coli_ and in mycobacteria, and has been more extensively studied as part of the TAC system. The TAC (toxin-antitoxin-chaperone) system from _M. tuberculosis_ is encoded by three genes organized in operon, _Rv1955-Rv1956-Rv1957_, respectively encoding the HigBA1 TA pair (_Rv1955-Rv1956_) and a chaperone _Rv1957_ related to the generic export chaperone SecB [64]. The operon also contains the upstream less conserved _Rv1954a_ gene of unknown function. It has been shown that HigBA1 of TAC is specifically controlled by Rv1957 through a direct interaction between the chaperone and the antitoxin, allowing antitoxin folding and protection from degradation (Figure 2) [64]. Accordingly, expression of the HigA1 antitoxin does not counteract the severe toxicity induced by HigB1 in the absence of the chaperone, both in _E. coli_ and mycobacteria [64]. In addition, single deletion of _higA1_ in _M. tuberculosis_ is lethal [65], while disruption of _Rv1957_ alone exhibits a slow growth phenotype most likely due to a reduced antitoxin activity [41]. Therefore, it is very likely that the HigB1 activation cascade is triggered either by a decrease in expression or by direct hijacking of the chaperone at the post-translational level (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 ClpP1 ClpP2 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. TAC is conserved in all members of the _M. tuberculosis_ complex and a recent evolutionarily study showed that SecB-like chaperones associated with toxin-antitoxin systems can be found in many bacterial phyla [66]. Remarkably, this analysis also revealed that the presence of a chaperone was not restricted to HigBA TA pairs [66]. In addition, some bacteria, including _M. smegmatis_, only possess an antitoxin/chaperone pair, possibly due to the loss of the upstream toxin gene [66]. As stated above, expression of the HigB1 toxin in the absence of HigA1 and Rv1957 severely inhibits _E. coli_, _M. smegmatis, M. marinum_, and _M. tuberculosis_ growth (Figure 2) [15,16,67]. A recent study performed in _M. tuberculosis TAC_ mutant revealed a general decrease of over 30 transcripts upon HigB1 overexpression, whereas only a limited number of genes were found induced in this context [67]. Strikingly, most of the dysregulated mRNA transcripts were putative targets of the iron- and zinc-transcriptional regulators IdeR/Rv2711 and/or Zur/Rv2359, known to limit the expression of iron and zinc uptake systems in conditions of high iron and zinc amounts, respectively. Therefore, these results suggest that HigB1 could respond to iron and/or zinc overload, and allow the rapid degradation of metal uptake systems, once the bacterial cell is replenished in iron and/or zinc, in order to avoid intoxication [68].