Figure 4. The cell-to-cell signaling circuitry of P. aeruginosa. The las cell-to-cell signaling system controls the rhl cell-to-cell signaling system in a hierarchy cascade. The LasR/3-oxo-C12-HSL complex activates the transcription of rhlR, and 3-oxo-C12-HSL blocks the activation of RhlR by C4-HSL. The las system itself is controlled positively by Vfr and GacA, and negatively by RsaL. 3-oxo-C12-HSL is required for biofilm differentiation and has immunomodulatory activity. Both cell-to-cell signaling systems regulate the expression of numerous genes (lasB: LasB elastase, lasA: LasA elastase, toxA: exotoxin A, aprA: alkaline protease, xcpP and xcpR: genes of the xcp secretory pathway, rhlAB: rhamnosyltransferase required for rhamnolipid production, rpoS: stationary phase sigma factor).