Figure 3. Regulation of V. cholerae Type 6 Secretion System (T6SS).

The V. cholerae T6SS plays an important role in the life cycle of this pathogen, enhancing inter- and intra-species competition, protection from predators, and virulence. In strains where this system is not constitutively active, the T6SS is regulated in response to a number of environmental signals. Though it is unknown what signal TsrA responds to, this regulator represses the T6SS and the master virulence regulator ToxT, while activating HapA expression, which is involved in mucin degradation. Low osmolarityresults in activation of the osmoregulator, OscR, which represses the T6SS. Quorum sensing (QS) also regulates the T6SS in response. At low cell density, LuxO is phosphorylated and activates the expression of quorum regulatory small RNAs (Qrr sRNAs), which repress the T6SS through both direct binding to the promoter regions of T6SS genes and through their inhibition of the positive regulator of T6SS, HapR. At high cell density, both HapR and the cAMP-CRP complex activate T6SS. HapR also actives QstR, which upregulates T6SS in response to growth on chitin. Flagellar regulatory genes are known to repress the T6SS through an unknown mechanism. Additionally, VasH, which is encoded by the T6SS pathogenicity island, is known to activate T6SS genes, potentially through its interaction with the alternative sigma factor RpoN, which appears to co-regulate T6SS genes in cAMP-CRP dependent manner. Intriguingly, RpoN is also known to active Qrr sRNAs, which repress the T6SS.