Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence.
Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence.
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DOI：
10.1093/nar/gkx406
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发表时间：
2017-06-20
影响因子：
14.9
通讯作者：
Green J
中科院分区：
文献类型：
--
作者：
Smith LJ;Bochkareva A;Rolfe MD;Hunt DM;Kahramanoglou C;Braun Y;Rodgers A;Blockley A;Coade S;Lougheed KEA;Hafneh NA;Glenn SM;Crack JC;Le Brun NE;Saldanha JW;Makarov V;Nobeli I;Arnvig K;Mukamolova GV;Buxton RS;Green J
结核分枝杆菌 (MTb) 是肺结核 (TB) 的病原体。 MTb 定植于人类肺部，通常在发展为危及生命的活动性感染之前进入非复制状态。转录重编程对于结核病发病机制至关重要。在体外，Cmr（转录调节因子 CRP/FNR 超家族的成员）结合在单个 DNA 位点上，充当 cmr 转录的双重调节因子和不同 rv1676 基因的激活因子。转录谱和 DNA 结合分析表明 Cmr 直接抑制 dosR 表达。 DosR 调节子被认为参与了对缺氧和一氧化氮的反应而建立潜伏性结核感染。因此，Cmr 与 DNA 的结合受到亚硝化的严重损害。 cmr突变体能够更好地承受亚硝化应激挑战，但在小鼠气溶胶感染模型中减弱。互补突变体的 cmr 表达增加约 2 倍，这导致对亚硝化应激的敏感性增加。这一点以及感染模型中无法恢复野生型行为表明，cmr 位点（与高毒力北京结核分枝杆菌菌株中的差异区 150 相关）的精确调控对于结核病发病机制非常重要。
Mycobacterium tuberculosis (MTb) is the causative agent of pulmonary tuberculosis (TB). MTb colonizes the human lung, often entering a non-replicating state before progressing to life-threatening active infections. Transcriptional reprogramming is essential for TB pathogenesis. In vitro, Cmr (a member of the CRP/FNR super-family of transcription regulators) bound at a single DNA site to act as a dual regulator of cmr transcription and an activator of the divergent rv1676 gene. Transcriptional profiling and DNA-binding assays suggested that Cmr directly represses dosR expression. The DosR regulon is thought to be involved in establishing latent tuberculosis infections in response to hypoxia and nitric oxide. Accordingly, DNA-binding by Cmr was severely impaired by nitrosation. A cmr mutant was better able to survive a nitrosative stress challenge but was attenuated in a mouse aerosol infection model. The complemented mutant exhibited a ∼2-fold increase in cmr expression, which led to increased sensitivity to nitrosative stress. This, and the inability to restore wild-type behaviour in the infection model, suggests that precise regulation of the cmr locus, which is associated with Region of Difference 150 in hypervirulent Beijing strains of Mtb, is important for TB pathogenesis.