## 2 Multi-Level Interactions between TA Systems
### TA Systems Sharing the Same Replicon
#### 2.1.2 TA systems Trans-Activation by Non-cognate Toxins  
As most type II toxins are endoribonucleases, the expression of these toxins may impact gene expression in general (see below) and, in particular, that of TA systems. It was shown that overexpression of _E. coli_ toxins (RelE, MazF, MqsR, HicA and HipA) trans-activates the _relBE_ system by alleviation of transcriptional repression [53]. In addition, post-transcriptional regulations of newly synthesized mRNAs occur, as toxin overexpression might lead to the degradation of the antitoxin-encoding portion of mRNAs and accumulation of the toxin-encoding region [53]. As a result, this could generate an unbalanced antitoxin:toxin ratio, leading to toxin accumulation. However, this might not be a universal phenomenon, as the antitoxin transcript of a plasmidic system was recently shown to be unaffected by its cognate toxin. The authors proposed that this would allow for reversible activation of TA systems [54]. Recently, the [PERSON] group showed that the _E. coli mqsRA_ system activates the type V _ghoST_ system [55]. The molecular mechanism relies on the endoribonuclease activity of the type II MqsR toxin. MqsR activates the expression of _ghoT_ by cleaving the antitoxin-encoding portion of the _ghoS-ghoT_ messenger [55].  
Trans-activation of _E. coli_ TA systems has also been reported upon overexpression of phage and plasmid-encoded toxins, e.g., overexpression of the type II Doc toxin encoded by the P1 phage leads to _relBE_ trans-activation [56] and that of the _Shigella_ plasmid, pMYSH6000 VapC, activates the type II _yefM-yoeB_ system [57]. However, it is not known whether these toxins specifically degrade the antitoxin-encoding portion of the messenger. In the same line of reasoning, one could also imagine that in the addiction phenomenon, plasmid-encoded toxins induce a chain reaction by indirectly activating chromosomally-encoded toxins.  
In general, the molecular mechanisms underlying trans-activation remain to be determined. In the case of type II systems, it is not clear how the first step of trans-activation occurs. How is the non-cognate toxin able to alleviate repression of a given TA operon? In the case of cognate systems, it has been  
Figure 2: Interactions between TA systems. (**A**) In most cases, antiotoxins and toxins only interact with their cognate partners; (**B**) chromosomal systems can interact with homologous systems, such as for anti-addiction; (**C**) TA systems can bind non-canonical antiotoxins and toxins, which can lead to network formation and (**D**) a toxin can be inhibited by a protein not related to TA systems, as in the case of Dmd of the T4 phage.  
shown by several groups [26, 27, 58] that disruption of the antitoxin:toxin ratio in favor of toxin allows the formation of a specific toxin-antitoxin complex unable to mediate repression, thereby allowing re-synthesis of both components. However, in the case of a non-cognate toxin, one would have to imagine that non-cognate complexes are formed and share the same properties. Another hypothesis relies on the fact that all these experiments have been performed with toxins showing translation inhibition activity. Overexpression of these toxins will lead to translation arrest. As antiotoxins are unstable, they would be rapidly degraded, leading to repression alleviation. Therefore, trans-activation could be a secondary effect of translation inhibition. However, as some specificity is observed (a given toxin does not trans-activate all the TA systems), the mechanisms involved might be subtler.