Maintenance of nitric oxide and redox homeostasis by the Salmonella flavohemoglobin Hmp
Maintenance of nitric oxide and redox homeostasis by the Salmonella flavohemoglobin Hmp
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DOI：
10.1074/jbc.m605174200
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发表时间：
2006-09-22
影响因子：
4.8
通讯作者：
Fang, Ferric C.
中科院分区：
文献类型：
--
作者：
Bang, Iel-Soo;Liu, Limin;Fang, Ferric C.
细胞内病原体必须抵抗宿主细胞产生的一氧化氮（NO）的抗菌作用。为此，病原体拥有几种代谢NO的酶。在此我们表明，黄素血红蛋白Hmp是负责鼠伤寒沙门氏菌有氧NO代谢的主要酶。我们进一步表明，与S - 亚硝基谷胱甘肽还原酶、黄素氧还蛋白或细胞色素c亚硝酸还原酶不同，Hmp是鼠伤寒沙门氏菌在小鼠体内致病所必需的。小鼠诱导型NO合酶的缺失可恢复hmp突变细菌的致病性。在亚硝化应激存在的情况下，缺乏Hmp的沙门氏菌表现出NO消耗减少、生长受损、蛋白质S - 亚硝基化增加以及丝状形态。然而，在有氧条件下且无亚硝化应激时，hmp表达升高会增加鼠伤寒沙门氏菌对过氧化氢的敏感性。血红素结合结构域和黄素还原酶结构域对于抵抗NO都是必需的，而黄素还原酶结构域是铁依赖的对氧化应激敏感性的原因。这为转录抑制因子NsrR根据亚硝化应激和细胞内游离铁浓度来调控hmp表达提供了理论依据。Hmp黄素血红蛋白在沙门氏菌对亚硝化应激的反应中起核心作用，但需要精确调控，以避免如果电子传递给外来铁可能导致的氧化应激加剧。
Intracellular pathogens must resist the antimicrobial actions of nitric oxide (NO.) produced by host cells. To this end pathogens possess several NO.-metabolizing enzymes. Here we show that the flavohemoglobin Hmp is the principal enzyme responsible for aerobic NO. metabolism by Salmonella enterica serovar typhimurium. We further show that Hmp is required for Salmonella virulence in mice, in contrast to S-nitrosoglutathione reductase, flavorubredoxin, or cytochrome c nitrite reductase. Abrogation of murine-inducible NO. synthase restores virulence to hmp mutant bacteria. In the presence of nitrosative stress, Hmp-deficient Salmonella exhibits reduced NO. consumption, impaired growth, increased protein S-nitrosylation, and filamentous morphology. However, under aerobic conditions in the absence of nitrosative stress, elevated hmp expression increases S. typhimurium susceptibility to hydrogen peroxide. Both the heme binding and flavoreductase domains are required for resistance to NO., whereas the flavoreductase domain is responsible for iron-dependent susceptibility to oxidative stress. This provides a rationale for the regulation of hmp expression by the transcriptional repressor NsrR in response to both nitrosative stress and intracellular free iron concentration. The Hmp flavohemoglobin plays a central role in the response of Salmonella to nitrosative stress but requires precise regulation to avoid the exacerbation of oxidative stress that can result if electrons are shuttled to extraneous iron.