title: Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N-(3-Oxo-Dodecanoyl)-L-Homoserine Lactone.
abstract: Pseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification.
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Horke
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Junhui
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schütz
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Kramer
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Wilgenbus
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Witte
authors.affiliation: Department of Pharmacology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Selbach
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA john.teiber@utsouthwestern.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Teiber
mesh_terms: D043303:Aryldialkylphosphatase / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006714:Homoserine / Q000031:analogs & derivatives* / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007783:Lactones / Q000378:metabolism*; D018613:Microscopy, Confocal; D011552:Pseudomonas Infections / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D053038:Quorum Sensing / Q000502:physiology; D034622:RNA Interference
chemical_list: D007783:Lactones; C085113:Pseudomonas aeruginosa autoinducer; D006714:Homoserine; D043303:Aryldialkylphosphatase