Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells
Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells
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DOI：
10.1016/j.freeradbiomed.2012.08.001
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发表时间：
2012-10-01
影响因子：
7.4
通讯作者：
Ledgerwood, Elizabeth C.
中科院分区：
文献类型：
--
作者：
Jarvis, Reagan M.;Hughes, Stephanie M.;Ledgerwood, Elizabeth C.
过氧化氢被广泛认为是氧化还原信号中的主要第二信使，并且有人提出抗氧化剂过氧化还蛋白(PRDX)酶的失活允许自由过氧化氢积累并直接氧化靶蛋白(闸门模型)。我们评估了胞质Prdxs1和2在过氧化氢诱导的凋亡信号激酶1(ASK1)/p38信号通路激活中的作用，其中ASK1的氧化是p38磷酸化所必需的。作为对过氧化氢的响应，Prdx1催化ASK1氧化成二硫键连接的多聚体，这是通过瞬间形成Prdx1-ASK1混合的二硫键中间体而发生的。Prdx1的敲除和Prdx2的过表达抑制了ASK1的氧化和p38的磷酸化。这表明这两个胞质Prdx在细胞过氧化反应中具有不同的作用，并竞争可用的过氧化底物。这些数据表明Prdx1可以作为一个过氧化氢受体来响应细胞外的过氧化氢，接收过氧化氢信号并将其转化为二硫键，然后传递到底物ASK1，导致p38磷酸化。有趣的是，对过氧化氢的反应。Prdx1和Prdx3瞬间形成可还原的高分子量复合体，表明多个蛋白质是PRDX通过二硫键交换机制介导的氧化的靶标。这种通过二硫键交换的活性过氧化氢信号分布模型与酵母中的PRDX功能是一致的，并解释了过氧化氢如何在哺乳动物细胞中触发特定的二硫键形成。(C)2012 Elsevier Inc.保留所有权利。
Hydrogen peroxide is widely viewed as the main second messenger in redox signaling, and it has been proposed that deactivation of the antioxidant peroxiredoxin (Prdx) enzymes allows free peroxide to accumulate and directly oxidize target proteins (the floodgate model). We assessed the role of cytosolic Prdxs 1 and 2 in peroxide-induced activation of the apoptosis signaling kinase 1 (ASK1)/p38 signaling pathway, in which oxidation of ASK1 is required for phosphorylation of p38. In response to peroxide, Prdx1 catalyzed oxidation of ASK1 to a disulfide-linked multimer, and this occurred via transient formation of a Prdx1-ASK1 mixed disulfide intermediate. Oxidation of ASK1 and phosphorylation of p38 were inhibited by knockdown of Prdx1, but also by overexpression of Prdx2. This suggests that these two cytosolic Prdxs have distinct roles in the cellular peroxide response and compete for available peroxide substrate. These data imply that Prdx1 can function as a peroxide receptor in response to extracellular H2O2, receiving the peroxide signal and transducing it into a disulfide bond that is subsequently transmitted to the substrate, ASK1, resulting in p38 phosphorylation. Interestingly, in response to peroxide. Prdx1 and Prdx3 transiently formed reducible higher molecular weight complexes, suggesting that multiple proteins are targets for Prdx-mediated oxidation via a disulfide-exchange mechanism. This model of active peroxide signal distribution via disulfide exchange is consistent with Prdx function in yeast and explains how peroxides may trigger specific disulfide bond formation in mammalian cells. (C) 2012 Elsevier Inc. All rights reserved.