title: Gingipain-dependent degradation of mammalian target of rapamycin pathway proteins by the periodontal pathogen Porphyromonas gingivalis during invasion.
abstract: Porphyromonas gingivalis and Tannerella forsythia are gram-negative pathogens strongly associated with periodontitis. Their abilities to interact, invade and persist within host cells are considered crucial to their pathogenicity, but the mechanisms by which they subvert host defences are not well understood. In this study, we set out to investigate whether P. gingivalis and T. forsythia directly target key signalling molecules that may modulate the host cell phenotype to favour invasion and persistence. Our data identify, for the first time, that P. gingivalis, but not T. forsythia, reduces levels of intracellular mammalian target of rapamycin (mTOR) in oral epithelial cells following invasion over a 4-h time course, via the action of gingipains. The ability of cytochalasin D to abrogate P. gingivalis-mediated mTOR degradation suggests that this effect is dependent upon cellular invasion. We also show that levels of several other proteins in the mTOR signalling pathway are modulated by gingipains, either directly or as a consequence of mTOR degradation including p-4E-BP1. Taken together, our data suggest that P. gingivalis manipulates the mTOR pathway, providing evidence for a potentially novel mechanism by which P. gingivalis mediates its effects on host cell responses to infection.
authors.affiliation: Integrated Bioscience, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.
authors.forename: P
authors.initials: P
authors.lastname: Stafford
authors.forename: J
authors.initials: J
authors.lastname: Higham
authors.forename: A
authors.initials: A
authors.lastname: Pinnock
authors.forename: C
authors.initials: C
authors.lastname: Murdoch
authors.forename: C W I
authors.initials: CW
authors.lastname: Douglas
authors.forename: G P
authors.initials: GP
authors.lastname: Stafford
authors.forename: D W
authors.initials: DW
authors.lastname: Lambert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects; D018829:Adhesins, Bacterial / Q000187:drug effects / Q000494:pharmacology*; D016866:Bacteroidaceae Infections / Q000382:microbiology; D001439:Bacteroides / Q000378:metabolism; D001442:Bacteroides Infections / Q000382:microbiology; D002352:Carrier Proteins / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000494:pharmacology*; D015638:Cytochalasin D / Q000494:pharmacology; D004847:Epithelial Cells / Q000382:microbiology; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D015603:Keratinocytes / Q000382:microbiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009061:Mouth Mucosa / Q000382:microbiology; D046912:Multiprotein Complexes / Q000187:drug effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000187:drug effects; D010518:Periodontitis / Q000382:microbiology*; D016966:Porphyromonas gingivalis / Q000187:drug effects / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018829:Adhesins, Bacterial; D002352:Carrier Proteins; D000080867:Gingipain Cysteine Endopeptidases; D046912:Multiprotein Complexes; D019384:Nucleic Acid Synthesis Inhibitors; C492571:RICTOR protein, human; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D015638:Cytochalasin D; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D003546:Cysteine Endopeptidases
keywords: Porphyromonas gingivalis; degradation; gingipains; mammalian target of rapamycin; periodontitis