Dataset Information

Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.

ABSTRACT: SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in Mycobacterium tuberculosis, and this sigma factor is required for virulence in animal models of infection. SigH is negatively regulated by RshA, its cognate anti-sigma factor, which functions as a stress sensor and redox switch. While RshA provides a direct mechanism for sensing stress and activating transcription, bacteria use several types of signal transduction systems to sense the external environment. M. tuberculosis encodes several serine-threonine protein kinase signaling molecules, 2 of which, PknA and PknB, are essential and have been shown to regulate cell morphology and cell wall synthesis. In this work, we demonstrate that SigH and RshA are phosphorylated in vitro and in vivo by PknB. We show that phosphorylation of RshA, but not SigH, interferes with the interaction of these 2 proteins in vitro. Consistent with this finding, negative regulation of SigH activity by RshA in vivo is partially relieved in strains in which pknB is over-expressed, resulting in increased resistance to oxidative stress. These findings demonstrate an interaction between the signaling pathways mediated by PknB and the stress response regulon controlled by SigH. The intersection of these apparently discrete regulatory systems provides a mechanism by which limited activation of the SigH-dependent stress response in M. tuberculosis can be achieved. Coordination of the PknB and SigH regulatory pathways through phosphorylation of RshA may lead to adaptive responses that are important in the pathogenesis of M. tuberculosis infection.

SUBMITTER: Park ST

PROVIDER: S-EPMC2529121 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.

Park Sang Tae ST Kang Choong-Min CM Husson Robert N RN

Proceedings of the National Academy of Sciences of the United States of America 20080826 35

SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in Mycobacterium tuberculosis, and this sigma factor is required for virulence in animal models of infection. SigH is negatively regulated by RshA, its cognate anti-sigma factor, which functions as a stress sensor and redox switch. While RshA provides a direct mechanism for sensing stress and activating transcription, bacteria use several types of signal transduction systems ...[more]

PMID: 18728196

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Project description:The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosR-dosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure. Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.

Dataset Information

Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.

Publications

Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis.

Similar Datasets

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