A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC

Tyrosine phosphatases are often weaponized by bacteria colonizing mucosal barriers to manipulate host cell signal transduction pathways. Porphyromonas gingivalis is a periodontal pathogen and emerging oncopathogen which interferes with gingival epithelial cell proliferation and migration, and induces a partial epithelial mesenchymal transition. P. gingivalis produces two tyrosine phosphatases, and we show here that the low molecular weight tyrosine phosphatase, Ltp1, is secreted within gingival epithelial cells and translocates to the nucleus. An ltp1 mutant of P. gingivalis showed a diminished ability to induce epithelial cell migration and proliferation. Ltp1 was also required for the transcriptional upregulation of Regulator of Growth and Cell Cycle (RGCC), one of the most differentially expressed genes in epithelial cells resulting from P. gingivalis infection. A phosphoarray and siRNA showed that P. gingivalis controlled RGCC expression through Akt, which was activated by phosphorylation on S473. Akt activation is opposed by PTEN, and P. gingivalis decreased the amount of PTEN in epithelial cells. Ectopically expressed Ltp1 bound to PTEN, and reduced phosphorylation of PTEN at Y336 which controls proteasomal degradation. Ltp-1 induced loss of PTEN stability was prevented by chemical inhibition of the proteosome. Knockdown of RGCC suppressed upregulation of Zeb2 and mesenchymal markers by P. gingivalis. RGCC inhibition was also accompanied by a reduction in production of the proinflammatory cytokine IL-6 in response to P. gingivalis. Elevated IL-6 levels can contribute to periodontal destruction, and the ltp1 mutant of P. gingivalis incited less bone loss compared to the parental strain in a murine model of periodontal disease. These results show that P. gingivalis can deliver Ltp1 within gingival epithelial cells, and establish PTEN as the target for Ltp1 phosphatase activity. Disruption of the Akt1/RGCC signaling axis by Ltp1 facilitates P. gingivalis-induced increases in epithelial cell migration, proliferation, EMT and inflammatory cytokine production. Author summary Bacteria colonizing the oral cavity can induce inflammatory destruction of the periodontal tissues, and are increasingly associated with oral squamous cell carcinoma. P. gingivalis, a major periodontal pathogen, can subvert epithelial pathways that control important physiological processes relating to innate immunity and cell fate; however, little is known about the effector molecules. Here we show that P. gingivalis can deliver a tyrosine phosphatase, Ltp1, within epithelial cells, and Ltp1 phosphatase activity destabilizes PTEN, a negative regulator of Akt1 signaling. The production of RGCC is thus increased and this leads to increased epithelial cell migration, proliferation, a partial mesenchymal phenotype and inflammatory cytokine production. Ltp1 phosphatase activity thus provides a mechanistic basis for a number of P. gingivalis properties that contribute to disease. Indeed, an Ltp1-deficient mutant was less pathogenic in a murine model of periodontitis. These results contribute to deciphering the pathophysiological events that underlie oral bacterial diseases that initiate at mucosal barriers.

Automated summary

The bacteria Porphyromonas gingivalis can deliver a tyrosine phosphatase, Ltp1, within epithelial cells, destabilizing PTEN and increasing RGCC production, leading to enhanced epithelial cell migration, proliferation, EMT, and inflammatory cytokine production. The disruption of the Akt1/RGCC signaling axis by Ltp1 facilitates P. gingivalis-induced pathogenic effects, contributing to oral bacterial diseases at mucosal barriers. The absence of Ltp1 leads to reduced pathogenicity in a murine model of periodontitis.