title: Attenuation of the phosphatidylinositol 3-kinase/Akt signaling pathway by Porphyromonas gingivalis gingipains RgpA, RgpB, and Kgp.
abstract: Porphyromonas gingivalis is a major pathogen of periodontal diseases, including periodontitis. We have investigated the effect of P. gingivalis infection on the PI3K/Akt (protein kinase B) signaling pathway in gingival epithelial cells. Here, we found that live P. gingivalis, but not heat-killed P. gingivalis, reduced Akt phosphorylation at both Thr-308 and Ser-473, which implies a decrease in Akt activity. Actually, PI3K, which is upstream of Akt, was also inactivated by P. gingivalis. Furthermore, glycogen synthase kinase 3α/β, mammalian target of rapamycin, and Bad, which are downstream proteins in the PI3K/Akt cascade, were also dephosphorylated, a phenomenon consistent with Akt inactivation by P. gingivalis. However, these events did not require direct interaction between bacteria and host cells and were independent of P. gingivalis invasion into the cells. The use of gingipain-specific inhibitors and a gingipain-deficient P. gingivalis mutant KDP136 revealed that the gingipains and their protease activities were essential for the inactivation of PI3K and Akt. The associations between the PI3K regulatory subunit p85α and membrane proteins were disrupted by wild-type P. gingivalis. Moreover, PDK1 translocation to the plasma membrane was reduced by wild-type P. gingivalis, but not KDP136, indicating little production of phosphatidylinositol 3,4,5-triphosphate by PI3K. Therefore, it is likely that PI3K failed to transmit homeostatic extracellular stimuli to intracellular signaling pathways by gingipains. Taken together, our findings indicate that P. gingivalis attenuates the PI3K/Akt signaling pathway via the proteolytic effects of gingipains, resulting in the dysregulation of PI3K/Akt-dependent cellular functions and the destruction of epithelial barriers.
authors.affiliation: From the Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and; the Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama 700-8558 and.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: From the Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and; the Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama 700-8558 and.
authors.forename: Tetsuyoshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: the Division of Microbiology and Oral Infection, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Naito
authors.affiliation: the Division of Microbiology and Oral Infection, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: From the Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and; the Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University, Okayama 700-8558 and. Electronic address: oharan@md.okayama-u.ac.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ohara
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D016866:Bacteroidaceae Infections / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000080867:Gingipain Cysteine Endopeptidases; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009154:Mutation; D010518:Periodontitis / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D003546:Cysteine Endopeptidases; D000080867:Gingipain Cysteine Endopeptidases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D058570:TOR Serine-Threonine Kinases; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C000631429:PDK1 protein, human; C546842:MTOR protein, human
keywords: Akt PKB; Gingipain; Phosphatidylinositide 3-Kinase (PI 3-Kinase); Porphyromonas gingivalis; Proteolysis; Signal Transduction; Virulence Factor