New roles for PagP in bacterial evasion of host immune defenses

PagP is an outer membrane enzyme of Gram-negative bacteria that functions to attenuate the host immune response to infections. The E. coli homologue is a small beta-barrel with an interior palmitoyl-group binding pocket known as the hydrocarbon ruler. The phospholipid donor must migrate into the external leaflet before diffusing laterally through the beta-barrel wall at a site known as the crenel. It is here that regiospecificity for the sn-1 acyl chain is enforced, with the result that C18 acyl chains at sn-2 are excluded. The main function of the hydrocarbon ruler is to exclude C14 acyl chains esterified at the sn-1 position. The acceptor of the palmitate chain is lipid A, or endotoxin, an acylated and phosphorylated disaccharide of glucosamine. Lipid A binds opposite the crenel at another lateral opening in the beta-barrel wall known as the embrasure. The reaction depends on the formation of a ternary complex with the acyltransfer dependent on His33 and Ser77, and with Arg114 functioning to position the head group of the phospholipid donor. Recently, we have observed that phosphatidylglycerol (PG) also functions as a palmitate acceptor for PagP, which leads to the accumulation of palmitoyl PG in the outer membrane. Additionally, despite the apparent absence of PagP from Pseudomonas aeruginosa, a divergent homologue does in fact exist, and serves to palmitoylate lipid A on the opposite glucosamine sugar compared to that of E. coli. Importantly, P. aeruginosa isolated from airways of chronically infected cystic fibrosis patients are found to possess constitutively palmitoylated lipid A.