Department of Microbiology and Molecular Genetics, Center for Infectious Disease Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509, USA.
J Bacteriol. 2011 Oct;193(19):5105-18. doi: 10.1128/JB.05562-11. Epub 2011 Aug 5.
Mycobacterium tuberculosis, the etiological agent of tuberculosis, remains a significant cause of morbidity and mortality throughout the world despite a vaccine and cost-effective antibiotics. The success of this organism can be attributed, in part, to its ability to adapt to potentially harmful stress within the host and establish, maintain, and reactivate from long-term persistent infection within granulomatous structures. The DosRS-DosT/DevRS-Rv2027c, and MprAB two-component signal transduction systems have previously been implicated in aspects of persistent infection by M. tuberculosis and are known to be responsive to conditions likely to be found within the granuloma. Here, we describe initial characterization of a locus (Rv0081-Rv0088) encoding components of a predicted formate hydrogenylase enzyme complex that is directly regulated by DosR/DevR and MprA, and the product of the first gene in this operon, Rv0081. In particular, we demonstrate that Rv0081 negatively regulates its own expression and that of downstream genes by binding an inverted repeat element in its upstream region. In contrast, DosR/DevR and MprA positively regulate Rv0081 expression by binding to recognition sequences that either partially or completely overlap that recognized by Rv0081, respectively. Expression of Rv0081 initiates from two promoter elements; one promoter located downstream of the DosR/DevR binding site but overlapping the sequence recognized by both Rv0081 and MprA and another promoter downstream of the DosR/DevR, Rv0081, and MprA binding sites. Interestingly, Rv0081 represses Rv0081 and downstream determinants following activation of DosRS-DosT/DevRS-Rv2027c by nitric oxide, suggesting that expression of this locus is complex and subject to multiple levels of regulation. Based on this and other published information, a model is proposed detailing Rv0081-Rv0088 expression by these transcription factors within particular growth environments.
结核分枝杆菌是结核病的病原体，尽管有疫苗和具有成本效益的抗生素，但它仍然是全世界发病率和死亡率的重要原因。该生物体的成功可以部分归因于其适应宿主内潜在有害压力的能力，并在肉芽肿结构内建立、维持和重新激活长期持续感染。DosRS-DosT/DevRS-Rv2027c 和 MprAB 双组分信号转导系统先前被认为与结核分枝杆菌的持续感染有关，并且已知对肉芽肿内可能存在的条件有反应。在这里，我们描述了一个编码预测的甲酸氢酶酶复合物成分的基因座（Rv0081-Rv0088）的初步特征，该基因座直接受 DosR/DevR 和 MprA 调控，并且该操纵子中的第一个基因的产物。特别是，我们证明 Rv0081 通过结合其上游区域中的反向重复元件来负调控自身表达和下游基因的表达。相比之下，DosR/DevR 和 MprA 通过结合分别部分或完全重叠由 Rv0081 识别的识别序列来正调控 Rv0081 的表达。Rv0081 的表达从两个启动子元件开始；一个启动子位于 DosR/DevR 结合位点的下游，但与 Rv0081 和 MprA 识别的序列重叠，另一个启动子位于 DosR/DevR、Rv0081 和 MprA 结合位点的下游。有趣的是，Rv0081 抑制了 DosRS-DosT/DevRS-Rv2027c 激活后由一氧化氮引起的 Rv0081 和下游决定因素的表达，这表明该基因座的表达是复杂的，受到多个水平的调控。基于这一点和其他已发表的信息，提出了一个模型，详细说明了这些转录因子在特定生长环境下对 Rv0081-Rv0088 表达的影响。
