H2O2-dependent Hyperoxidation of Peroxiredoxin 6 (Prdx6) Plays a Role in Cellular Toxicity via Up-regulation of iPLA2 Activity
H2O2-dependent Hyperoxidation of Peroxiredoxin 6 (Prdx6) Plays a Role in Cellular Toxicity via Up-regulation of iPLA2 Activity
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DOI：
10.1074/jbc.m806578200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Lee, Ki-Young
中科院分区：
文献类型：
--
作者：
Kim, So Yong;Jo, Hee-Yeon;Lee, Ki-Young
过氧化还蛋白6(Prdx6)是一种具有过氧化物酶活性和非钙非依赖性磷脂酶A2(IPLA2)活性的双功能酶。在这里，我们报告了H_2O_2诱导的细胞毒性是通过Prdx6过氧化起作用的。在高浓度的H_2O_2(100µM)下，Prdx6和2-Cys Prdxs被高氧化。与2-Cys Prdxs的过氧化相反，Prdx6的过氧化在体内是不可逆的。令人惊讶的是，过氧化氢诱导的细胞周期停滞在G2/M期与过氧化和增加Prdx6的iPLA2活性有关。这种抑制也与p53和p21的上调以及细胞周期蛋白B1的下调有关。此外，在Prdx6的一个过氧化突变体(C47A)、一个iPLA2突变体(S32A)和一个双突变体(C47A/S32A)中，H_2O_2介导的iPLA2活性的增加被显著取消，这表明Prdx6 C47的过氧化对其iPLA2活性的基本要求。综上所述，我们的结果表明，过氧化氢介导的Prdx6过度氧化通过上调iPLA2活性而诱导细胞周期停滞于G2/M转变。
Peroxiredoxin 6 (Prdx6) is a bifunctional enzyme with peroxidase activity and Ca2+-independent phospholipase A2 (iPLA2) activity. Here, we report that H2O2-induced cellular toxicity acts through Prdx6 hyperoxidation. Under high concentrations of H2O2 (> 100 mu M), Prdx6, and 2-Cys Prdxs were hyperoxidized. Contrary to hyperoxidation of 2-Cys Prdxs, hyperoxidation of Prdx6 was irreversible in vivo. Surprisingly, H2O2-induced cell cycle arrest at the G2/M transition correlated with hyperoxidation and increased iPLA2 activity of Prdx6. This arrest was also associated with up-regulation of p53 and p21 and with down-regulation of cyclin B1. Furthermore, the H2O2-mediated increase in iPLA2 activity was dramatically abolished in a hyperoxidation mutant (C47A), an iPLA2 mutant (S32A), and a double mutant (C47A/S32A) of Prdx6, demonstrating the essential requirement of Prdx6 C47 hyperoxidation for its iPLA2 activity. Together, our results demonstrate that H2O2-mediated hyperoxidation of Prdx6 induces cell cycle arrest at the G2/M transition through up-regulation of iPLA2 activity.