According to the established model, cognate antitoxin and toxin, which are encoded by co-transcribed genes, form a tight complex and antitoxin inhibits the toxin through direct protein-protein interaction.
Antitoxin, both alone and in complex with the toxin, binds to the operator DNA and auto-represses transcription of the TA operon. Free toxin in excess disrupts this DNA-protein interaction and induces transcriptional de-repression. We show that transcription of TA genes can be induced also by non-cognate Selleckchem Eltanexor toxins. Moreover, cleavage of the TA mRNA by both cognate and non-cognate toxins results in accumulation of the toxin-encoding mRNA fragments. Translation of these fragments can lead to accumulation of free toxin. Induction of the chromosomal relBEF in response to the ectopically produced RelE can be explained by conditional cooperativity (dependence of transcriptional regulation
on the T:A ratio) . However, according to our current knowledge, such mechanism is not applicable to cross-induction. Activation of YoeB by VapC depended on Lon protease . Also, Lon was required for Fedratinib chemical structure induction of TA operons in response to amino acid starvation and chloramphenicol [14, 17, 18, 61]. Our experiments do not provide a solid support for the role of Lon and ClpP in cross-regulation between TA systems of E. coli (Figure 4). Since the Quisinostat cross-induction was present in the knock-out strains, an additional, Lon-, ClpP-, HslV-, and polyphosphate-independent mechanism of regulation must be involved. Unlocking this mechanism remains a task
for future studies. The simplest explanation to activation of TA systems would be depletion of antitoxins. It must inevitably happen when protein synthesis decreases. That predicts nonselective induction of all TA operons in response to inhibition of translation, no matter if it is caused by starvation or artificial production of a toxin. Requirement of relBE for transcriptional activation of mazEF during amino acid starvation (Figure 3) contradicts this prediction click here as well as the lack of mqsRA induction in response to overproduction of MazF and HicA (data not shown). An option for a mechanism of cross-activation is positive feedback regulation due to selective accumulation of toxin-encoding fragments upon mRNA cleavage. As we saw, after cleavage by overproduced toxin, the antitoxin-encoding RNA fragments are rapidly degraded while the toxin-encoding fragments may serve as templates for translation of toxin. Different toxins produce different cleavage products. That can potentially explain why they cause unequal level of trans-activation when overproduced. Another intriguing issue of TA cross-reaction is the possible cross-inhibition due to non-cognate interactions. Some authors report such cross-reactions [63–68] while others have tested but not found them [69, 70]. As a part of this study, we examined non-cognate inhibition between E.