H2O2 sensing through oxidation of the Yap1 transcription factor
H2O2 sensing through oxidation of the Yap1 transcription factor
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DOI：
10.1093/emboj/19.19.5157
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发表时间：
2000-10-02
期刊：
影响因子：
11.4
通讯作者：
Toledano, MB
中科院分区：
文献类型：
--
作者：
Delaunay, A;Isnard, AD;Toledano, MB
酵母转录因子YAP1因氧化应激而激活抗氧化基因的表达。 YAP1调节涉及核积累，但是感知氧化应激信号的机制仍然未知。我们提供了生化和遗传学证据，即在H2O2处理后，YAP1被氧化激活，并通过用YAP1控制的硫氧还蛋白通过酶促减少而失活，从而为自动调节提供了一种自动化的机制，这是YAP1氧化必不可少的，这对于H2O2的激活也是必不可少的。数据与YAP1氧化导致的模型一致二硫键形成，导致构象掩盖识别CRM1/XPO1对核输出信号的识别，从而促进蛋白质的核积累。与H2O2形成鲜明对比的是，二敏不会导致相同的YAP1氧化形式，并且仍然激活缺乏H2O2激活必不可少的半胱氨酸的突变体，这为这些氧化剂提供了yap1激活的分子基础，这是H2O2-敏感性的第一个示例真核生物中利用半胱氨酸的氧化以迅速对应激条件做出反应的机制。
The yeast transcription factor Yap1 activates expression of antioxidant genes in response to oxidative stress. Yap1 regulation involves nuclear accumulation, but the mechanism sensing the oxidative stress signal remains unknown. We provide biochemical and genetic evidence that upon H2O2 treatment, Yap1 is activated by oxidation and deactivated by enzymatic reduction with Yap1-controlled thioredoxins, thus providing a mechanism for autoregulation, Two cysteines essential for Yap1 oxidation are also essential for its activation by H2O2, The data are consistent with a model in which oxidation of Yap1 leads to disulfide bond formation with the resulting change of conformation masking recognition of the nuclear export signal by Crm1/Xpo1, thereby promoting nuclear accumulation of the protein. In sharp contrast to H2O2, diamide does not lead to the same Yap1 oxidized form and still activates mutants lacking cysteines essential for H2O2 activation, providing a molecular basis for differential activation of Yap1 by these oxidants, This is the first example of an H2O2-sensing mechanism in a eukaryote that exploits the oxidation of cysteines in order to respond rapidly to stress conditions.