Gingipain‐dependent degradation of mammalian target of rapamycin pathway proteins by the periodontal pathogen Porphyromonas gingivalis during invasion

Abstract

SUMMARYPorphyromonas 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 which 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 hour 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 suggests 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.

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

“…Some reports have shown a causal relationship between the Akt/mTOR signaling pathway and P. gingivalis and gingipains (59,60), suggesting that gingipains might cause a decrease in mTOR function via attenuation of the PI3K/Akt signaling pathway.…”

Noncanonical Activation of β-Catenin by Porphyromonas gingivalis

“…Gingipains can also proteolytically process proteins on the epithelial cell surface, causing release and redistribution, with consequent effects on signal transduction and inflammatory re- sponses (53,54). Intracellularly, P. gingivalis gingipains can degrade mammalian target of rapamycin (mTOR), thus disrupting the mTOR pathway which regulates the cytoskeleton, as well as cleave ␤-actin directly (55,56). In trophoblasts, gingipains can degrade P53 and the E3 ubiquitin protein ligase homolog protein (MDM2) and modulate the activity of multiple signaling pathways, resulting in both cell cycle arrest and cell death (57).…”

Autophagy, One of the Main Steps in Periodontitis Pathogenesis and Evolution

“…Conversely, ROS can activate the phosphoinositide-3-kinase (PI3K)-protein kinase B (Akt)-mTORC1 signaling pathway by directly activating PI3K or by controlling the Akt phosphorylation state, therefore inhibiting autophagy induction ( Figure 1 ) [ 81 , 82 , 83 ]. Stafford et al revealed that P. gingivalis invasion induced the mTOR pathway inhibition in oral epithelial cells, representing the first reported evidence that conferred a potential role to mTORC1 in the molecular landscape of periodontitis [ 84 , 85 ].…”