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Gene Review

cnf1  -  cytotoxic necrotizing factor 1

Escherichia coli UTI89

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Disease relevance of cnf1

  • One milliliter of a culture of Escherichia coli (with five uro-pathogenic virulence factors as identified by PCR: pap, sfa, hlyA, cnf1 and fim) was inoculated intra-vaginally daily throughout the simulated estrus (Group 2) [1].
  • The prevalence of sfa, hly and cnf1 was higher in prostatitis isolates than in pyelonephritis and cystitis isolates, and the pap+sfa+hly+cnf1+ genotype was dominant among prostatitis isolates (48.8%) [2].
  • The N-terminal half of CNF2 showed striking homology (27% identity and 80% conserved residues) to the N-terminal portion of Pasteurella multocida toxin [3].
  • Preincubation of cells with CNF1 impairs the cytotoxic effects of Clostridium difficile toxin B, which inactivates Rho but not those of Clostridium sordellii LT toxin, which inhibits Ras and Rac [4].
  • Recently, a novel cytotoxic necrotizing factor termed CNFY was identified in Yersinia pseudotuberculosis strains (Lockman, H. A., Gillespie, R. A., Baker, B. D., and Shakhnovich, E. (2002) Infect. Immun. 70, 2708-2714) [5].

High impact information on cnf1

  • Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks [6].
  • The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866 [6].
  • Here we show that the catalytic region of CNF1 exhibits a novel protein fold as determined by its 1.83 A resolution crystal structure [7].
  • We cloned the CNF2 gene from a large plasmid carried by an Escherichia coli strain isolated from a lamb with septicemia [3].
  • Although it is clear that the CNF toxins can affect a wide variety of adherent nonhematopoietic cell lines, we propose that the response to CNF, in terms of reorganizing actin structure and increase in DNA content in hematologic suspension cells, correlates with the capability of these target cells to differentiate along the megakaryocytic lineage [8].

Chemical compound and disease context of cnf1


Biological context of cnf1


Anatomical context of cnf1

  • Seven of the cnf1-positive isolates were tested and shown to have a cytopathic effect on HeLa cell monolayers [18].
  • The cnf1 sequences from the mink and bovine isolates of E. coli were compared to each other and to cnf1 sequences of E. coli from urinary tract and diarrhoea-associated infections of humans [19].
  • CNF1 belongs to a unique group of large cytotoxins that cause constitutive activation of Rho guanosine triphosphatases (GTPases), which are key regulators of the actin cytoskeleton [7].
  • We have examined the effect of CNF toxin on one of the few cell types that naturally increase nuclear DNA content, megakaryocytes [8].
  • In addition, CNF1-enhanced E. coli invasion of brain endothelial cells and stress fiber formation were independent of focal adhesion kinase and phosphatidylinositol 3-kinase activation [20].

Associations of cnf1 with chemical compounds

  • Some strains possessed toxin genes cdt-IIIB and cnf1/2 (both 14.3%), the invasion gene tia (23.8%), and the serine protease encoding gene espP (23.8%) [21].
  • The data indicate that CNF1 shares a catalytic dyad of cysteine and histidine residues with eukaryotic transglutaminases and cysteine proteases [10].
  • When immobilized onto polystyrene beads, CNF1 was sufficient to induce internalization of coupled beads into HBMEC through interaction with 67LR [22].
  • In addition, we identified histidine 881 to be essential for the enzyme activity of CNF1 [10].
  • Cytochalasin D and high concentrations of platelet-derived growth factor disrupted the actin cytoskeleton and completely inhibited CNF1 and DNT induced tyrosine phosphorylation [11].

Analytical, diagnostic and therapeutic context of cnf1


  1. A model for cystic endometrial hyperplasia/pyometra complex in the bitch. Arora, N., Sandford, J., Browning, G.F., Sandy, J.R., Wright, P.J. Theriogenology (2006) [Pubmed]
  2. Escherichia coli virulence factors and serotypes in acute bacterial prostatitis. Terai, A., Yamamoto, S., Mitsumori, K., Okada, Y., Kurazono, H., Takeda, Y., Yoshida, O. International journal of urology : official journal of the Japanese Urological Association. (1997) [Pubmed]
  3. Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Oswald, E., Sugai, M., Labigne, A., Wu, H.C., Fiorentini, C., Boquet, P., O'Brien, A.D. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  4. Escherichia coli cytotoxic necrotizing factor 1 (CNF1), a toxin that activates the Rho GTPase. Fiorentini, C., Fabbri, A., Flatau, G., Donelli, G., Matarrese, P., Lemichez, E., Falzano, L., Boquet, P. J. Biol. Chem. (1997) [Pubmed]
  5. The Yersinia pseudotuberculosis cytotoxic necrotizing factor (CNFY) selectively activates RhoA. Hoffmann, C., Pop, M., Leemhuis, J., Schirmer, J., Aktories, K., Schmidt, G. J. Biol. Chem. (2004) [Pubmed]
  6. Enhancement of learning and memory after activation of cerebral Rho GTPases. Diana, G., Valentini, G., Travaglione, S., Falzano, L., Pieri, M., Zona, C., Meschini, S., Fabbri, A., Fiorentini, C. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Structure of the Rho-activating domain of Escherichia coli cytotoxic necrotizing factor 1. Buetow, L., Flatau, G., Chiu, K., Boquet, P., Ghosh, P. Nat. Struct. Biol. (2001) [Pubmed]
  8. Megakaryocytic cell line-specific hyperploidy by cytotoxic necrotizing factor bacterial toxins. Hudson, K.M., Denko, N.C., Schwab, E., Oswald, E., Weiss, A., Lieberman, M.A. Blood (1996) [Pubmed]
  9. Isotype-specific degradation of Rac activated by the cytotoxic necrotizing factor 1. Pop, M., Aktories, K., Schmidt, G. J. Biol. Chem. (2004) [Pubmed]
  10. The Rho-deamidating cytotoxic necrotizing factor 1 from Escherichia coli possesses transglutaminase activity. Cysteine 866 and histidine 881 are essential for enzyme activity. Schmidt, G., Selzer, J., Lerm, M., Aktories, K. J. Biol. Chem. (1998) [Pubmed]
  11. Cytotoxic necrotizing factor 1 from Escherichia coli and dermonecrotic toxin from Bordetella bronchiseptica induce p21(rho)-dependent tyrosine phosphorylation of focal adhesion kinase and paxillin in Swiss 3T3 cells. Lacerda, H.M., Pullinger, G.D., Lax, A.J., Rozengurt, E. J. Biol. Chem. (1997) [Pubmed]
  12. Induction of phagocytic behaviour in human epithelial cells by Escherichia coli cytotoxic necrotizing factor type 1. Falzano, L., Fiorentini, C., Donelli, G., Michel, E., Kocks, C., Cossart, P., Cabanié, L., Oswald, E., Boquet, P. Mol. Microbiol. (1993) [Pubmed]
  13. Uncoupling of S-phase and mitosis by recombinant cytotoxic necrotizing factor 2 (CNF2). Denko, N., Langland, R., Barton, M., Lieberman, M.A. Exp. Cell Res. (1997) [Pubmed]
  14. Expression of cnf1 by Escherichia coli J96 involves a large upstream DNA region including the hlyCABD operon, and is regulated by the RfaH protein. Landraud, L., Gibert, M., Popoff, M.R., Boquet, P., Gauthier, M. Mol. Microbiol. (2003) [Pubmed]
  15. Lack of a role of cytotoxic necrotizing factor 1 toxin from Escherichia coli in bacterial pathogenicity and host cytokine response in infected germfree piglets. Fournout, S., Dozois, C.M., Odin, M., Desautels, C., Pérès, S., Hérault, F., Daigle, F., Segafredo, C., Laffitte, J., Oswald, E., Fairbrother, J.M., Oswald, I.P. Infect. Immun. (2000) [Pubmed]
  16. Rho-dependent cell spreading activated by E.coli cytotoxic necrotizing factor 1 hinders apoptosis in epithelial cells. Fiorentini, C., Matarrese, P., Straface, E., Falzano, L., Donelli, G., Boquet, P., Malorni, W. Cell Death Differ. (1998) [Pubmed]
  17. Effect of cytotoxic necrotizing factor-1 on actin cytoskeleton in human monocytes: role in the regulation of integrin-dependent phagocytosis. Capo, C., Meconi, S., Sanguedolce, M.V., Bardin, N., Flatau, G., Boquet, P., Mege, J.L. J. Immunol. (1998) [Pubmed]
  18. Characterization of hemolytic Escherichia coli strains in ferrets: recognition of candidate virulence factor CNF1. Marini, R.P., Taylor, N.S., Liang, A.Y., Knox, K.A., Peña, J.A., Schauer, D.B., Fox, J.G. J. Clin. Microbiol. (2004) [Pubmed]
  19. Cloning and sequencing of cnf1 from Escherichia coli incriminated in mink and bovine colibacillosis. Horne, S.M., Goplin, J.L., Giddings, C.W., Dyer, N.W., Nolan, L.K. Vet. Res. Commun. (2004) [Pubmed]
  20. Cytotoxic necrotizing factor-1 contributes to Escherichia coli K1 invasion of the central nervous system. Khan, N.A., Wang, Y., Kim, K.J., Chung, J.W., Wass, C.A., Kim, K.S. J. Biol. Chem. (2002) [Pubmed]
  21. Molecular characteristics of Escherichia coli serogroup O78 strains isolated from diarrheal cases in bovines urge further investigations on their zoonotic potential. Ewers, C., Schüffner, C., Weiss, R., Baljer, G., Wieler, L.H. Molecular nutrition & food research. (2004) [Pubmed]
  22. 67-kDa laminin receptor promotes internalization of cytotoxic necrotizing factor 1-expressing Escherichia coli K1 into human brain microvascular endothelial cells. Kim, K.J., Chung, J.W., Kim, K.S. J. Biol. Chem. (2005) [Pubmed]
  23. Detection of Escherichia coli 16S RNA and Cytotoxic Necrotizing Factor 1 Gene in Benign Prostate Hyperplasia. Bergh, J., Marklund, I., Thellenberg-Karlsson, C., Gr??nberg, H., Elgh, F., Alexeyev, O.A. Eur. Urol. (2007) [Pubmed]
  24. Identification of the region of rho involved in substrate recognition by Escherichia coli cytotoxic necrotizing factor 1 (CNF1). Lerm, M., Schmidt, G., Goehring, U.M., Schirmer, J., Aktories, K. J. Biol. Chem. (1999) [Pubmed]
  25. Epitope mapping of monoclonal antibodies capable of neutralizing cytotoxic necrotizing factor type 1 of uropathogenic Escherichia coli. Meysick, K.C., Mills, M., O'Brien, A.D. Infect. Immun. (2001) [Pubmed]
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