title: Porphyromonas gingivalis-derived RgpA-Kgp Complex Activates the Macrophage Urokinase Plasminogen Activator System: IMPLICATIONS FOR PERIODONTITIS.
abstract: Urokinase plasminogen activator (uPA) converts plasminogen to plasmin, resulting in a proteolytic cascade that has been implicated in tissue destruction during inflammation. Periodontitis is a highly prevalent chronic inflammatory disease characterized by destruction of the tissue and bone that support the teeth. We demonstrate that stimulation of macrophages with the arginine- and lysine-specific cysteine protease complex (RgpA-Kgp complex), produced by the keystone pathogen Porphyromonas gingivalis, dramatically increased their ability to degrade matrix in a uPA-dependent manner. We show that the RgpA-Kgp complex cleaves the inactive zymogens, pro-uPA (at consensus sites Lys(158)-Ile(159) and Lys(135)-Lys(136)) and plasminogen, yielding active uPA and plasmin, respectively. These findings are consistent with activation of the uPA proteolytic cascade by P. gingivalis being required for the pathogen to induce alveolar bone loss in a model of periodontitis and reveal a new host-pathogen interaction in which P. gingivalis activates a critical host proteolytic pathway to promote tissue destruction and pathogen virulence.
authors.affiliation: From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia, andrew.fleetwood@unimelb.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fleetwood
authors.affiliation: the Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and.
authors.forename: Neil M
authors.initials: NM
authors.lastname: O'Brien-Simpson
authors.affiliation: the Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Veith
authors.affiliation: the Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and.
authors.forename: Roselind S
authors.initials: RS
authors.lastname: Lam
authors.affiliation: From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Achuthan
authors.affiliation: From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.affiliation: the Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and.
authors.forename: William
authors.initials: W
authors.lastname: Singleton
authors.affiliation: the Finsen Laboratory, Rigshospitalet and the Biotech Research and Innovation Centre, Copenhagen University, 1165 Copenhagen, Denmark.
authors.forename: Ida K
authors.initials: IK
authors.lastname: Lund
authors.affiliation: the Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Reynolds
authors.affiliation: From the Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D000080867:Gingipain Cysteine Endopeptidases; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000201:enzymology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010518:Periodontitis / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D003546:Cysteine Endopeptidases
keywords: extracellular matrix; macrophage; periodontal disease; plasmin; plasminogen