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L. A. Brennan, W. Lee, R. McGreal, L. David, M. Kantorow; TXNL6 (RdCVF) is a Novel Lens Reducing System Required for MsrA Repair of -Crystallin and Cytochrome c. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1595.
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Significant evidence points to a role for methionine sulfoxide reductases (Msrs) in diseases of aging including age-related cataract. Protein methionine sulfoxide levels increase in the human lens with age and upon cataract formation and deletion of MsrA results in stress-induced cataract in mice. We have identified two key proteins as targets for MsrA repair in the lens, α-crystallin and cytochrome c. Key to the MsrA mediated repair of these lens proteins is the identity and levels of MsrA reducing systems needed for MsrA repair. Here we identified a novel lens reducing system that is utilized by lens MsrA called thioredoxin-like 6 (TXNL6) and we explored its function in lens repair and aging.α
Western blot analysis was used to detect TXNL6 in the epithelium and fibers of the lens, TXNL6 and MsrA in aging whole human lenses and TXNL6 in HLE cells treated with oxidants. α-crystallin chaperone ability was assessed using light scattering assays following chemical denaturation. Cytochrome c redox status was assessed using cytochrome c oxidase and peroxidase assays. The oxidation of methionines in cytochrome c and α-crystallin was confirmed using cyanogen bromide cleavage of oxidized purified proteins and tandem mass spec analysis.
MsrA decreases in the human lens upon aging whereas TXNL6 levels were found to increase with age. TXNL6 was found in both epithelial and fiber cells of the human lens and is induced in lens cells upon oxidative stress treatment. Oxidation of methionines in both α-crystallin and cytochrome c leads to loss of function. TXNL6 acted as a reducing system for MsrA repair of oxidized methionines of α-crystallin and cytochrome c resulting in restoration of their respective chaperone and oxidoreductase functions.
Oxidation of methionines in key proteins during aging and oxidative stress likely plays a significant role in lens aging and cataractogenesis. The novel reducing system identified here, TXNL6, likely serves to activate the lens repair activity of MsrA and possibly other important lens repair systems requiring thioredoxin-like proteins. Increased TXNL6 expression upon oxidative stress and aging likely serves to aid MsrA in the repair of oxidized α-crystallin, cytochrome c and other key lens proteins to avert cataract formation.
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