Control of protein function through oxidation and reduction of persulfidated states
Control of protein function through oxidation and reduction of persulfidated states
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DOI：
10.1126/sciadv.aax8358
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
Nagy, P.
中科院分区：
文献类型：
--
作者：
Doka, E.;Ida, T.;Nagy, P.
半胱氨酸残基不可逆氧化为亚磺酸/磺酸形式通常会损害蛋白质功能。我们发现，过硫化(CysSSH)通过形成CysSSO(1-3)H衍生物来保护Cys免受不可逆转的氧化功能丧失，这些衍生物随后可以还原为天然硫醇。在白蛋白、Prx2和PTP1B中，硫氧还蛋白体系证明了氧化过硫化物的还原再活化。在细胞中，这种机制保护和调节信号通路的关键蛋白，包括Prx2、PTEN、PTP1B、HSP90和Keap1。利用定量质谱仪，我们发现(I)CysSSH和CysSSO(3)H物种在小鼠肝脏中含量丰富，并受谷胱甘肽和硫氧还蛋白系统的酶调控，以及(Ii)小鼠中硫氧还蛋白相关蛋白TRP14的缺失改变了CysSSH在蛋白质子集上的水平，这预示了TRP14在过硫化物信号转导中的作用。此外，补硒、多硫化物处理或敲除TRP14介导了细胞对EGF的反应，这表明TrxR1/TRP14调节的氧化过硫化在生长因子反应中发挥了作用。
Irreversible oxidation of Cys residues to sulfinic/sulfonic forms typically impairs protein function. We found that persulfidation (CysSSH) protects Cys from irreversible oxidative loss of function by the formation of CysSSO(1-3)H derivatives that can subsequently be reduced back to native thiols. Reductive reactivation of oxidized persulfides by the thioredoxin system was demonstrated in albumin, Prx2, and PTP1B. In cells, this mechanism protects and regulates key proteins of signaling pathways, including Prx2, PTEN, PTP1B, HSP90, and KEAP1. Using quantitative mass spectrometry, we show that (i) CysSSH and CysSSO(3)H species are abundant in mouse liver and enzymatically regulated by the glutathione and thioredoxin systems and (ii) deletion of the thioredoxin-related protein TRP14 in mice altered CysSSH levels on a subset of proteins, predicting a role for TRP14 in persulfide signaling. Furthermore, selenium supplementation, polysulfide treatment, or knockdown of TRP14 mediated cellular responses to EGF, suggesting a role for TrxR1/TRP14-regulated oxidative persulfidation in growth factor responsiveness.