Home Host cell-surface proteins as substrates of gingipains, the main proteases of Porphyromonas gingivalis
Article
Licensed
Unlicensed Requires Authentication

Host cell-surface proteins as substrates of gingipains, the main proteases of Porphyromonas gingivalis

  • Katarina Hočevar , Jan Potempa EMAIL logo and Boris Turk EMAIL logo
Published/Copyright: July 20, 2018

Abstract

Gingipains are extracellular cysteine proteases of the oral pathogen Porphyromonas gingivalis and are its most potent virulence factors. They can degrade a great variety of host proteins, thereby helping the bacterium to evade the host immune response, deregulate signaling pathways, trigger anoikis and, finally, cause tissue destruction. Host cell-surface proteins targeted by gingipains are the main focus of this review and span three groups of substrates: immune-regulatory proteins, signaling pathways regulators and adhesion molecules. The analysis of published data revealed that gingipains predominantly inactivate their substrates by cleaving them at one or more sites, or through complete degradation. Sometimes, gingipains were even found to initially shed their membrane substrates, but this was mostly just the first step in the degradation of cell-surface proteins.

Acknowledgments

The work was supported by the Slovenian Research Agency, Funder Id: 10.13039/501100004329, grant: P1-0140 (B.T.), the US National Institutes of Health, NIDCR, grants: DE 09761 and DE026280 (J.P.), and the Polish National Science Center, project SYMFONIA: UMO-2013/08/W/NZ1/00696 (J.P.).

References

Abfalter, C.M., Schubert, M., Gotz, C., Schmidt, T.P., Posselt, G., and Wessler, S. (2016). HtrA-mediated E-cadherin cleavage is limited to DegP and DegQ homologs expressed by Gram-negative pathogens. Cell Commun. Signal. 14, 30.10.1186/s12964-016-0153-ySearch in Google Scholar PubMed PubMed Central

Andrian, E., Grenier, D., and Rouabhia, M. (2006). Porphyromonas gingivalis gingipains mediate the shedding of syndecan-1 from the surface of gingival epithelial cells. Oral. Microbiol. Immunol. 21, 123–128.10.1111/j.1399-302X.2006.00248.xSearch in Google Scholar PubMed

Aquino, R.S., Teng, Y.H., and Park, P.W. (2018). Glycobiology of syndecan-1 in bacterial infections. Biochem. Soc. Trans. 46, 371–377.10.1042/BST20170395Search in Google Scholar PubMed PubMed Central

Baba, A., Abe, N., Kadowaki, T., Nakanishi, H., Ohishi, M., Asao, T., and Yamamoto, K. (2001). Arg-gingipain is responsible for the degradation of cell adhesion molecules of human gingival fibroblasts and their death induced by Porphyromonas gingivalis. Biol. Chem. 382, 817–824.10.1515/bchm.2001.382.5.817Search in Google Scholar

Belibasakis, G.N., Öztürk, V.-Ö., Emingil, G., and Bostanci, N. (2014). Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in gingival crevicular fluid: association with clinical and microbiologic parameters. J. Periodontol. 85, 204–210.10.1902/jop.2013.130144Search in Google Scholar PubMed

Black, R.A., Rauch, C.T., Kozlosky, C.J., Peschon, J.J., Slack, J.L., Wolfson, M.F., Castner, B.J., Stocking, K.L., Reddy, P., Srinivasan, S., et al. (1997). A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733.10.1038/385729a0Search in Google Scholar PubMed

Blobel, C.P. (2005). ADAMs: key components in EGFR signalling and development. Nat. Rev. Mol. Cell Biol. 6, 32–43.10.1038/nrm1548Search in Google Scholar PubMed

Bostanci, N., Thurnheer, T., Aduse-Opoku, J., Curtis, M.A., Zinkernagel, A.S., and Belibasakis, G.N. (2013). Porphyromonas gingivalis regulates TREM-1 in human polymorphonuclear neutrophils via its gingipains. PLoS One 8, e75784.10.1371/journal.pone.0075784Search in Google Scholar PubMed PubMed Central

Chen, Z., Potempa, J., Polanowski, A., Wikstrom, M., and Travis, J. (1992). Purification and characterization of a 50-kDa cysteine proteinase (gingipain) from Porphyromonas gingivalis. J. Biol. Chem. 267, 18896–18901.10.1016/S0021-9258(19)37045-0Search in Google Scholar

Chiarugi, P. and Giannoni, E. (2008). Anoikis: a necessary death program for anchorage-dependent cells. Biochem. Pharmacol. 76, 1352–1364.10.1016/j.bcp.2008.07.023Search in Google Scholar PubMed

Feldman, M., La, V.D., Lombardo Bedran, T.B., Palomari Spolidorio, D.M., and Grenier, D. (2011). Porphyromonas gingivalis-mediated shedding of extracellular matrix metalloproteinase inducer (EMMPRIN) by oral epithelial cells: a potential role in inflammatory periodontal disease. Microbes Infect. 13, 1261–1269.10.1016/j.micinf.2011.07.009Search in Google Scholar PubMed

Fitzpatrick, R.E., Wijeyewickrema, L.C., and Pike, R.N. (2009). The gingipains: scissors and glue of the periodontal pathogen, Porphyromonas gingivalis. Future Microbiol. 4, 471–487.10.2217/fmb.09.18Search in Google Scholar PubMed

Guo, Y., Nguyen, K.A., and Potempa, J. (2010). Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon’s knife to a meat chopper-like brutal degradation of proteins. Periodontol. 2000 54, 15–44.10.1111/j.1600-0757.2010.00377.xSearch in Google Scholar PubMed PubMed Central

Guzik, K. and Potempa, J. (2008). Friendly fire against neutrophils: proteolytic enzymes confuse the recognition of apoptotic cells by macrophages. Biochimie 90, 405–415.10.1016/j.biochi.2007.09.008Search in Google Scholar PubMed

Hajishengallis, G. (2014). The inflammophilic character of the periodontitis-associated microbiota. Mol. Oral Microbiol. 29, 248–257.10.1111/omi.12065Search in Google Scholar PubMed PubMed Central

Hajishengallis, G. (2015). Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30–44.10.1038/nri3785Search in Google Scholar PubMed PubMed Central

Houle, M.-A., Grenier, D., Plamondon, P., and Nakayama, K. (2003). The collagenase activity of Porphyromonas gingivalis is due to Arg-gingipain. FEMS Microbiol. Lett. 221, 181–185.10.1016/S0378-1097(03)00178-2Search in Google Scholar PubMed

Hoy, B., Lower, M., Weydig, C., Carra, G., Tegtmeyer, N., Geppert, T., Schroder, P., Sewald, N., Backert, S., Schneider, G., et al. (2010). Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep. 11, 798–804.10.1038/embor.2010.114Search in Google Scholar PubMed PubMed Central

Inomata, M., Ishihara, Y., Matsuyama, T., Imamura, T., Maruyama, I., Noguchi, T., and Matsushita, K. (2009). Degradation of vascular endothelial thrombomodulin by arginine- and lysine-specific cysteine proteases from Porphyromonas gingivalis. J. Periodontol. 80, 1511–1517.10.1902/jop.2009.090114Search in Google Scholar PubMed

Jagels, M.A., Travis, J., Potempa, J., Pike, R., and Hugli, T.E. (1996). Proteolytic inactivation of the leukocyte C5a receptor by proteinases derived from Porphyromonas gingivalis. Infect. Immun. 64, 1984–1991.10.1128/iai.64.6.1984-1991.1996Search in Google Scholar PubMed PubMed Central

Katz, J., Sambandam, V., Wu, J.H., Michalek, S.M., and Balkovetz, D.F. (2000). Characterization of Porphyromonas gingivalis-induced degradation of epithelial cell junctional complexes. Infect. Immun. 68, 1441–1449.10.1128/IAI.68.3.1441-1449.2000Search in Google Scholar PubMed PubMed Central

Katz, J., Yang, Q.-B., Zhang, P., Potempa, J., Travis, J., Michalek, S.M., and Balkovetz, D.F. (2002). Hydrolysis of epithelial junctional proteins by Porphyromonas gingivalis gingipains. Infect. Immun. 70, 2512–2518.10.1128/IAI.70.5.2512-2518.2002Search in Google Scholar PubMed PubMed Central

Kaup, M., Dassler, K., Reineke, U., Weise, C., Tauber, R., and Fuchs, H. (2002). Processing of the human transferrin receptor at distinct positions within the stalk region by neutrophil elastase and cathepsin G. Biol. Chem. 383, 1011–1020.10.1515/BC.2002.108Search in Google Scholar PubMed

Kitamura, Y., Matono, S., Aida, Y., Hirofuji, T., and Maeda, K. (2002). Gingipains in the culture supernatant of Porphyromonas gingivalis cleave CD4 and CD8 on human T cells. J. Periodontal. Res. 37, 464–468.10.1034/j.1600-0765.2002.01364.xSearch in Google Scholar PubMed

Lourbakos, A., Potempa, J., Travis, J., D’Andrea, M.R., Andrade-Gordon, P., Santulli, R., Mackie, E.J., and Pike, R.N. (2001a). Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect. Immun. 69, 5121–5130.10.1128/IAI.69.8.5121-5130.2001Search in Google Scholar PubMed PubMed Central

Lourbakos, A., Yuan, Y., Jenkins, A.L., Travis, J., Andrade-Gordon, P., Santulli, R., Potempa, J., and Pike, R.N. (2001b). Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood 97, 3790–3797.10.1182/blood.V97.12.3790Search in Google Scholar

Mahtout, H., Chandad, F., Rojo, J.M., and Grenier, D. (2009). Porphyromonas gingivalis mediates the shedding and proteolysis of complement regulatory protein CD46 expressed by oral epithelial cells. Oral Microbiol. Immunol. 24, 396–400.10.1111/j.1399-302X.2009.00532.xSearch in Google Scholar PubMed

Mezyk-Kopec, R., Bzowska, M., Potempa, J., Jura, N., Sroka, A., Black, R.A., and Bereta, J. (2005). Inactivation of membrane tumor necrosis factor α by gingipains from Porphyromonas gingivalis. Infect. Immun. 73, 1506–1514.10.1128/IAI.73.3.1506-1514.2005Search in Google Scholar PubMed PubMed Central

Oleksy, A., Banbula, A., Bugno, M., Travis, J., and Potempa, J. (2002). Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation. Microb. Pathog. 32, 173–181.10.1006/mpat.2002.0491Search in Google Scholar PubMed

Pike, R., McGraw, W., Potempa, J., and Travis, J. (1994). Lysine- and arginine-specific proteinases from Porphyromonas gingivalis. Isolation, characterization, and evidence for the existence of complexes with hemagglutinins. J. Biol. Chem. 269, 406–411.10.1016/S0021-9258(17)42365-9Search in Google Scholar

Potempa, J., Banbula, A., and Travis, J. (2000). Role of bacterial proteinases in matrix destruction and modulation of host responses. Periodontology 24, 153–192.10.1034/j.1600-0757.2000.2240108.xSearch in Google Scholar PubMed

Rovai, E.S. and Holzhausen, M. (2017). The role of proteinase-activated receptors 1 and 2 in the regulation of periodontal tissue metabolism and disease. J. Immunol. Res. 2017. https://doi.org/10.1155/2017/5193572.10.1155/2017/5193572Search in Google Scholar PubMed PubMed Central

Ruggiero, S., Cosgarea, R., Potempa, J., Potempa, B., Eick, S., and Chiquet, M. (2013). Cleavage of extracellular matrix in periodontitis: gingipains differentially affect cell adhesion activities of fibronectin and tenascin-C. Biochim. Biophys. Acta 1832, 517–526.10.1016/j.bbadis.2013.01.003Search in Google Scholar PubMed PubMed Central

Scragg, M.A., Cannon, S.J., Rangarajan, M., Williams, D.M., and Curtis, M.A. (1999). Targeted disruption of fibronectin-integrin interactions in human gingival fibroblasts by the RI protease of Porphyromonas gingivalis W50. Infect. Immun. 67, 1837–1843.10.1128/IAI.67.4.1837-1843.1999Search in Google Scholar PubMed PubMed Central

Sheets, S.M., Potempa, J., Travis, J., Casiano, C.A., and Fletcher, H.M. (2005). Gingipains from Porphyromonas gingivalis W83 induce cell adhesion molecule cleavage and apoptosis in endothelial cells. Infect. Immun. 73, 1543–1552.10.1128/IAI.73.3.1543-1552.2005Search in Google Scholar PubMed PubMed Central

Sheets, S.M., Potempa, J., Travis, J., Fletcher, H.M., and Casiano, C.A. (2006). Gingipains from Porphyromonas gingivalis W83 synergistically disrupt endothelial cell adhesion and can induce caspase-independent apoptosis. Infect. Immun. 74, 5667–5678.10.1128/IAI.01140-05Search in Google Scholar PubMed PubMed Central

Sobotic, B., Vizovisek, M., Vidmar, R., Van Damme, P., Gocheva, V., Joyce, J.A., Gevaert, K., Turk, V., Turk, B., and Fonovic, M. (2015). Proteomic identification of cysteine cathepsin substrates shed from the surface of cancer cells. Mol. Cell Proteomics 14, 2213–2228.10.1074/mcp.M114.044628Search in Google Scholar PubMed PubMed Central

Sugawara, S., Nemoto, E., Tada, H., Miyake, K., Imamura, T., and Takada, H. (2000). Proteolysis of human monocyte CD14 by cysteine proteinases (gingipains) from Porphyromonas gingivalis leading to lipopolysaccharide hyporesponsiveness. J. Immunol. 165, 411–418.10.4049/jimmunol.165.1.411Search in Google Scholar PubMed

Tada, H., Sugawara, S., Nemoto, E., Imamura, T., Potempa, J., Travis, J., Shimauchi, H., and Takada, H. (2003). Proteolysis of ICAM-1 on human oral epithelial cells by gingipains. J. Dent. Res. 82, 796–801.10.1177/154405910308201007Search in Google Scholar PubMed

Takii, R., Kadowaki, T., Baba, A., Tsukuba, T., and Yamamoto, K. (2005). A functional virulence complex composed of gingipains, adhesins, and lipopolysaccharide shows high affinity to host cells and matrix proteins and escapes recognition by host immune systems. Infect. Immun. 73, 883–893.10.1128/IAI.73.2.883-893.2005Search in Google Scholar PubMed PubMed Central

Turk, B., Turk, D., and Turk, V. (2012). Protease signalling: the cutting edge. EMBO J. 31, 1630–1643.10.1038/emboj.2012.42Search in Google Scholar PubMed PubMed Central

Wang, P.L., Shinohara, M., Murakawa, N., Endo, M., Sakata, S., Okamura, M., and Ohura, K. (1999). Effect of cysteine protease of Porphyromonas gingivalis on adhesion molecules in gingival epithelial cells. Jpn. J. Pharmacol. 80, 75–79.10.1254/jjp.80.75Search in Google Scholar PubMed

Wilensky, A., Tzach-Nahman, R., Potempa, J., Shapira, L., and Nussbaum, G. (2014). Porphyromonas gingivalis gingipains selectively reduce CD14 expression, leading to macrophage hyporesponsiveness to bacterial infection. J. Innate. Immun. 7, 127–135.10.1159/000365970Search in Google Scholar PubMed PubMed Central

Wong, D.M., Tam, V., Lam, R., Walsh, K.A., Tatarczuch, L., Pagel, C.N., Reynolds, E.C., O’Brien-Simpson, N.M., Mackie, E.J., and Pike, R.N. (2010). Protease-activated receptor 2 has pivotal roles in cellular mechanisms involved in experimental periodontitis. Infect. Immun. 78, 629–638.10.1128/IAI.01019-09Search in Google Scholar PubMed PubMed Central

Yun, P.L., Decarlo, A.A., Chapple, C.C., Collyer, C.A., and Hunter, N. (2005a). Binding of Porphyromonas gingivalis gingipains to human CD4+ T cells preferentially down-regulates surface CD2 and CD4 with little affect on co-stimulatory molecule expression. Microb. Pathog. 38, 85–96.10.1016/j.micpath.2005.01.001Search in Google Scholar PubMed

Yun, P.L.W., Decarlo, A.A., Chapple, C.C., and Hunter, N. (2005b). Functional implication of the hydrolysis of platelet endothelial cell adhesion molecule 1 (CD31) by gingipains of Porphyromonas gingivalis for the pathology of periodontal disease. Infect. Immun. 73, 1386–1398.10.1128/IAI.73.3.1386-1398.2005Search in Google Scholar PubMed PubMed Central

Yun, P.L., Decarlo, A.A., and Hunter, N. (2006). Gingipains of Porphyromonas gingivalis modulate leukocyte adhesion molecule expression induced in human endothelial cells by ligation of CD99. Infect. Immun. 74, 1661–1672.10.1128/IAI.74.3.1661-1672.2006Search in Google Scholar PubMed PubMed Central

Yun, L.W.P., Decarlo, A.A., and Hunter, N. (2007). Blockade of protease-activated receptors on T cells correlates with altered proteolysis of CD27 by gingipains of Porphyromonas gingivalis. Clin. Exp. Immunol. 150, 217–229.10.1111/j.1365-2249.2007.03488.xSearch in Google Scholar PubMed PubMed Central

Received: 2018-04-09
Accepted: 2018-06-18
Published Online: 2018-07-20
Published in Print: 2018-11-27

©2018 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 6.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0215/html
Scroll to top button