EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System.
EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System.
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EspM 是一种保守转录因子，可调节基因表达以响应 ESX-1 系统。
DOI：
10.1128/mbio.02807-19
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发表时间：
2020
期刊：
影响因子：
6.4
通讯作者：
Champion,PatriciaA
中科院分区：
文献类型：
--
作者：
Sanchez,KevinG;Ferrell,MicahJ;Chirakos,AlexandraE;Nicholson,KathleenR;Abramovitch,RobertB;Champion,MatthewM;Champion,PatriciaA
在巨噬细胞感染过程中，致病分支杆菌会遇到多种环境。在时间上，细菌被吞噬到吞噬小体中，溶解吞噬小体的膜，并在扩散到另一个细胞之前与胞浆相互作用。分枝杆菌ESX-1(ESAT-6-System-1)分泌系统分泌的毒力因子介导了从吞噬小体到胞浆的本质转变。最近发现，ESX-1系统还调节海洋分枝杆菌(R.E.Bosserman，T.T.Nguyen，K.G.Sanchez，A.E.Chirakos，等，Proc Natl Acad Sci U S A114：E10772-E10781,2017年，https://doi.org/10.1073/pnas.1710167114)，，一种非结核分枝杆菌病原体)以及在人类致病物种结核分枝杆菌(A.M.Abdallah，E.M.Weerdenburg，Q.Guan，R.Ummels等，PLoS One 14：E0211003,2019，Https://doi.org/10.1371/journal.pone.0211003).目前尚不清楚ESX-1系统是如何调控基因表达的。在这里，我们确定了致病分枝杆菌中ESX-1依赖的转录反应所需的第一个转录因子。我们证明了该基因从WhiB6基因差异转录而来，在分枝杆菌病原体中与ESX-1基因座相邻，编码一个保守的转录因子(MMAR_5438，Rv3863，now espM)。我们证明了来自海洋分枝杆菌和结核分枝杆菌的ESPM直接和特异性地结合了WhiB6-esp基因间区。我们表明，ESPM是ESX-1依赖的抑制WhiB6表达和调节ESX-1相关基因表达所必需的。最后，我们证明了ESPM在微调海洋分枝杆菌ESX-1活性方面的作用。综上所述，本报告扩展了esx-1基因座，定义了ESX-1毒力途径的保守调节因子，并开始阐明ESX-1系统如何调节基因表达。重要的是，分枝杆菌病原体利用ESX-1系统运输蛋白质底物，在感染过程中介导与宿主的必要相互作用。我们先前证明，除了运输蛋白质外，ESX-1分泌系统还调节基因表达。在这里，我们确定了一个保守的转录因子，它调节基因的表达，以响应ESX-1系统。我们证明，这种转录因子在海洋分枝杆菌、结核分枝杆菌和污垢分枝杆菌中功能上是保守的。海洋分枝杆菌是一种外温动物的病原体；结核分枝杆菌是导致结核病的人类致病物种；这些发现为ESX-1系统如何引发转录反应提供了第一个机械性的见解，转录反应是这个蛋白质运输系统以前未知的功能。
Pathogenic mycobacteria encounter multiple environments during macrophage infection. Temporally, the bacteria are engulfed into the phagosome, lyse the phagosomal membrane, and interact with the cytosol before spreading to another cell. Virulence factors secreted by the mycobacterial ESX-1 (ESAT-6-system-1) secretion system mediate the essential transition from the phagosome to the cytosol. It was recently discovered that the ESX-1 system also regulates mycobacterial gene expression in Mycobacterium marinum (R. E. Bosserman, T. T. Nguyen, K. G. Sanchez, A. E. Chirakos, et al., Proc Natl Acad Sci U S A 114:E10772–E10781, 2017, https://doi.org/10.1073/pnas.1710167114), a nontuberculous mycobacterial pathogen, and in the human-pathogenic species M. tuberculosis (A. M. Abdallah, E. M. Weerdenburg, Q. Guan, R. Ummels, et al., PLoS One 14:e0211003, 2019, https://doi.org/10.1371/journal.pone.0211003). It is not known how the ESX-1 system regulates gene expression. Here, we identify the first transcription factor required for the ESX-1-dependent transcriptional response in pathogenic mycobacteria. We demonstrate that the gene divergently transcribed from thewhiB6gene and adjacent to the ESX-1 locus in mycobacterial pathogens encodes a conserved transcription factor (MMAR_5438,Rv3863, nowespM). We prove that EspM from both M. marinum and M. tuberculosis directly and specifically binds thewhiB6-espMintergenic region. We show that EspM is required for ESX-1-dependent repression ofwhiB6expression and for the regulation ofESX-1-associated gene expression. Finally, we demonstrate that EspM functions to fine-tune ESX-1 activity in M. marinum. Taking the data together, this report extends theesx-1locus, defines a conserved regulator of the ESX-1 virulence pathway, and begins to elucidate how the ESX-1 system regulates gene expression.IMPORTANCEMycobacterial pathogens use the ESX-1 system to transport protein substrates that mediate essential interactions with the host during infection. We previously demonstrated that in addition to transporting proteins, the ESX-1 secretion system regulates gene expression. Here, we identify a conserved transcription factor that regulates gene expression in response to the ESX-1 system. We demonstrate that this transcription factor is functionally conserved in M. marinum, a pathogen of ectothermic animals; M. tuberculosis, the human-pathogenic species that causes tuberculosis; and M. smegmatis, a nonpathogenic mycobacterial species. These findings provide the first mechanistic insight into how the ESX-1 system elicits a transcriptional response, a function of this protein transport system that was previously unknown.