Mechanistic scheme of SUMO E1-mediated SMAD4 SUMOylation in lens fibrogenesis. (IMAGE)
Caption
In TGFβ/SMAD signaling, the SAE1/UBA2 heterodimer (SUMO E1) catalyzes SMAD4 SUMOylation at Lys113/159 residues, enhancing nucleocytoplasmic trafficking efficiency of the SMAD complex. SUMOylated SMAD4 accumulates in the nucleus, stabilizing the transcriptional machinery of epithelial-mesenchymal transition (EMT)-related genes (e.g., SNAIL, SLUG, FN1, COL1A1), thereby amplifying fibrotic gene expression. Sustained SUMOylation drives lens epithelial cell (LEC) transdifferentiation, characterized by α-SMA expression and extracellular matrix overproduction, culminating in anterior subcapsular cataract (ASC) progression. Pharmacological inhibition of SUMO E1 by ML792 blocks SMAD4 SUMOylation, disrupting nuclear translocation and abrogating pro-fibrotic transcriptional programs.
Credit
Min Hou, Yujie Ding, Xuan Bao, Liangping Liu, Yulan Wang, Mingxing Wu
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CC BY-NC-ND