title: Pseudomonas aeruginosa Uses Dihydrolipoamide Dehydrogenase (Lpd) to Bind to the Human Terminal Pathway Regulators Vitronectin and Clusterin to Inhibit Terminal Pathway Complement Attack.
abstract: The opportunistic human pathogen Pseudomonas aeruginosa controls host innate immune and complement attack. Here we identify Dihydrolipoamide dehydrogenase (Lpd), a 57 kDa moonlighting protein, as the first P. aeruginosa protein that binds the two human terminal pathway inhibitors vitronectin and clusterin. Both human regulators when bound to the bacterium inhibited effector function of the terminal complement, blocked C5b-9 deposition and protected the bacterium from complement damage. P. aeruginosa when challenged with complement active human serum depleted from vitronectin was severely damaged and bacterial survival was reduced by over 50%. Similarly, when in human serum clusterin was blocked by a mAb, bacterial survival was reduced by 44%. Thus, demonstrating that Pseudomonas benefits from attachment of each human regulator and controls complement attack. The Lpd binding site in vitronectin was localized to the C-terminal region, i.e. to residues 354-363. Thus, Lpd of P. aeruginosa is a surface exposed moonlighting protein that binds two human terminal pathway inhibitors, vitronectin and clusterin and each human inhibitor when attached protected the bacterial pathogen from the action of the terminal complement pathway. Our results showed insights into the important function of Lpd as a complement regulator binding protein that might play an important role in virulence of P. aeruginosa.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
authors.forename: Teresia
authors.initials: T
authors.lastname: Hallström
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Uhde
authors.affiliation: Medical Microbiology, Department of Translational Medicine Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Birendra
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Medical Microbiology, Department of Translational Medicine Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Riesbeck
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany; Faculty of Biology, Friedrich Schiller University, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism*; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050296:Microbial Viability; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000235:genetics; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C495242:CLU protein, human; D051152:Clusterin; D015938:Complement Membrane Attack Complex; D019096:Vitronectin; D008058:Dihydrolipoamide Dehydrogenase