Mao Xinmu, Ji Min, Kang Lihua, Qin Bai, Luo Jiawei, Zhang Wenyi, Wu Anran, Yuan Yurong, Zhang Guowei, Guan Huaijin
Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Cell Signal. 2022 Jun;94:110314. doi: 10.1016/j.cellsig.2022.110314. Epub 2022 Mar 22.
Exposure of the lens to UVB can lead to oxidative stress, which would result in age-related cataract (ARC) formation. In this study, we investigate the regulatory mechanism of tripartite motif containing 25 (TRIM25) in ARC. The protein level of TRIM25 was elevated in ARC specimens and UVB-exposed SRA01/04 cells. Bioinformatic analysis indicated that X-ray repair cross complementing 5 (XRCC5) might interact with TRIM25, and the interaction was validated via immunoprecipitation. TRIM25 interacted with XRCC5 and ubiquitinated it for degradation. Further studies showed that XRCC5 overexpression notably repressed UVB-induced apoptosis, while XRCC5 knockdown promoted apoptosis. Of note, ubiquitination of XRCC5 mediated by TRIM25 overexpression facilitated apoptosis. Attenuation of XRCC5 ubiquitination by mutant with substitution of lysine residues with arginine residues rescued its anti-apoptosis effect. Moreover, we observed that TRIM25-mediated XRCC5 degradation was reversed by proteasome inhibitor MG-132 or lysosome inhibitor 3-MA. In conclusion, TRIM25 mediates ubiquitination of XRCC5 to regulate the function and degradation of XRCC5, suggesting that interventions targeting TRIM25 might be a promising therapeutic strategy for ARC.
晶状体暴露于中波紫外线（UVB）可导致氧化应激，进而引发年龄相关性白内障（ARC）的形成。在本研究中，我们探究了含三联基序蛋白25（TRIM25）在ARC中的调控机制。TRIM25的蛋白水平在ARC标本及UVB照射的SRA01/04细胞中升高。生物信息学分析表明，X射线修复交叉互补蛋白5（XRCC5）可能与TRIM25相互作用，且该相互作用通过免疫沉淀得到验证。TRIM25与XRCC5相互作用并使其泛素化以进行降解。进一步研究表明，XRCC5过表达显著抑制UVB诱导的细胞凋亡，而XRCC5敲低则促进细胞凋亡。值得注意的是，TRIM25过表达介导的XRCC5泛素化促进了细胞凋亡。用精氨酸取代赖氨酸残基的突变体减弱XRCC5泛素化可挽救其抗凋亡作用。此外，我们观察到蛋白酶体抑制剂MG - 132或溶酶体抑制剂3 - MA可逆转TRIM25介导的XRCC5降解。总之，TRIM25介导XRCC5的泛素化以调节XRCC5的功能和降解，这表明针对TRIM25的干预措施可能是ARC一种有前景的治疗策略。
