A 2-Cys peroxiredoxin regulates peroxide-induced oxidation and activation of a stress-activated MAP kinase
A 2-Cys peroxiredoxin regulates peroxide-induced oxidation and activation of a stress-activated MAP kinase
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DOI：
10.1016/j.molcel.2004.06.021
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发表时间：
2004-07-02
期刊：
影响因子：
16
通讯作者：
Morgan, BA
中科院分区：
文献类型：
--
作者：
Veal, EA;Findlay, VJ;Morgan, BA
氧化应激诱导的细胞损伤是许多疾病和衰老的重要组成部分。在真核生物中，JNK/p38应激激活蛋白激酶(SAPK)信号通路的激活对细胞的应激反应至关重要。2-半胱氨酸(2-Cys；Peroxiredoxins，2-Cys PRX)是一种高度保守、含量极其丰富的抗氧化酶，能催化过氧化产物的分解，保护细胞免受氧化应激的伤害。在这里，我们揭示了Ppx1，一个在裂殖酵母中单一的2-Cys Prx，是过氧化氢诱导p38/JNK同源物Sty1激活所必需的。Tpx1通过在Tpx1和Sty1之间形成过氧化氢诱导的二硫化物复合体的机制来激活先前发现的氧化还原传感器下游的Sty1。我们已经在Tpx1和Sty1中发现了保守的半胱氨酸，它们对于正常的过氧化氢诱导的Tpx1-Sty1二硫化物的形成和Tpx1依赖的过氧化氢诱导的Sty1激活的调节是必不可少的。因此，我们通过揭示SAPK的激活机制，特别是通过氧化应激，为SAPKs对不同刺激的反应提供了新的见解。
Oxidative stress-induced cell damage is an important component of many diseases and ageing. In eukaryotes, activation of JNK/p38 stress-activated protein kinase (SAPK) signaling pathways is critical for the cellular response to stress. 2-Cys; peroxiredoxins (2-Cys Prx) are highly conserved, extremely abundant antioxidant enzymes that catalyze the breakdown of peroxides to protect cells from oxidative stress. Here we reveal that Tpx1, the single 2-Cys Prx in Schizosaccharomyces pombe, is required for the peroxide-induced activation of the p38/JNK homolog, Sty1. Tpx1 activates Sty1, downstream of previously identified redox sensors, by a mechanism that involves formation of a peroxide-induced disulphide complex between Tpx1 and Sty1. We have identified conserved cysteines in Tpx1 and Sty1 that are essential for normal peroxide-induced Tpx1-Sty1 disulphide formation and Tpx1-dependent regulation of peroxide-induced Sty1 activation. Thus we provide new insight into the response of SAPKs to diverse stimuli by revealing a mechanism for SAPK activation specifically by oxidative stress.