Papers

Peer-reviewed Last author Corresponding author
Feb, 2015

Attenuation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway by Porphyromonas gingivalis Gingipains RgpA, RgpB, and Kgp

JOURNAL OF BIOLOGICAL CHEMISTRY
  • Masaaki Nakayama
  • ,
  • Tetsuyoshi Inoue
  • ,
  • Mariko Naito
  • ,
  • Koji Nakayama
  • ,
  • Naoya Ohara

Volume
290
Number
8
First page
5190
Last page
5202
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1074/jbc.M114.591610
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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 3 alpha/beta, 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 p85 alpha 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.

Link information
DOI
https://doi.org/10.1074/jbc.M114.591610
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000350042000057&DestApp=WOS_CPL
ID information
  • DOI : 10.1074/jbc.M114.591610
  • ISSN : 0021-9258
  • eISSN : 1083-351X
  • Web of Science ID : WOS:000350042000057

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