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J Biol Chem. 2015 Feb 20;290(8):5190-202. doi: 10.1074/jbc.M114.591610. Epub 2015 Jan 6.

Attenuation of the phosphatidylinositol 3-kinase/Akt signaling pathway by Porphyromonas gingivalis gingipains RgpA, RgpB, and Kgp.

Author information

1
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.
2
the Division of Microbiology and Oral Infection, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan.
3
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 oharan@md.okayama-u.ac.jp.

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.

KEYWORDS:

Akt PKB; Gingipain; Phosphatidylinositide 3-Kinase (PI 3-Kinase); Porphyromonas gingivalis; Proteolysis; Signal Transduction; Virulence Factor

PMID:
25564612
PMCID:
PMC4335252
DOI:
10.1074/jbc.M114.591610
[Indexed for MEDLINE]
Free PMC Article

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