Global mapping of MtrA-binding sites links MtrA to regulation of its targets in Mycobacterium tuberculosis
Global mapping of MtrA-binding sites links MtrA to regulation of its targets in Mycobacterium tuberculosis
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DOI：
10.1099/mic.0.000585
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发表时间：
2018-01-01
期刊：
影响因子：
2.8
通讯作者：
Kundu, Manikuntala
中科院分区：
文献类型：
--
作者：
Chatterjee, Ayan;Sharma, Arun Kumar;Kundu, Manikuntala
结核分枝杆菌采用双组分系统（TCS）在其宿主内存活。TCS MtrAB在分枝杆菌中是保守的。响应调节因子MtrA是M.结核本研究中进行的全基因组染色质免疫沉淀（ChIP）测序表明，MtrA结合至少45个M基因的上游。结核病，包括那些参与细胞壁重塑，应激反应，持久性和转录调控。它与启动子区结合并调节从休眠复苏所需的肽聚糖水解酶rpfA和rpfC。它还调节氧化应激反应的关键调节因子whiB 4和毒素-抗毒素基因座relFG的一半relF的表达。我们已经确定了一个新的共识9 bp松散的MtrA结合基序。共有序列中的突变变化大大降低了MtrA与其新鉴定的靶标的结合。重要的是，我们观察到功能获得性突变体MtrAY 102 C的过表达增强了上述基因在M.结核分枝杆菌分离自巨噬细胞，而这些目标中的每一个的表达在M.结核杆菌过表达磷酸化缺陷突变体MtrAD 56 N。该结果表明，磷酸化的MtrA（MtrA-P）是其靶在巨噬细胞中表达所必需的。我们的数据已经发现了新的MtrA靶点，表明MtrA是转录反应所必需的，可能使M。结核病在宿主体内持续存在，并在条件有利时摆脱休眠。
Mycobacterium tuberculosis employs two-component systems (TCSs) for survival within its host. The TCS MtrAB is conserved among mycobacteria. The response regulator MtrA is essential in M. tuberculosis. The genome-wide chromatin immunoprecipitation (ChIP) sequencing performed in this study suggested that MtrA binds upstream of at least 45 genes of M. tuberculosis, including those involved in cell wall remodelling, stress responses, persistence and regulation of transcription. It binds to the promoter regions and regulates the peptidoglycan hydrolases rpfA and rpfC, which are required for resuscitation from dormancy. It also regulates the expression of whiB4, a critical regulator of the oxidative stress response, and relF, one-half of the toxin-antitoxin locus relFG. We have identified a new consensus 9 bp loose motif for MtrA binding. Mutational changes in the consensus sequence greatly reduced the binding of MtrA to its newly identified targets. Importantly, we observed that overexpression of a gain-of-function mutant, MtrAY102C, enhanced expression of the aforesaid genes in M. tuberculosis isolated from macrophages, whereas expression of each of these targets was lower in M. tuberculosis overexpressing a phosphorylation-defective mutant, MtrAD56N. This result suggests that phosphorylated MtrA (MtrA-P) is required for the expression of its targets in macrophages. Our data have uncovered new MtrA targets that suggest that MtrA is required for a transcriptional response that likely enables M. tuberculosis to persist within its host and emerge out of dormancy when the conditions are favourable.