Methionine oxidation activates a transcription factor in response to oxidative stress
Methionine oxidation activates a transcription factor in response to oxidative stress
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DOI：
10.1073/pnas.1300578110
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发表时间：
2013-06-04
影响因子：
11.1
通讯作者：
Winter, Jeannette
中科院分区：
文献类型：
--
作者：
Drazic, Adrian;Miura, Haruko;Winter, Jeannette
氧化剂介导的抗菌反应系统被广泛用于控制细菌的增殖。次氯酸盐(HOCl)是中性粒细胞和特定上皮细胞产生的天然免疫系统的重要组成部分。它的抗微生物活性是由于破坏了细胞大分子。关于细菌是如何逃脱HOCl造成的损害的，人们知之甚少。最近，转录因子YjiE被发现能特异性地保护大肠杆菌免受HOCl的杀伤。根据其功能，YjiE现在被重新命名为HypT(次氯酸盐反应转录因子)。在这里，我们揭示了HypT是通过蛋氨酸氧化为蛋氨酸亚砜而激活的。有趣的是，到目前为止，只有蛋氨酸氧化使细胞蛋白失活的报道。突变分析揭示了三种蛋氨酸，它们是授予HOCl抗性所必需的。它们同时被谷氨酰胺取代，模拟蛋氨酸亚砜的状态，提高了大肠杆菌细胞在HOCl胁迫下的生存能力。三重谷氨酰胺替代产生一种结构性活性HypT，它独立于HOCl胁迫调节靶基因，并永久下调细胞内铁水平。HypT的失活依赖于蛋氨酸亚砜还原酶A/B。因此，随着抗菌剂控制系统的进化，微生物保护机制已经进化，允许细菌在宿主环境中生存。
Oxidant-mediated antibacterial response systems are broadly used to control bacterial proliferation. Hypochlorite (HOCl) is an important component of the innate immune system produced in neutrophils and specific epithelia. Its antimicrobial activity is due to damaging cellular macromolecules. Little is known about how bacteria escape HOCl-inflicted damage. Recently, the transcription factor YjiE was identified that specifically protects Escherichia coli from HOCl killing. According to its function, YjiE is now renamed HypT (hypochlorite-responsive transcription factor). Here we unravel that HypT is activated by methionine oxidation to methionine sulfoxide. Interestingly, so far only inactivation of cellular proteins by methionine oxidation has been reported. Mutational analysis revealed three methionines that are essential to confer HOCl resistance. Their simultaneous substitution by glutamine, mimicking the methionine sulfoxide state, increased the viability of E. coli cells upon HOCl stress. Triple glutamine substitution generates a constitutively active HypT that regulates target genes independently of HOCl stress and permanently down-regulates intracellular iron levels. Inactivation of HypT depends on the methionine sulfoxide reductases A/B. Thus, microbial protection mechanisms have evolved along the evolution of antimicrobial control systems, allowing bacteria to survive within the host environment.