Dataset Information

Acetylation of lysine 182 inhibits the ability of Mycobacterium tuberculosis DosR to bind DNA and regulate gene expression during hypoxia.

ABSTRACT: The DosR regulon is believed to be a key factor in latency adaptation of Mycobacterium tuberculosis and is strongly induced by multiple stresses, including hypoxia. Previous studies have revealed reversible acetylation of the conserved core DNA-binding lysine residue 182 (K182) of DosR in M. tuberculosis. In this study, we demonstrated that acetylated K182 plays an important role in the DNA-binding ability of DosR and that acetylation of K182 completely abolished the affinity of DosR for DNA in vitro. Antibodies that specifically recognized acetyllysine at position 182 of DosR were used to monitor DosR acetylation. We found that in vitro acetylation of K182 could be removed by deacetylase Rv1151c and that either the deacetylase-deletion strain ∆npdA or treatment with a deacetylase inhibitor resulted in increased levels of K182 acetylation in vivo. The physiological significance of DosR acetylation was demonstrated by decreased levels of acetylated K182 in M. tuberculosis in response to hypoxia and by the effects of K182 acetylation on the transcript levels of DosR regulon genes. Since the DosR regulon plays a critical role during host infection by M. tuberculosis, our findings suggest that targeting DosR acetylation may be a viable strategy for antituberculosis drug development.

SUBMITTER: Bi J

PROVIDER: S-EPMC5999986 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Acetylation of lysine 182 inhibits the ability of Mycobacterium tuberculosis DosR to bind DNA and regulate gene expression during hypoxia.

Bi Jing J Gou Zongchao Z Zhou Fengzhu F Chen Yiqing Y Gan Jianhua J Liu Jun J Wang Honghai H Zhang Xuelian X

Emerging microbes & infections 20180613 1

The DosR regulon is believed to be a key factor in latency adaptation of Mycobacterium tuberculosis and is strongly induced by multiple stresses, including hypoxia. Previous studies have revealed reversible acetylation of the conserved core DNA-binding lysine residue 182 (K182) of DosR in M. tuberculosis. In this study, we demonstrated that acetylated K182 plays an important role in the DNA-binding ability of DosR and that acetylation of K182 completely abolished the affinity of DosR for DNA in ...[more]

PMID: 29899473

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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

Acetylation of lysine 182 inhibits the ability of Mycobacterium tuberculosis DosR to bind DNA and regulate gene expression during hypoxia.

Publications

Acetylation of lysine 182 inhibits the ability of Mycobacterium tuberculosis DosR to bind DNA and regulate gene expression during hypoxia.

Similar Datasets

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