Phosphate starvation: a novel signal that triggers ESX-5 secretion in Mycobacterium tuberculosis.
Phosphate starvation: a novel signal that triggers ESX-5 secretion in Mycobacterium tuberculosis.
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DOI：
10.1111/mmi.13332
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发表时间：
2016-05
影响因子：
3.6
通讯作者：
Tischler AD
中科院分区：
文献类型：
--
作者：
Elliott SR;Tischler AD
结核分枝杆菌使用VII型ESX分泌系统将蛋白质转运穿过其复杂的细胞壁。ESX-5与M.结核毒力，但控制ESX-5分泌的调控机制尚不清楚。在这里，我们揭示了ESX-5和Pst/SenX 3-RegX 3系统之间的联系，该系统控制基因表达以响应磷酸盐的可用性。DNA结合反应调节剂RegX 3通常通过磷酸盐限制激活。缺失编码Pst磷酸盐摄取系统组分的pstA 1导致RegX 3的组成性激活。当细菌在富磷酸盐培养基中生长时，Δ pstA 1突变体表现出RegX 3依赖性的esx-5基因过表达和ESX-5底物EsxN和PPE 41的高分泌。野生型M.在结核病中，磷酸盐限制激活esx-5转录和EsxN和PPE 41两者的分泌，并且这种应答需要RegX 3。电泳迁移率变动分析表明，RegX 3直接结合到esx-5基因座内的启动子。值得注意的是，磷酸盐限制也诱导了EsxB的分泌，EsxB是毒性相关ESX-1分泌系统的效应子，尽管这种诱导是RegX 3独立的。我们的工作表明，Pst/SenX 3-RegX 3系统直接调节ESX-5的分泌在转录水平上响应磷酸盐的可用性，并定义磷酸盐限制作为激活ESX-5分泌的环境信号。
Mycobacterium tuberculosis uses the Type VII ESX secretion systems to transport proteins across its complex cell wall. ESX-5 has been implicated in M. tuberculosis virulence, but the regulatory mechanisms controlling ESX-5 secretion were unknown. Here we uncover a link between ESX-5 and the Pst/SenX3-RegX3 system that controls gene expression in response to phosphate availability. The DNA-binding response regulator RegX3 is normally activated by phosphate limitation. Deletion of pstA1, which encodes a Pst phosphate uptake system component, causes constitutive activation of RegX3. A ΔpstA1 mutant exhibited RegX3-dependent over-expression of esx-5 genes and hyper-secretion of the ESX-5 substrates EsxN and PPE41 when the bacteria were grown in phosphate-rich medium. In wild-type M. tuberculosis, phosphate limitation activated esx-5 transcription and secretion of both EsxN and PPE41, and this response required RegX3. Electrophoretic mobility shift assays revealed that RegX3 binds directly to a promoter within the esx-5 locus. Remarkably, phosphate limitation also induced secretion of EsxB, an effector of the virulence-associated ESX-1 secretion system, though this induction was RegX3 independent. Our work demonstrates that the Pst/SenX3-RegX3 system directly regulates ESX-5 secretion at the transcriptional level in response to phosphate availability and defines phosphate limitation as an environmental signal that activates ESX-5 secretion.