Cell-type-specific hypertranslocation of effectors by the Pseudomonas aeruginosa type III secretion system

Many Gram-negative pathogens use a type III secretion system (T3SS) to promote disease by injecting effector proteins into host cells. Common to many T3SSs is that injection of effector proteins is feedback inhibited. The mechanism of feedback inhibition and its role in pathogenesis are unclear. In the case of P. aeruginosa, the effector protein ExoS is central to limiting effector injection. ExoS is bifunctional, with an amino-terminal RhoGAP and a carboxy-terminal ADP-ribosyltransferase domain. We demonstrate that both domains are required to fully feedback inhibit effector injection. The RhoGAP-, but not the ADP-ribosyltransferase domain of the related effector protein ExoT also participates. Feedback inhibition does not involve translocator insertion nor pore-formation. Instead, feedback inhibition is due, in part, to a loss of the activating trigger for effector injection, and likely also decreased translocon stability. Surprisingly, feedback inhibition is abrogated in phagocytic cells. The lack of feedback inhibition in these cells requires phagocytic uptake of the bacteria, but cannot be explained through acidification of the phagosome or calcium limitation. Given that phagocytes are crucial for controlling P. aeruginosa infections, our data suggest that feedback inhibition allows P. aeruginosa to direct its effector arsenal against the cell types most damaging to its survival.

Automated summary

It has been found that many Gram-negative pathogens use a type III secretion system to inject effector proteins into host cells, but the injection is feedback inhibited. The effector protein ExoS in P. aeruginosa plays a central role in this feedback inhibition. The feedback inhibition is due to the loss of the activating trigger for effector injection and potentially decreased translocon stability. Surprisingly, feedback inhibition is abrogated in phagocytic cells, which suggests its importance in controlling P. aeruginosa infections.