title: Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase.
abstract: Many intracellular pathogens evade the innate immune response in order to survive and proliferate within infected cells. We show that Porphyromonas gingivalis, an intracellular opportunistic pathogen, uses a nucleoside-diphosphate kinase (NDK) homolog to inhibit innate immune responses due to stimulation by extracellular ATP, which acts as a danger signal that binds to P2X7 receptors and induces activation of an inflammasome and caspase-1. Thus, infection of gingival epithelial cells (GECs) with wild-type P. gingivalis results in inhibition of ATP-induced caspase-1 activation. However, ndk-deficient P. gingivalis is less effective than wild-type P. gingivalis in reducing ATP-mediated caspase-1 activation and secretion of the pro-inflammatory cytokine, IL-1β, from infected GECs. Furthermore, P. gingivalis NDK modulates release of high-mobility group protein B1 (HMGB1), a pro-inflammatory danger signal, which remains associated with chromatin in healthy cells. Unexpectedly, infection with either wild-type or ndk-deficient P. gingivalis causes release of HMGB1 from the nucleus to the cytosol. But HMGB1 is released to the extracellular space when uninfected GECs are further stimulated with ATP, and there is more HMGB1 released from the cells when ATP-treated cells are infected with ndk-deficient mutant than wild-type P. gingivalis. Our results reveal that NDK plays a significant role in inhibiting P2X7-dependent inflammasome activation and HMGB1 release from infected GECs.
authors.affiliation: Department of Molecular Cell Biology, University of California, Merced, CA 95343, USA; Health Sciences Research Institute, University of California, Merced, CA 95343, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Department of Periodontology, University of Florida, Gainesville, FL 32610, USA; Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Kalina R
authors.initials: KR
authors.lastname: Atanasova
authors.affiliation: Department of Molecular Cell Biology, University of California, Merced, CA 95343, USA; Health Sciences Research Institute, University of California, Merced, CA 95343, USA.
authors.forename: Phuong Q
authors.initials: PQ
authors.lastname: Bui
authors.affiliation: Department of Periodontology, University of Florida, Gainesville, FL 32610, USA; Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jungnam
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Molecular Cell Biology, University of California, Merced, CA 95343, USA; Health Sciences Research Institute, University of California, Merced, CA 95343, USA.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Hung
authors.affiliation: Department of Periodontology, University of Florida, Gainesville, FL 32610, USA; Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: oyilmaz@ufl.edu.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Yilmaz
authors.affiliation: Department of Molecular Cell Biology, University of California, Merced, CA 95343, USA; Health Sciences Research Institute, University of California, Merced, CA 95343, USA. Electronic address: david.ojcius@gmail.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured / Q000382:microbiology; D005881:Gingiva / Q000166:cytology; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D009701:Nucleoside-Diphosphate Kinase / Q000276:immunology / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024243:HMGB1 Protein; D058847:Inflammasomes; D000255:Adenosine Triphosphate; D009701:Nucleoside-Diphosphate Kinase
keywords: Inflammation; Innate immunity; Interleukins; Porphyromonas gingivalis; Purinergic receptor
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