Figure 3.

Regulation of the P. aeruginosa T3SS. Genetic regulation of the P. aeruginosa T3SS is complex. The O₂ sensor, ANR, activates T3SS gene expression indirectly (dashed lines) via activation of narL gene expression under low O₂ conditions and subsequent effects of the regulatory RNAs, rgRsmY and rgRsmZ on expression of the regulator RsmA. The activity of the rgRsmY and rgRsmZ regulatory RNAs is also controlled by the RetS/LadS/GacS/GacA cascade. The two-component system GacS–GacA is required for virulence in many hosts and phosphorylated GacA activates expression of rgRsmY and rgRsmZ. GacS is inhibited by formation of heterodimers with RetS and LadS activates the GacS–GacA system by an as yet unknown mechanism. In the presence of high Ca(II) concentrations, ExsE sequesters the anti-anti-activator ExsC, permitting the anti-activator ExsD to interact with the activator ExsA. Consequently, expression of the 43 genes required for the function of the T3SS is not activated. In the presence of low Ca(II) concentrations, ExsE is secreted. As a result ExsC sequesters ExsD, releasing ExsA to activate genes encoding the T3SS. ExsA-mediated activation is also antagonized by the anti-activator PtrA, by PtrB via the RecA response to DNA damage, and by PsrA (in response to long chain fatty acids, LCFA). The alginate regulators (MucA, AlgT/U, AlgR) act to repress T3SS expression indirectly. In addition, the efflux pump regulator MexT controls T3SS gene expression via the action of PtrC. T3SS genes are represented by a single rectangle. Arrows indicate activation, T-junctions indicate repression, solid lines indicate direct regulation, and dashed lines indirect regulation.