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Age-related cataract: GSTP1 ubiquitination and degradation by Parkin inhibits its anti-apoptosis in lens epithelial cells

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 inhibitor), 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 corresponding 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. Mechanistically, 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.

Comments：

In this study, the researchers aimed to investigate the potential mechanism of E3 ligase Parkin and its oxidative stress-associated substrate in the pathogenesis of age-related cataract (ARC). They collected central anterior capsules from patients with ARC, Emory mice, and corresponding controls, and used SRA01/04 cells to study the effects of H2O2 combined with different inhibitors on apoptosis.

The researchers identified Glutathione-S-transferase P1 (GSTP1) as a novel Parkin substrate. They found that GSTP1 was significantly decreased in the anterior lens capsules obtained from human cataracts and Emory mice, as well as in H2O2-stimulated SRA01/04 cells. The researchers also demonstrated that ectopic expression of GSTP1 mitigated H2O2-induced apoptosis, while silencing GSTP1 aggravated apoptosis.

Furthermore, the researchers found that H2O2 stimulation and Parkin overexpression promoted the degradation of GSTP1 through the ubiquitin-proteasome system, autophagy-lysosome pathway, and mitophagy. They also showed that the non-ubiquitinatable GSTP1 mutant maintained its anti-apoptotic function after co-transfection with Parkin, while wildtype GSTP1 failed.

Mechanistically, the researchers proposed that GSTP1 might promote mitochondrial fusion through upregulating Mitofusins 1/2 (MFN1/2).

In conclusion, the study suggests that oxidative stress induces lens epithelial cells (LECs) apoptosis via Parkin-regulated degradation of GSTP1, and that GSTP1 may provide a potential target for ARC therapy.

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