Porphyromonas gingivalis is an established pathogen in periodontal disease and an emerging pathogen in serious systemic conditions, including some forms of cancer. We investigated the effect of P. gingivalis on beta-catenin signaling, a major pathway in the control of cell proliferation and tumorigenesis. Infection of gingival epithelial cells with P. gingivalis did not influence the phosphorylation status of beta-catenin but resulted in proteolytic processing. The use of mutants deficient in gingipain production, along with gingipain-specific inhibitors, revealed that gingipain proteolytic activity was required for beta-catenin processing. The beta-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3 beta were also proteolytically processed by P. gingivalis gingipains. Cell fractionation and Western blotting demonstrated that beta-catenin fragments were translocated to the nucleus. The accumulation of beta-catenin in the nucleus following P. gingivalis infection was confirmed by immunofluorescence microscopy. A luciferase reporter assay showed that P. gingivalis increased the activity of the beta-catenin-dependent TCF/LEF promoter. P. gingivalis did not increase Wnt3a mRNA levels, a finding consistent with P. gingivalis-induced proteolytic processing causing the increase in TCF/LEF promoter activity. Thus, our data indicate that P. gingivalis can induce the non-canonical activation of beta-catenin and disassociation of the beta-catenin destruction complex by gingipain-dependent proteolytic processing. beta-Catenin activation in epithelial cells by P. gingivalis may contribute to a proliferative phenotype.
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