Ubiquitination of Ku70 by Parkin promotes apoptosis of lens epithelial cells.
Wenyi ZhangAnran WuGuowei ZhangXuemeng DingLihua KangTianqiu ZhouMin JiHuaijin GuanPublished in: The FEBS journal (2023)
Oxidative damage-triggered apoptosis in lens epithelial cells (LECs) is considered as a main risk factor in the pathogenesis of age-related cataract (ARC). Ku70 is a key factor in the DNA repair process of double-strand breaks. Herein, we aim to investigate the role of Ku70 and its related E3 ubiquitin ligase in LECs apoptosis. The levels of Ku70 in the anterior lens capsules of human cataracts and Emory mice were declined compared to controls. H 2 O 2 treatment resulted in decreased expression of Ku70 through accelerating Ku70 ubiquitination. Parkin, an E3 ubiquitin ligase, could interact with Ku70 and promote the ubiquitination and degradation of this protein. In addition, ubiquitinated Ku70 was regulated by ubiquitin-proteasome, autophagy-lysosome and mitophagy pathways. Ectopic expression of Ku70 protected SRA01/04 cells from H 2 O 2 -induced apoptosis, whereas silencing Ku70 exhibited the opposite trend. Co-transfected with Parkin, non-ubiquitinatable Ku70 mutant could maintain its anti-apoptosis ability, but wildtype Ku70 failed. Moreover, Ku70 might facilitate mitochondrial fusion by increasing the expression of mitofusin 1 and 2. Our study revealed that Parkin-mediated Ku70 ubiquitination facilitated H 2 O 2 -induced lens epithelial cells apoptosis through alleviating mitochondrial fusion, which could provide potential targets for ARC treatment.