Multiple toxin-antitoxin systems in Mycobacterium tuberculosis

Abstract

The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence phase are poorly understood. Remarkably, M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. In agreement with the capacity of stress-responsive TA systems to generate persisters in other bacteria, it has been proposed that activation of TA systems in M. tuberculosis could contribute to its pathogenesis. Herein, we review the current knowledge on the multiple TA families present in this bacterium, their mechanism, and their potential role in physiology and virulence.

Figure 1

Chromosomal map of M. tuberculosis H37Rv TA systems. TA systems are annotated according to the tuberculist database except for VapBC45 (Rv2018-Rv2019), VapBC49 (Rv3181c-Rv3180c), VapBC50 (Rv3750c-Rv3749c), HigBA2 (Rv2022c-Rv2021c), HigBA3 (Rv3182-Rv3183), YefM/YoeB (Rv3357-Rv3358), and MazEF10 (Rv0298-Rv0299). Most of the TA systems depicted here likely belong to type II, expect for those marked with an asterisk, which are putative type IV systems. For each system, the functionality in E. coli (Ec), M. smegmatis (Msm), and M. tuberculosis (Mtb), is depicted: red color stands for “inhibition of growth”, grey for “no inhibition of growth”, and white for “not tested”. The 10 most induced TA systems in drug-tolerant persister cells are highlighted on dark blue background.

Figure 2

Proposed mechanism for TAC. In M. tuberculosis, the TAC genes Rv1955-Rv1956-Rv1957, respectively, encode the toxin HigB1 (T), the antitoxin HigA1 (A) and the chaperone Rv1957 (C). They are located within an operon also containing the less conserved upstream Rv1954A gene of unknown function. Expression of TAC is regulated by two promoters: the promoter P1, which contains a RecA-NDp motif characteristic of LexA/RecA-independent genes in M. tuberculosis and the promoter P2, recognized by the HigA1 antitoxin. Repression of the TAC operon by HigA1 could occur in complex with its HigB1 and/or Rv1957 partners and HigA1 could regulate other genes as well. The SecB-like chaperone Rv1957 facilitates the folding of HigA1 and prevents its degradation by proteases (potentially ClpC1 or ClpX together with the ClpP1ClpP2 proteolytic subunit). Although interaction with the chaperone renders HigA1 competent to neutralize the toxin, it is not known whether Rv1957 is part of the final inactive complex. Activation of the HigB1 toxin in response to stress, which induces growth inhibition through mRNA cleavage, mostly likely requires chaperone unavailability and subsequent degradation of the antitoxin, perhaps triggered by recruitment of the chaperone for Sec-dependent functions or by unbalanced proteostasis.