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 induce...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1009598 |
| _version_ | 1818348765793222656 |
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| author | Chengcheng Liu Kendall Stocke Zackary R Fitzsimonds Lan Yakoumatos Daniel P Miller Richard J Lamont |
| author_facet | Chengcheng Liu Kendall Stocke Zackary R Fitzsimonds Lan Yakoumatos Daniel P Miller Richard J Lamont |
| author_sort | Chengcheng Liu |
| collection | DOAJ |
| description | 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 proteasome. 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. |
| first_indexed | 2024-12-13T17:55:16Z |
| format | Article |
| id | doaj.art-300417e242c04540b8f54d65891425d2 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-13T17:55:16Z |
| publishDate | 2021-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-300417e242c04540b8f54d65891425d22022-12-21T23:36:23ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-05-01175e100959810.1371/journal.ppat.1009598A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC.Chengcheng LiuKendall StockeZackary R FitzsimondsLan YakoumatosDaniel P MillerRichard J LamontTyrosine 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 proteasome. 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.https://doi.org/10.1371/journal.ppat.1009598 |
| spellingShingle | Chengcheng Liu Kendall Stocke Zackary R Fitzsimonds Lan Yakoumatos Daniel P Miller Richard J Lamont A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. PLoS Pathogens |
| title | A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. |
| title_full | A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. |
| title_fullStr | A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. |
| title_full_unstemmed | A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. |
| title_short | A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC. |
| title_sort | bacterial tyrosine phosphatase modulates cell proliferation through targeting rgcc |
| url | https://doi.org/10.1371/journal.ppat.1009598 |
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