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Wanda Lee, Lisa A. Brennan, Marc Kantorow; TXNL6 Is A Novel Oxidative Stress-Inducible Activator Of MsrA Repair In Lens And Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1557.
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Oxidative damage to essential proteins is a key factor in the etiology of many age-related diseases including age-related cataract. A major protein modification associated with these diseases is conversion of methionine to protein methionine sulfoxide (PMSO) resulting in loss of many cellular functions. PMSO can be repaired by MsrA which acts to restore protein function and tissue viability. Its activity depends on the availability of a specific reducing system to regenerate its catalytic activity that has not to date been identified. We sought to discover this reducing system in lens and retinal cells and we report here the discovery of TXNL6 as a novel oxidative stress-inducible activator of MsrA in lens and retinal cells.
TXNL6 transcript and protein levels were examined with or without oxidative stress treatment in human lens, retina and other human cell-types. TXNL6 levels were also examined in older (>65 yrs) and younger (<45yrs) human lenses. TXNL6 was subcellularly localized by immunoflouresence staining. The ability of TXNL6 to activate MsrA repair of cytochrome C and alpha-crystallin was also evaluated. The ability of TXNL6 to protect cells against oxidative stress treatment through MsrA activation was examined by siRNA-targeted gene silencing and over-expression of TXNL6.
TXNL6 is highly expressed in human lens epithelia and fiber cells. TXNL6 is ubiquitously expressed in multiple other MsrA expressing human tissues including the retina where it is localized to the mitochondria. Importantly, TXNL6 is highly induced by oxidative stress in lens and retinal cells and unlike other reducing systems that decrease with aging (Trx1 and Trx2), its levels appear to increase in the lens upon aging. TXNL6 is a potent activator for MsrA repair of cytochrome c and alpha-crystallin.
These results identify TXNL6 as a novel activator and reducing system for MsrA repair of essential lens proteins that is rapidly and highly induced by oxidative stress exposure of lens and retinal cells. These findings point to a critical role for TXNL6 in repair of these tissues and suggest that modulation of TXNL6 levels could prove therapeutic for the treatment of cataract and age-related macular degeneration.
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