Independent Regulation of Type VI Secretion in Vibrio cholerae by TfoX and TfoY

Type VI secretion systems (T6SSs) are nanomachines used for interbacterial killing and intoxication of eukaryotes. Although Vibrio cholerae is a model organism for structural studies on T6SSs, the underlying regulatory network is less understood. A recent study showed that the T6SS is part of the natural competence regulon in V. cholerae and is activated by the regulator TfoX. Here, we identify the TfoX homolog TfoY as a second activator of the T6SS. Importantly, despite inducing the same T6SS core machinery, the overall regulons differ significantly for TfoX and TfoY. We show that TfoY does not contribute to competence induction. Instead, TfoY drives the production of T6SS-dependent and T6SS-independent toxins, together with an increased motility phenotype. Hence, we conclude that V. cholerae uses its sole T6SS in response to diverse cues and for distinctive outcomes: either to kill for the prey's DNA, leading to horizontal gene transfer, or as part of a defensive escape reaction. Metzger et al. find that the type VI secretion system (T6SS) of Vibrio cholerae is activated by TfoX and TfoY. Such dual regulation of the T6SS of V. cholerae suggests that this molecular killing device is activated by diverse environmental cues.