Skip to main content
SpringerLink
Log in

The Cytotoxic Necrotizing Factor of Yersinia pseudotuberculosis

  • REVIEWS
  • Published:
Molecular Genetics, Microbiology and Virology Aims and scope Submit manuscript

Abstract

Cytotoxic necrotic factor (CNF) of Yersinia pseudotuberculosis (CNFY) is a 114-kDa toxin protein that is similar to CNF1, which is prevalent among pathogenic and saprophytic Escherichia coli isolates. In 2002, the CNF of Y. pseudotuberculosis YPIII strain (United States) was first described. The Rho family small GTP-binding proteins (GTPases) are inactivated by CNFY acting on eukaryotic cells of humans and mammals, which causes the formation of large multinucleated cells. An analysis of Y. pseudotuberculosis toxins isolated in Russia showed that the thermolabile toxin TLT described earlier was identified as identical to CNFY except for three amino acid substitutions. The TLT’s cytotoxic activity is similar to that of CNFY. Screening of Y. pseudotuberculosis strains collection isolated during the outbreaks of Far East scarletlike fever (FESLF) and in sporadic cases from patients with pseudotuberculosis/FESLF, rodents, and the environment in the Far East, Siberia, and the northwest of the Russian Federation showed that most isolates carry the specific cnfY gene allele encoding the inactive CNFY isoform. This allele contains a stop codon and two large deletions that block the production of the full-sized toxin. Interestingly, all isolates obtained from patients with FESLF, which is a severe form of pseudotuberculosis and endemic to the Far East region, contain inactivated CNFY. Possible causes of CNFY inactivation in strains associated with Far East scarletlike fever are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.

Similar content being viewed by others

REFERENCES

  1. Grunin, I.I., Somov, G.P., and Zalmover, I.Yu., Far east scarlet-like fever, Voen.-Med. Zh., 1960, vol. 8, pp. 62–66.

    CAS  PubMed  Google Scholar 

  2. Somov, G.P., Dal’nevostochnaya skarlatinopodobnaya likhoradka (Far East Scarlet-Like Fever), Moscow: Meditsina, 1979.

  3. Timchenko, N.F. and Popov, A.F., Pseudotuberculosis–past and present, Infekts.Bolezni, 2014, vol. 4, pp. 51–56.

    Google Scholar 

  4. Timchenko, N.F., Adgamov, R.R., Popof, A.F., Psareva, E.K., Sobyanin, K.A., Gintsburg, A.L., and Ermolaeva, S.A., Far east scarlet-like fever caused by a few related genotypes of Yersinia pseudotuberculosis, Russia, Emerging Infect. Dis., 2016, vol. 22, no. 3, pp. 503–506.

    Article  CAS  Google Scholar 

  5. Znamenskii, V.A. and Vishnyakov, A.K., Etiology of Far east scarlet-like fever, Zh. Mikrobiol., 1967, vol. 2, pp. 125–130.

    Google Scholar 

  6. Amphlett, A., Far east scarlet-like fever: a review of the epidemiology, symptomatology, and role of super-antigenic toxin: Yersinia pseudotuberculosis-derived mitogen A, Open Forum Infect. Dis., 2015, vol. 3, no. 1, pp. 17–35.

    Google Scholar 

  7. Timchenko, N.F., Nedashkovskaya, E.P., Dolmatova, L.S., and Somova-Isachkova, L.M., Toksiny Yersinia pseudotuberculosis (Toxins of Yersinia pseudotuberculosis), Vladivostok: Primpoligrafkombinat, 2004.

  8. Nuss, A.M., Schuster, F., Roselius, L., Klein, J., Bücker, R., Herbst, K., et al., Precise temperature-responsive bistable switch controlling Yersinia virulence,PLoS Pathog., 2016, vol. 12, no. 12, p. e1006091.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Sadana, P., Mönnich, M., Unverzagt, C., and Scrima, A., Structure of the Y. pseudotuberculosis adhesion Invasin E, Protein Sci., 2017, vol. 26, no. 6, pp. 1182–1195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pashin, A.Yu., Ponomarev, N.G., Dzhaparidze, M.I., and Verenkov, M.S., Improving the ways for identifying exotoxin of a pseudo-tuberculous microbe and antibodies homologous to it, in Aktual’nye voprosy laboratornoi diagnostiki i biokhimii vozbuditelei chumy i kholery. Sbornik nauchnykh trudov (Topical Problems on Laboratory Diagnostics and Biochemistry of Causative Agents of Plague and Cholera. Collection of Scientific Works), Saratov, 1984, pp. 14–18.

    Google Scholar 

  11. Pokrovskii, V.K., Timchenko, N.F., Nedashkovskaya, E.P., and Grigor’yeva, E.A., Biological properties of the thermolabile lethal toxin of Yersinia pseudotuberculosis,Zh. Mikrobiol., Epidemiol. Immunobiol., 2008, vol. 6, pp. 63–66.

    Google Scholar 

  12. Nedashkovskaya, E.P., Timchenko, N.F., Besednov, A.L., and Vertiyev, Yu.V., Thermostable toxin of Yersinia pseudotuberculosis: secretion, purification, characterization of properties, J. Microbiol., 1995, vol. 4, pp. 5–9.

    Google Scholar 

  13. Raznik, S.D., Characteristics for the biological effect of the thermostable toxin of Yersinia pseudotuberculosis, Cand. Sci. (Med.) Dissertation, Vladivostok, 1999.

  14. Rosqvist, R., Forsberg, A., and Wolf-Watz, H., Intracellular targeting of the Yersinia YopE cytotoxin in mammalian cells induces actin microfilament disruption, Infect. Immun., 1991, vol. 59, pp. 4562–4569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Carnoy, C., Mullet, C., Muller-Alouf, H., Leteurtre, E., and Simonet, M., Superantigen ypmA exacerbates the virulence of Yersinia pseudotuberculosis in mice, Infect. Immun., 2000, vol. 68, pp. 2553–2559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lockman, H.A., Gillespie, R.A., Baker, B.D., and Shakhnovich, E., Yersinia pseudotuberculosis produces a cytotoxic necrotizing factor, Infect. Immun., 2002, vol. 70, pp. 2708–2714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wan, M., Zhou, Y., and Zhu, Y., Subversion of macrophage functions by bacterial protein toxins and effectors, Curr. Issues Mol. Biol., 2017, vol. 25, pp. 61–80.

    PubMed  Google Scholar 

  18. Miller, A.A. and Gladkii, V.Z., To the problem on pseudotuberculosis in rodents, VMEP, 1927, vol. 6, no. 2, pp. 146–153.

    Google Scholar 

  19. Schar, M. and Thal, E., Comparative studies on toxin of Pasteurella pestis and Pasteurella pseudotuberculosis,Proc. Soc. Exp. Biol. Med., 1955, vol. 88, no. 1, pp. 39–42.

    Article  CAS  PubMed  Google Scholar 

  20. Somova, L.M., Plekhova, N.G., Drobot, E.I., Nedashkovskaya, E.P., and Timchenko, N.F., Pathomorphological changes in the case of experimental toxemia caused by thermolabile toxin of Yersinia pseudotuberculosis,Tikhookean. Med. Zh., 2010, vol. 3, pp. 67–72.

    Google Scholar 

  21. Persiyanova, E.V., Kiselev, K.V., Bulgakov, V.P., Timchenko, N.F., Chernoded, G.K., and Zhuravlev, Yu.N., Defense response mechanisms of ginseng callus cultures induced by Yersinia pseudotuberculosis, a human pathogen, Russ. J. Plant Physiol., 2008, vol. 55, no. 6, pp. 748–755.

    Article  CAS  Google Scholar 

  22. Persiyanova, E.V., Adgamov, R.R., Surin, A.K., Psareva, E.K., Yermolayeva, S.A., and Timchenko, N.F., Cytotoxic necrotizing factor of Yersinia Pseudotuberculosis, pathogen of Far eastern scarlet-like fever, Byull. Sib. Otd. Ross. Akad. Med. Nauk, 2013, vol. 33, no. 2, pp. 16–20.

    Google Scholar 

  23. Caprioil, A., Falbo, V., Roda, L.G., Ruggeri, F.M., and Zona, C., Partial purification and characterization of an Escherichia coli toxic factor that induces morphological cell alterations, Infect. Immun., 1983, vol. 39, no. 3, pp. 1300–1306.

    Article  Google Scholar 

  24. Blum, G., Falbo, V., Caprioli, A., and Hacker, J., Gene clusters encoding the cytotoxic necrotizing factor type 1, Prs-fim-briae and -hemolysin form the pathogenicity island II of the uropathogenic Escherichia coli strain J96, FEMS Microbiol. Lett., 1995, vol. 126, pp. 189–196.

    CAS  PubMed  Google Scholar 

  25. Oswald, E., Pohl, P., Jacquemin, E., Lintermans, P., Van Muylem, K., O’Brien, A.D., and Mainil, J., Specific DNA probes to detect Escherichia coli strains producing cytotoxic necrotizing factor type 1 or type 2, J. Med. Microbiol., 1994, vol. 40, no. 6, pp. 428–434.

    Article  CAS  PubMed  Google Scholar 

  26. Orden, J.A., Dominguez-Bernal, G., Martinez-Pulgarin, S., Blanco, M., Blanco, J.E., Mora, A., et al., Necro-toxigenic Escherichia coli from sheep and goats produce a new type of cytotoxic necrotizing factor (CNF3) associated with the eae and ehxA genes, Int. Microbiol., 2007, vol. 10, pp. 47–55.

    CAS  PubMed  Google Scholar 

  27. Mills, M., Meysick, K.C., and O’Brien, A.D., Cytotoxic necrotizing factor type 1 of uropathogenic Escherichia coli kills cultured human uroepithelial 5637 cells by an apoptotic mechanism, Infect. Immun., 2000, vol. 68, no. 10, pp. 5869–5880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blumenthal, B., Hoffmann, C., Aktories, K., Backert, S., and Schmidt, G., The cytotoxic necrotizing factors from Yersinia pseudotuberculosis and from Escherichia coli bind to different cellular receptors but take the same route to the cytosol, Infect. Immun., 2007, vol. 75, pp. 3344–3353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lemichez, E., Flatau, G., Bruzzone, M., Boquet, P., and Gauthier, M., Molecular localization of the Escherichia coli cytotoxic necrotizing factor CNF1 cell-binding and catalytic domains, Mol. Microbiol., 1997, vol. 24, no. 5, pp. 1061–1070.

    Article  CAS  PubMed  Google Scholar 

  30. Knust, Z. and Schmidt, G., Cytotoxic necrotizing factors (cnfs) - a growing toxin family, Toxins, 2010, vol. 2, no. 1, pp. 116–127.

    Article  CAS  PubMed  Google Scholar 

  31. Aktories, K., Rho proteins: targets for bacterial toxins, Trends Microbiol., 1997, vol. 5, pp. 282–288.

    Article  CAS  PubMed  Google Scholar 

  32. Aref'yev, V.A. and Lisovenko, L.A., Anglo-Russkii tolkovyi slovar’ geneticheskikh terminov (English-Russian Explanatory Dictionary of Genetic Terms), Moscow: Russian Federal Research Institute of Fisheries and Oceanography, 1995.

  33. Hoffmann, C., Pop, M., Leemhuis, J., Schirmer, J., Aktories, K., and Schmidt, G., The Yersinia pseudotuberculosis cytotoxic necrotizing factor (CNFY) selectively activates RhoA, J. Biol. Chem., 2004, vol. 279, pp. 16026–16032.

    Article  CAS  PubMed  Google Scholar 

  34. May, M., Kolbe, T., Wang, T., Schmidt, G., and Genth, H., Increased cell-matrix adhesion upon constitutive activation of rho proteins by cytotoxic necrotizing factors from E. coli and Y. pseudotuberculosis,J. Signal Transduction, 2012, vol. 10, pp. 1142–1155.

    Google Scholar 

  35. Repella, T.L., Ho, M., and Wilson, B.A., Determinants of pH-dependent modulation of translocation in dermonecrotic G-protein-deamidating toxins, Toxins (Basel), 2013, vol. 5, no. 6, pp. 1167–1179.

    Article  CAS  Google Scholar 

  36. Augspach, A., List, J.H., Wolf, P., Bielek, H., Schwan, C., Elsässer-Beile, U., Aktories, K., and Schmidt, G., Activation of RhoA, B, C by yersinia cytotoxic necrotizing factor (CNFY) induces apoptosis in lncap prostate cancer cells, Toxins (Basel), 2013, vol. 5, no. 11, pp. 2241–2257.

    Article  CAS  Google Scholar 

  37. Schweer, J., Kulkarni, D., Kochut, A., Pezoldt, J., Pisano, F., Pils, M.C., et al., The cytotoxic necrotizing factor of Yersinia pseudotuberculosis (CNFY) enhances inflammation and Yop delivery during infection by activation of Rho GT-Pases, PLoS Pathog., 2013, vol. 9, no. 11, p. e1003746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Worsham, P.L., Mou, S., Cote, C.K., and Fritz, D., Virulence of Yersinia pseudotuberculosis in aerosol model, Adv. Exp. Med. Biol., 2012, vol. 954, pp. 217–222.

    Article  CAS  PubMed  Google Scholar 

  39. Mou, S., Cote, C.K., and Worsham, P.L., Cytotoxic necrotizing factor is an effective immunogen in a Yersinia pseudotuberculosis aerosol mouse model, Adv. Exp. Med. Biol., 2012, vol. 954, pp. 179–181.

    Article  CAS  PubMed  Google Scholar 

  40. Heine, W., Beckstette, M., Heroven, A.K., Thiemann, S., Heise, U., Nuss, A.M., et al., Loss of CNF Y toxin-induced inflammation drives Yersinia pseudotuberculosis in to persistency, PLoS Pathog., 2018, vol. 14, no. 2, p. e1006858.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Wolters, M., Boyle, E.C., Lardong, K., Trülzsch, K., Steffen, A., and Rottner, K., Cytotoxic necrotizing factor-Y boosts Yersinia effector translocation by activating Rac protein, J. Biol. Chem., 2013, vol. 288, no. 32, pp. 23543–23553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Aili, M., Isaksson, E., Hallberg, B., et al., Functional analysis of the Yope GTF-ase-activating protein (GAP) activity of Yersinia pseudotuberculosis,Cell. Microbiol., 2006, vol. 8, pp. 1020–1033.

    Article  CAS  PubMed  Google Scholar 

  43. Timchenko, N.F., Adgamov, R., and Ermolaeva, S., Variability in the functional domains of the Rho-modifying toxins of Yersinia pseudotuberculosis,Adv. Exp. Med. Biol., 2012, vol. 954, pp. 261–266.

    Article  CAS  PubMed  Google Scholar 

  44. Psareva, E.K., Ermolaeva, S.A., and Timchenko, N.F., A PCR system for Yersinia pseudotuberculosis identification, Mol. Genet., Microbiol. Virol., 2018, vol. 33, no. 2, pp. 118–123.

    Article  Google Scholar 

  45. Psareva, E.K., Timchenko, N.F., Ermolaeva, S.A., Terenteva, N.A., and Kompanets, G.G., The recombinant protein cytotoxic necrotizing factor from Yersinia pseudotuberculosis strain isolated in the territory of the Russian Federation, Zdorov’e. Med. Ekol. Nauka, 2016, vol. 65, no. 2, pp. 40–43.

    Google Scholar 

  46. Psareva, E.K., Characterization of the cytotoxic necrotizing factor gene in Yersinia pseudotuberculosis strains isolated in the territory of the Russian Federation, Cand. Sci. (Biol.) Dissertation, Moscow: N.F. Gamaleya Federal Research Center for Epidemiology and Microbiology, 2018.

Download references

Author information

Authors and Affiliations

  1. Somov Institute of Epidemiology and Microbiology, 690087, Vladivostok, Russia

    N. F. Timchenko & E. K. Psareva

  2. Federal Research Center for Virology and Microbiology, 601125, Vol’ginskii, Russia

    E. K. Psareva & S. A. Ermolaeva

  3. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098, Moscow, Russia

    S. A. Ermolaeva

Authors
  1. N. F. Timchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. K. Psareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. A. Ermolaeva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. K. Psareva.

Ethics declarations

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

COMPLIANCE WITH ETHICAL STANDARDS

This article does not contain any studies involving animals or human participants performed by any of the authors.

Additional information

Translated by M. Novikova

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Timchenko, N.F., Psareva, E.K. & Ermolaeva, S.A. The Cytotoxic Necrotizing Factor of Yersinia pseudotuberculosis. Mol. Genet. Microbiol. Virol. 34, 201–207 (2019). https://doi.org/10.3103/S0891416819040104

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0891416819040104

Keywords:

Search

Navigation