Secreted transcription factor controls Mycobacterium tuberculosis virulence

Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA.
Nature (Impact Factor: 41.46). 09/2008; 454(7205):717-21. DOI: 10.1038/nature07219
Source: PubMed


Bacterial pathogens trigger specialized virulence factor secretion systems on encountering host cells. The ESX-1 protein secretion system of Mycobacterium tuberculosis-the causative agent of the human disease tuberculosis-delivers bacterial proteins into host cells during infection and is critical for virulence, but how it is regulated is unknown. Here we show that EspR (also known as Rv3849) is a key regulator of ESX-1 that is required for secretion and virulence in mice. EspR activates transcription of an operon that includes three ESX-1 components, Rv3616c-Rv3614c, whose expression in turn promotes secretion of ESX-1 substrates. EspR directly binds to and activates the Rv3616c-Rv3614c promoter and, unexpectedly, is itself secreted from the bacterial cell by the ESX-1 system that it regulates. Efflux of the DNA-binding regulator results in reduced Rv3616c-Rv3614c transcription, and thus reduced ESX-1 secretion. Our results reveal a direct negative feedback loop that regulates the activity of a secretion system essential for virulence. As the virulence factors secreted by the ESX-1 system are highly antigenic, fine control of secretion may be critical to successful infection.

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Available from: Kaman Chan, Jul 18, 2014
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    • "). Studies thus far have largely implicated transcriptional regulators, such as PhoP (Walters et al., 2006; Frigui et al., 2008; Gonzalo-Asensio et al., 2008), EspR (Raghavan et al., 2008; Blasco et al., 2012) and MprAB (Pang et al., 2013) in orchestrating ESX-1 gene expression. Here, EspI is shown for the first time to exert an additional layer of control which is dependent on cellular ATP levels in M. "
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    ABSTRACT: The function of EspI, a 70-kDa protein in Mycobacterium tuberculosis, has remained unclear. Although EspI is encoded by a gene within the esx-1 locus, in this study we clarify previous conflicting results and show that EspI is not essential for ESX-1-mediated secretion or virulence in M. tuberculosis. We also provide evidence that reduction of cellular ATP levels in wild-type M. tuberculosis using the drug bedaquiline completely blocks ESX-1-mediated secretion. Remarkably, M. tuberculosis lacking EspI fails to exhibit this phenotype. Furthermore, mutagenesis of a highly conserved ATP-binding motif in EspI renders M. tuberculosis incapable of shutting down ESX-1-mediated secretion during ATP depletion. Collectively these results show that M. tuberculosis EspI negatively regulates the ESX-1 secretion system in response to low cellular ATP levels and this function requires the ATP-binding motif. In light of our results the potential significance of EspI in ESX-1 function during latent tuberculosis infection and reactivation is also discussed.
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    • "ESX-1 secretion system is the intensely studied T7SS in M. tuberculosis. ESX-1 secretion is required for early replication and full virulence in macrophages, and has multiple effects on host cells (Brodin et al., 2004; McLaughlin et al., 2007; Raghavan et al., 2008). Studies in M. tuberculosis and related mycobacteria have identifi ed components necessary for ESX-1 export activity, including predicted ATPases (EccA1 and EccCb1) and several membrane proteins (MycP1, EccB1, EccCa1, EccD1, and EccE1) (Stanley et al., 2003; Ligon et al., 2012). "
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    ABSTRACT: Mycosin-1 protease (MycP1) is a serine protease anchored to the inner membrane of Mycobacterium tuberculosis, and is essential in virulence factor secretion through the ESX-1 type VII secretion system (T7SS). Bacterial physiology studies demonstrated that MycP1 plays a dual role in the regulation of ESX-1 secretion and virulence, primarily through cleavage of its secretion substrate EspB. MycP1 contains a putative N-terminal inhibitory propeptide and a catalytic triad of Asp-His-Ser, classic hallmarks of a subtilase family serine protease. The MycP1 propeptide was previously reported to be initially inactive and activated after prolonged incubation. In this study, we have determined crystal structures of MycP1 with (MycP1(24-422)) and without (MycP1(63-422)) the propeptide, and conducted EspB cleavage assays using the two proteins. Very high structural similarity was observed in the two crystal structures. Interestingly, protease assays demonstrated positive EspB cleavage for both proteins, indicating that the putative propeptide does not inhibit protease activity. Molecular dynamic simulations showed higher rigidity in regions guarding the entrance to the catalytic site in MycP1(24-422) than in MycP1(63-422), suggesting that the putative propeptide might contribute to the conformational stability of the active site cleft and surrounding regions.
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