Age-related Cataract: GSTP1 Ubiquitination and Degradation by Parkin Inhibits Its Anti-Apoptosis in Lens Epithelial Cells

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Abstract

Purpose: Oxidative stress-induced apoptosis of lens epithelial cells (LECs) contributes to the pathogenesis of age -related cataract (ARC). The purpose of this research is to underlie the potential mechanism of E3 ligase Parkin and its oxidative stress-associated substrate in cataractogenesis. Methods: The central anterior capsules were obtained from patients with ARC, Emory mice, and corresponding controls. SRA01/04 cells were exposed to H2O2 combined with cycloheximide (a translational inhibitor), MG -132 (a proteasome inhibitor), chloroquine (an autophagy inhibitor), Mdivi-1 (a mitochondrial division inhibi-tor), respectively. Co-immunoprecipitation was employed to detect protein-protein interactions and ubiquitin-tagged protein products. Levels of proteins and mRNA were evaluated by western blotting and quantitative RT-PCR assays. Results: Glutathione-S-transferase P1 (GSTP1) was identified as a novel Parkin substrate. Compared with cor-responding controls, GSTP1 was significantly decreased in the anterior lens capsules obtained from human cataracts and Emory mice. Similarly, GSTP1 was declined in H2O2-stimulated SRA01/04 cells. Ectopic expression of GSTP1 mitigated H2O2-induced apoptosis, whereas silencing GSTP1 aggregated apoptosis. In addition, H2O2 stimulation and Parkin overexpression could promote the degradation of GSTP1 through the ubiquitin-proteasome system, autophagy-lysosome pathway, and mitophagy. After co-transfection with Parkin, the non-ubiquitinatable GSTP1 mutant maintained its anti-apoptotic function, while wildtype GSTP1 failed. Mechanis-tically, GSTP1 might promote mitochondrial fusion through upregulating Mitofusins 1/2 (MFN1/2). Conclusion: Oxidative stress induces LECs apoptosis via Parkin-regulated degradation of GSTP1, which may provide potential targets for ARC therapy.

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Key words

Age-related cataract,Ubiquitination,Mitochondrial dynamics,Apoptosis,Parkin,GSTP1

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