title: Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa has the capacity to invade lung epithelial cells by co-opting the intrinsic endocytic properties of lipid rafts, which are rich in cholesterol, sphingolipids, and proteins, such as caveolin-1 and -2. We compared intratracheal Pseudomonas infection in wild type and caveolin-deficient mice to investigate the role of caveolin proteins in the pathogenesis of Pseudomonas pneumonia. Unlike wild type mice, which succumb to pneumonia, caveolin-deficient mice are resistant to Pseudomonas. We observed that Pseudomonas invasion of lung epithelial cells is dependent on caveolin-2 but not caveolin-1. Phosphorylation of caveolin-2 by Src family kinases is an essential event for Pseudomonas invasion. Our studies also reveal the existence of a distinct signaling mechanism in lung epithelial cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion. Csk migrates to lipid raft domains, where it decreases phosphorylation of caveolin-2 by inactivating c-Src. Whereas Pseudomonas co-opts the endocytic properties of caveolin-2 for invasion, there also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impairing this activity. The success of Pseudomonas in co-opting lipid raft-mediated endocytosis to invade lung epithelial cells may depend on the relative strengths of these counteracting signaling activities.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. david.zaas@duke.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Zaas
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Swan
authors.forename: Bethany J
authors.initials: BJ
authors.lastname: Brown
authors.forename: Guojie
authors.initials: G
authors.lastname: Li
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Simone
authors.initials: S
authors.lastname: Degan
authors.forename: Mary E
authors.initials: ME
authors.lastname: Sunday
authors.forename: Jo Rae
authors.initials: JR
authors.lastname: Wright
authors.forename: Soman N
authors.initials: SN
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D022461:Caveolins / Q000378:metabolism; D002465:Cell Movement; D004705:Endocytosis; D004847:Epithelial Cells / Q000382:microbiology*; D008168:Lung / Q000382:microbiology*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011552:Pseudomonas Infections / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D013997:Time Factors; D019061:src-Family Kinases
chemical_list: D022461:Caveolins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases