Control of Pseudomonas aeruginosa AlgW protease cleavage of MucA by peptide signals and MucB

The ability of a pathogen to survive the defensive attacks of its host requires the detection of and response to perturbations in its own physiology. Activation of the extracytoplasmic stress response in the pathogen Pseudomonas aeruginosa results in higher tolerance against immune defences as well as in the production of alginate, a surface polysaccharide that also confers resistance to many host defences and antibiotic treatments. The alginate response is regulated by proteolytic cleavage of MucA, a transmembrane protein that inhibits the transcription factor AlgU, and by the periplasmic protein MucB. Here we show that specific peptides bind to the periplasmic AlgW protease and activate its cleavage of MucA. We demonstrate that tight binding of MucB to MucA strongly inhibits this cleavage. We also probe the roles of structural features of AlgW, including a key regulatory loop and its PDZ domain, in regulating substrate binding and cleavage.