Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen <i>Enterococcus faecalis</i>

ABSTRACTWe discovered a chromosomal locus containing two toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the <i>E. faecalis</i> clinical isolate V583. These TAs are homologous to the type I <i>txpA-ratA</i> system and the type II <i>mazEF</i>, respectively. We have shown that the putative MazF is toxic for <i>E. coli</i> and triggers RNA degradation, and its cognate antitoxin MazE counteracts toxicity. The second module, adjacent to <i>mazEF</i>, expresses a toxin predicted to belong to the TxpA type I family found in <i>Firmicutes</i>, and the antisense RNA antidote, RatA. Genomic analysis indicates that the <i>cis</i>-association of <i>mazEF</i> and <i>txpA-ratA</i> modules has been favored during evolution, suggesting a selective advantage for this TA organization in the <i>E. faecalis</i> species. We showed regulatory interplays between the two modules, involving transcription control and RNA stability. Remarkably, our data reveal that MazE and MazEF have a dual transcriptional activity: they act as autorepressors and activate <i>ratA</i> transcription, most likely in a direct manner. RatA controls <i>txpA</i> RNA levels through stability. Our data suggest a pivotal role of MazEF in the coordinated expression of <i>mazEF</i> and <i>txpA-ratA</i> modules in V583. To our knowledge, this is the first report describing a crosstalk between type I and II TAs.