Such overlap is in agreement with the very low conservation observed between the different MazE antioxins in this bacterium (4% to 22% of identity) and with the fact that VapB27 and VapB40 are closely related to the _E. coli_ MazE. Accordingly, the non-cognate antiotoxins MazE1 to 7 and MazE9 could neither interact with MazF6 nor alleviate its toxicity [45]. In contrast, _M. tuberculosis_ MazF toxins are well conserved with up to 46% sequence identity. Together, these findings suggest that intricate networks of TA systems may exist in this pathogen. Mutations in the _relB_ gene in _E. coli_ were originally identified as conferring a delayed relaxed phenotype of the stringent response to amino acid starvation [46]. Later, it was shown that this phenotype was due to destabilization of the RelB antitoxin, leading to hyperactivation of the toxin RelE [47]. The YefM/YoeB family, named after its _E. coli_ member, was first described as homologous of the Axe-Txe addiction system of the _Enterococcus faecium_ plasmid pRUM [48]. _The YefM antitoxins are homologous to_ Phd, the antitoxin of the Phd-Doc module of phage P1, whereas the YoeB toxins belong to the RelE superfamily [1]. Both RelE and YoeB toxins from _E. coli_ are ribosome-dependent ribonucleases that cleave mRNA at the ribosomal A site [32]. Nevertheless, despite sequence and structural homology, _E. coli_ RelE and YoeB seem to act by distinct mechanisms: RelE binds to the 30S subunit of 70S ribosomes and inhibits translation elongation, whereas YoeBbinds to the 50S subunit and inhibits translation initiation [32]. RelE from _E. coli_ was also shown to cleave tmRNA, thus, suggesting delicate interplay between such toxins and quality control mechanisms in response to amino acid starvation [49]. _M. tuberculosis_ encodes for two RelBE systems, namely RelBE1 (Rv1247c-Rv1246c) and RelBE2 (Rv2865-Rv2866), and one YefM/YoeB (Rv3357-Rv3358). Note that the YefM/YoeB module discussed here was previously annotated as RelEB3, due to the fact that the toxin belongs to the RelE superfamily of ribonucleases. Yet, the YefM/YoeB (RelBE3) proteins from _M. tuberculosis_ are very close to those of the _E. coli_ YefM/YoeB system (58% and 68% sequence similarity respectively), with the mycobacterial toxin containing the conserved C-terminal histidine and tyrosine residues of YoeB involved in RNAse activity and not present in RelE [50, 51]. Therefore, in contrast with RelBE1 and 2, the RelBE3 system clearly belongs to the YefM/YoeB family. Previous gel filtration analyses of the _M. tuberculosis_ YefM/YoeB complex suggested that it may form a heterotrimeric complex, as it is the case for the _E. coli_ homologs [52]. However, structural analysis of both RelBE2 and YefM/YoeB revealed very similar heterotetrameric complexes composed of two heterodimers of one toxin bound to one antitoxin, with tetramerization occurring mainly via interaction between the two antitoxins [53]. Interestingly, while both RelE2 and YoeB toxins showed characteristic folds of RelE-like toxins [53], the structure of their respective antitoxins RelB2 and YefM were related the YefM/Phd antitoxins and not to either the _E. coli_ or the archeal RelB [53]. As for YoeB, inactivation of _E. coli_ RelE upon binding to RelB seems to occur via a conformational shift in the catalytic site of the toxin [50, 54]. The two RelBE and the YefM/YoeB systems of _M. tuberculosis_ were shown to be functional TA systems in _E. coli_, _M. smegmatis_, and in _M. tuberculosis_[18, 55]. In agreement with their different mechanisms of action, the toxin YoeB was less toxic than RelE1 and RelE2 when expressed in _M. smegmatis_[53]. Similar results were obtained in _E. coli_, where YoeB expression only weakly affected colony-forming [47]. Intriguingly, [PERSON] and colleagues [56] proposed that there might be complex interplays between these three systems with different patterns of cross interaction and promoter regulation.