TRIM25 promotes epithelial-mesenchymal transition of lens epithelial cells by mediating the degradation of PCBP1 to activate the Notch signaling pathway.

OBJECTIVES: Fibrosis represents a complex pathological process that culminates in organ damage and failure. Cataract, specifically anterior subcapsular cataract (ASC) and posterior capsular opacity (PCO), is a common manifestation of ocular fibrosis, primarily driven by the epithelial mesenchymal transition (EMT) of lens epithelial cells (LECs). Tripartite motif containing 25 (TRIM25), an E3 ubiquitin ligase and member of the TRIM protein family, plays a pivotal role in various biological processes including protein homeostasis, signaling pathways, immune responses, and cell growth. This study aims to elucidate the role of TRIM25 in LECs EMT and its underlying molecular mechanisms, thereby identifying a novel therapeutic target for the prevention and treatment of fibrotic cataracts.

METHODS: To investigate the expression level of TRIM25, we utilized an TGF-β2-induced human lens epithelial cell (SRA01/04) EMT model and employed lentivirus mediated knockdown techniques to examine the effects of TRIM25 on cellular proliferation, migration, and EMT in lens epithelial cells. These effects were assessed using Western blot analysis, wound healing assays, EdU incorporation assays, and immunoprecipitation experiments. Additionally, we explored the interaction between TRIM25 and PCBP1, as well as the regulation of the Notch signaling pathway.

RESULTS: TRIM25 was found to be up-regulated in the TGF-β2-induced EMT model of lens epithelial cells. The knockdown of TRIM25 significantly attenuated the TGF-β2-induced EMT process, leading to a reduction in cell proliferation and migration. Furthermore, TRIM25 interacts with PCBP1 and potentially targets PCBP1 for degradation via its E3 ubiquitin ligase activity, thereby activating the Notch signaling pathway and promoting EMT along with associated cellular behavior changes.

CONCLUSIONS: TRIM25 activates the Notch signaling pathway through the targeted degradation of PCBP1, thereby promoting the epithelial-mesenchymal transition and fibrosis in lens epithelial cells. These findings suggest that TRIM25 may serve as a potential therapeutic target for the treatment of fibrotic cataracts.