu
SUMOylation, a conserved enzymatic post-translational modification, is involved in numerous cellular physiological processes and also in the pathogenesis of various diseases. It is also implicated in ocular pathophysiology, where it plays multifaceted regulatory roles in photoreceptor development, retinal homeostasis, lens differentiation, and the aging process.
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.
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