Noncanonical activation of ?-catenin by Porphyromonas gingivalis.

ABSTRACT: 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 ?-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 ?-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 ?-catenin processing. The ?-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3? were also proteolytically processed by P. gingivalis gingipains. Cell fractionation and Western blotting demonstrated that ?-catenin fragments were translocated to the nucleus. The accumulation of ?-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 ?-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 noncanonical activation of ?-catenin and disassociation of the ?-catenin destruction complex by gingipain-dependent proteolytic processing. ?-Catenin activation in epithelial cells by P. gingivalis may contribute to a proliferative phenotype.

SUBMITTER: Zhou Y 

PROVIDER: S-EPMC4496596 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature