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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis
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Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis

机译：必需蛋白激酶在结核分枝杆菌中对SigH应激反应调节的调控

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摘要

SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in Mycobacterium tuberculosis, and this sigma factor is required for virulence in animal models of infection. SigH is negatively regulated by RshA, its cognate anti-sigma factor, which functions as a stress sensor and redox switch. While RshA provides a direct mechanism for sensing stress and activating transcription, bacteria use several types of signal transduction systems to sense the external environment. M. tuberculosis encodes several serine-threonine protein kinase signaling molecules, 2 of which, PknA and PknB, are essential and have been shown to regulate cell morphology and cell wall synthesis. In this work, we demonstrate that SigH and RshA are. phosphorylated in vitro and in vivo by PknB. We show that phosphorylation of RshA, but not SigH, interferes with the interaction of these 2 proteins in vitro. Consistent with this finding, negative regulation of SigH activity by RshA in vivo is partially relieved in strains in which pknB is over-expressed, resulting in increased resistance to oxidative stress. These findings demonstrate an interaction between the signaling pathways mediated by PknB and the stress response regulon controlled by SigH. The intersection of these apparently discrete regulatory systems provides a mechanism by which limited activation of the SigH-depen-dent stress response in M. tuberculosis can be achieved. Coordination of the PknB and SigH regulatory pathways through phosphorylation of RshA may lead to adaptive responses that are important in the pathogenesis of M. tuberculosis infection.
机译：SigH是广泛转录网络的关键调节因子，可响应结核分枝杆菌中的氧化，亚硝化和热应激，而此sigma因子是感染动物模型中毒力所必需的。 SigH受其相关的反西格玛因子RshA负调节，RshA用作压力传感器和氧化还原开关。尽管RshA提供了一种直接的机制来感应压力并激活转录，但细菌使用多种类型的信号转导系统来感应外部环境。结核分枝杆菌编码几种丝氨酸-苏氨酸蛋白激酶信号分子，其中2个PknA和PknB是必不可少的，并且已显示出可以调节细胞形态和细胞壁合成。在这项工作中，我们证明了SigH和RshA是。在体外和体内被PknB磷酸化。我们显示，RshA而不是SigH的磷酸化会干扰这2种蛋白质在体外的相互作用。与该发现一致，在pknB过度表达的菌株中，RshA在体内对SigH活性的负调节得到部分缓解，导致对氧化应激的抵抗力增强。这些发现表明，PknB介导的信号通路与SigH控制的应激反应调节因子之间存在相互作用。这些看似离散的调节系统的交叉点提供了一种机制，通过该机制可以实现结核分枝杆菌中SigH依赖性应激反应的有限激活。通过RshA磷酸化的PknB和SigH调节途径的协调可能会导致适应性反应，这在结核分枝杆菌感染的发病机理中很重要。

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