Abstract
RelBE represents a typical bacterial toxin-antitoxin (TA) system. Mycobacterium tuberculosis H37Rv, the pathogen responsible for human tuberculosis, contains three RelBE-like modules, RelBE, RelFG, and RelJK, which are at least partly expressed in human macrophages during infection. RelBE modules appear to be autoregulated in an atypical manner compared to other TA systems; however, the molecular mechanisms and potential interactions between different RelBE modules remain to be elucidated. In the present study, we characterized the interaction and cross-regulation of these Rel toxin-antitoxin modules from this unique pathogen. The physical interactions between the three pairs of RelBE proteins were confirmed and the DNA-binding domain recognized by three RelBE-like pairs and domain structure characteristics were described. The three RelE-like proteins physically interacted with the same RelB-like protein, and could conditionally regulate its binding with promoter DNA. The RelBE-like modules exerted complex cross-regulation effects on mycobacterial growth. The relB antitoxin gene could replace relF in cross-neutralizing the relG toxin gene. Conversely, relF enhanced the toxicity of the relE toxin gene, while relB increased the toxicity of relK. This is the first report of interactions between different pairs of RelBE modules of M. tuberculosis.
Highlights
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to pose a serious threat to human health [1]
We first used a bacterial two-hybrid technique to detect the interactions between the three pairs of M. tuberculosis RelBE-like proteins
For M. tuberculosis, its dormancy within a macrophage could potentially be mediated by three pairs of relBE-like genes that are expressed during infection [21]
Summary
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to pose a serious threat to human health [1]. Eradication of tuberculosis is hampered by our poor understanding of the strategies used by this pathogen for surviving in a dormant state within the phagosome following infection of macrophages [3]. As in a number of other pathogens, dormant infection of M. tuberculosis is likely to involve bacterial toxin-antitoxin (TA) systems, which are ubiquitous in free-living bacteria and archaea [4,5,6]. TA modules are defined as protein pairs consisting of a toxin and its antitoxin; the antitoxin can bind to the toxin and neutralize its toxic effects [3]. A pair of toxinantitoxin proteins will exist as a stable complex [7,8]. In response to stressful or unfavorable growth conditions, the antitoxin is often triggered to degrade, which results in liberation of the toxin. M. tuberculosis contains more than 38 toxin-antitoxin loci [8,9]
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