Veal Elizabeth A, Findlay Victoria J, Day Alison M, Bozonet Stephanie M, Evans Jennifer M, Quinn Janet, Morgan Brian A
Institute of Cell and Molecular Biosciences, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom.
Mol Cell. 2004 Jul 2;15(1):129-39. doi: 10.1016/j.molcel.2004.06.021.
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.
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）信号通路的激活对于细胞对应激的反应至关重要。2-半胱氨酸过氧化物酶（2-Cys Prx）是高度保守、极其丰富的抗氧化酶，可催化过氧化物的分解，保护细胞免受氧化应激。在此我们揭示，粟酒裂殖酵母中的单一2-Cys Prx即Tpx1，是过氧化物诱导的p38/JNK同源物Sty1激活所必需的。Tpx1通过一种机制激活Sty1，该机制涉及在Tpx1和Sty1之间形成过氧化物诱导的二硫键复合物，位于先前确定的氧化还原传感器的下游。我们已经在Tpx1和Sty1中鉴定出保守的半胱氨酸，它们对于正常的过氧化物诱导的Tpx1-Sty1二硫键形成以及Tpx1依赖的过氧化物诱导的Sty1激活调节至关重要。因此，我们通过揭示一种特定于氧化应激的SAPK激活机制，为SAPK对多种刺激的反应提供了新的见解。
