Proteolytic feedback of quorum sensing promotes infection by Pseudomonas aeruginosa

Proteolytic degradation plays a crucial role in regulating quorum sensing (QS) in Pseudomonas aeruginosa, a bacterium responsible for chronic infections in cystic fibrosis patients. Researchers have discovered a negative feedback loop involving the RhlR protein, a LuxR-type transcription factor that controls virulence gene expression at high cell densities.

RhlR's activity is tightly regulated by the accessory protein PqsE, which is required for its full functionality. However, the mechanism by which QS circuits are reset or attenuated has remained elusive. In this study, scientists identified an N-terminal degron within RhlR that is protected from protease recognition by PqsE binding. This degron is essential for RhlR degradation by both the Lon and ClpP1-ClpP2 protease complexes.

Removing the degron stabilizes RhlR, leading to earlier QS-regulated gene expression. This alteration enhances biofilm formation, imposes a competitive fitness cost in vitro, and reduces virulence in an acute mouse lung infection. Mechanistically, RhlR directly activates the transcription of clpP2, encoding a subunit of the protease complex responsible for its own degradation.

This self-limiting negative feedback loop establishes a mechanism by which receptor turnover may facilitate the transition away from high-cell density states. The findings reveal proteolytic turnover as an underappreciated regulatory layer of QS activation, shedding light on the complex interplay between bacterial signaling and virulence.