title: Proapoptotic effects of P. aeruginosa involve inhibition of surfactant phosphatidylcholine synthesis.
abstract: Pseudomonas aeruginosa causes sepsis-induced acute lung injury, a disorder associated with deficiency of surfactant phosphatidylcholine (PtdCho). P. aeruginosa (PA103) utilizes a type III secretion system (TTSS) to induce programmed cell death. Herein, we observed that PA103 reduced alveolar PtdCho levels, resulting in impaired lung biophysical activity, an effect partly attributed to caspase-dependent cleavage of the key PtdCho biosynthetic enzyme, CTP:phosphocholine cytidylyltransferase-alpha (CCTalpha). Expression of recombinant CCTalpha variants harboring point mutations at putative caspase cleavage sites in murine lung epithelia resulted in partial proteolytic resistance of CCTalpha to PA103. Further, caspase-directed CCTalpha degradation, decreased PtdCho levels, and cell death in murine lung epithelia were lessened after exposure of cells to bacterial strains lacking the TTSS gene product, exotoxin U (ExoU), but not ExoT. These observations suggest that during the proapoptotic program driven by P. aeruginosa, deleterious effects on phospholipid metabolism are mediated by a TTSS in concert with caspase activation, resulting in proteolysis of a key surfactant biosynthetic enzyme.
authors.affiliation: Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Florita C
authors.initials: FC
authors.lastname: Henderson
authors.forename: Olga L
authors.initials: OL
authors.lastname: Miakotina
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity* / Q000502:physiology*; D011663:Pulmonary Surfactants / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants