Inactivation of a Peroxiredoxin by Hydrogen Peroxide Is Critical for Thioredoxin-Mediated Repair of Oxidized Proteins and Cell Survival
Inactivation of a Peroxiredoxin by Hydrogen Peroxide Is Critical for Thioredoxin-Mediated Repair of Oxidized Proteins and Cell Survival
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DOI：
10.1016/j.molcel.2011.11.027
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发表时间：
2012-02-10
期刊：
影响因子：
16
通讯作者：
Veal, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Day, Alison M.;Brown, Jonathon D.;Veal, Elizabeth A.
真核生物2-半胱氨酸过氧化物酶（2-Cys peroxiredoxins，Prx）是一种丰富的抗氧化酶，其硫氧还蛋白过氧化物酶活性在抗氧化应激、抗衰老、抗肿瘤等方面发挥重要作用。特别地，这种硫氧还蛋白过氧化物酶活性对过氧化物诱导的Prx过氧化失活高度敏感。然而，在氧化应激条件下防止Prx清除过氧化物的任何可能的优势仍然不清楚。在这里，我们证明，在过氧化氢处理的细胞中，Prx Tpx 1是裂殖酵母裂殖酵母中硫氧还蛋白的主要底物，因此，竞争性地抑制硫氧还蛋白介导的其他氧化蛋白的还原。因此，我们揭示了Tpx 1的过氧化是至关重要的，允许硫氧还蛋白作用于其他底物，确保氧化蛋白的修复和细胞存活后暴露于有毒水平的过氧化氢。我们的结论是，失活的硫氧还蛋白过氧化物酶活性的Prx是重要的，以保持硫氧还蛋白的活性和细胞活力在氧化应激条件下。
Eukaryotic 2-Cys peroxiredoxins (Prx) are abundant antioxidant enzymes whose thioredoxin peroxidase activity plays an important role in protecting against oxidative stress, aging, and cancer. Paradoxically, this thioredoxin peroxidase activity is highly sensitive to inactivation by peroxide-induced Prx hyperoxidation. However, any possible advantage in preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. Here we demonstrate that, in cells treated with hydrogen peroxide, the Prx Tpx1 is a major substrate for thioredoxin in the fission yeast Schizosaccharomyces pombe and, as such, competitively inhibits thioredoxin-mediated reduction of other oxidized proteins. Consequently, we reveal that the hyperoxidation of Tpx1 is critical to allow thioredoxin to act on other substrates ensuring repair of oxidized proteins and cell survival following exposure to toxic levels of hydrogen peroxide. We conclude that the inactivation of the thioredoxin peroxidase activity of Prx is important to maintain thioredoxin activity and cell viability under oxidative stress conditions.