SYVN1‐mediated ubiquitination and degradation of MSH3 promotes the apoptosis of lens epithelial cells

• Published in: The FEBS journal 2022-09, Vol.289 (18), p.5682-5696
• Main Authors: Chen, Xiaojuan, Zhang, Guowei, Li, Pengfei, Yu, Jianfeng, Kang, Lihua, Qin, Bai, Wang, Ying, Wu, Jian, Wang, Yong, Zhang, Junfang, Qin, Miaomiao, Guan, Huaijin
• Format: Article
• Language: English
• Subjects: age‐related cataract; Apoptosis; Autophagy; Biodegradation; Cataracts; Degradation; Ectopic expression; Epithelial cells; Epithelium; Genomes; Irradiation; Lenses; Mismatch repair; MSH3; Msh3 protein; oxidative damage repair; Pathogenesis; Proteasomes; protein degradation; Proteins; Repair; SYVN1; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Ultraviolet radiation
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16447

The pathology of age‐related cataract (ARC) mainly involves the misfolding and aggregation of proteins, especially oxidative damage repair proteins, in the lens, induced by ultraviolet‐B (UVB). MSH3, as a key member of the mismatch repair family, primarily maintains genome stability. However, the function of MSH3 and the mechanism by which cells maintain MSH3 proteostasis during cataractogenesis remains unknown. In the present study, the protein expression levels of MSH3 were found to be attenuated in ARC specimens and SRA01/04 cells under UVB exposure. The ectopic expression of MSH3 notably impeded UVB‐induced apoptosis, whereas the knockdown of MSH3 promoted apoptosis. Protein half‐life assay revealed that UVB irradiation accelerated the decline of MSH3 by ubiquitination and degradation. Subsequently, we found that E3 ubiquitin ligase synoviolin (SYVN1) interacted with MSH3 and promoted its ubiquitination and degradation. Of note, the expression and function of SYVN1 were contrary to those of MSH3 and SYVN1 regulated MSH3 protein degradation via the ubiquitin‐proteasome pathway and the autophagy‐lysosome pathway. Based on these findings, we propose a mechanism for ARC pathogenesis that involves SYVN1‐mediated degradation of MSH3 via the ubiquitin‐proteasome pathway and the autophagy‐lysosome pathway, and suggest that interventions targeting SYVN1 might be a potential therapeutic strategy for ARC. As a result of the impairment of ubiquitinated protein degradation pathways, the abnormal aggregation of proteins results in the apoptosis of lens epithelial cells (LECs) and, ultimately, the formation of age‐related cataract (ARC). Here, we demonstrate that E3 ubiquitin ligase synoviolin (SYVN1) modulates mismatch repair protein MSH3 and investigate the role of SYVN1‐mediated ubiquitination and degradation of MSH3 in LECs apoptosis during ARC progression.