Inactivation of Peroxiredoxin I by Phosphorylation Allows Localized H2O2 Accumulation for Cell Signaling
Inactivation of Peroxiredoxin I by Phosphorylation Allows Localized H2O2 Accumulation for Cell Signaling
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DOI：
10.1016/j.cell.2010.01.009
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发表时间：
2010-02-19
期刊：
影响因子：
64.5
通讯作者：
Rhee, Sue Goo
中科院分区：
文献类型：
--
作者：
Woo, Hyun Ae;Yim, Sun Hee;Rhee, Sue Goo
尽管有毒性，但过氧化氢是作为一种信号分子产生的，它能氧化蛋白酪氨酸磷酸酶等效应物的关键半胱氨酸残基，以响应细胞表面受体的激活。然而，目前尚不清楚在存在丰富的解毒酶过氧化氢还蛋白(PRX)I和II的情况下，如何达到修饰效应器所需的阈值以上的过氧化氢浓度。我们现在证明，与膜相关的PrxI在酪氨酸-194上被瞬时磷酸化，从而在体外通过生长因子或免疫受体刺激的细胞中以及在小鼠皮肤伤口愈合的边缘的细胞中失活。PrxI的局部失活允许H_2O_2在信号成分集中的膜周围瞬时积累，同时防止H_2O_2在其他地方有毒积累。相比之下，PrxII的失活不是通过磷酸化，而是在持续的氧化应激过程中其催化半胱氨酸的过度氧化。
Despite its toxicity, H2O2 is produced as a signaling molecule that oxidizes critical cysteine residues of effectors such as protein tyrosine phosphatases in response to activation of cell surface receptors. It has remained unclear, however, how H2O2 concentrations above the threshold required to modify effectors are achieved in the presence of the abundant detoxification enzymes peroxiredoxin (Prx) I and II. We now show that PrxI associated with membranes is transiently phosphorylated on tyrosine-194 and thereby inactivated both in cells stimulated via growth factor or immune receptors in vitro and in those at the margin of healing cutaneous wounds in mice. The localized inactivation of PrxI allows for the transient accumulation of H2O2 around membranes, where signaling components are concentrated, while preventing the toxic accumulation of H2O2 elsewhere. In contrast, PrxII was inactivated not by phosphorylation but rather by hyperoxidation of its catalytic cysteine during sustained oxidative stress.