1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

EcoSal Plus

Domain 8:

Pathogenesis

Cytotoxic Necrotizing Factors: Rho-Activating Toxins from

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Buy article
Choose downloadable ePub or PDF files.
Buy this Chapter
Digital (?) $30.00
  • Authors: Gudula Schmidt1, and Klaus Aktories2
  • Editor: Michael S. Donnenberg3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs-Universität Freiburg, Albertstr. 25, D-79104 Freiburg, Germany; 2: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs-Universität Freiburg, Albertstr. 25, D-79104 Freiburg, Germany; 3: University of Maryland, School of Medicine, Baltimore, MD
  • Received 17 September 2003 Accepted 12 December 2003 Published 12 April 2004
  • Address correspondence to Klaus AktoriesKlaus.Aktories@pharmakol.uni-freiburg.de
image of Cytotoxic Necrotizing Factors: Rho-Activating Toxins from <span class="jp-italic">Escherichia coli</span>
    Preview this reference work article:
    Zoom in
    Zoomout

    Cytotoxic Necrotizing Factors: Rho-Activating Toxins from , Page 1 of 2

    | /docserver/preview/fulltext/ecosalplus/1/1/8_7_4_module-1.gif /docserver/preview/fulltext/ecosalplus/1/1/8_7_4_module-2.gif
  • Abstract:

    This article reviews the toxins called cytotoxic necrotizing factors (CNFs), which cause activation of Rho GTPases. It describes their modes of action, structure-function relationships, and roles in disease. Rho GTPases, the targets of CNFs, belong to the Ras superfamily of low molecular mass GTPases and act as molecular switches in various signaling pathways. Low molecular mass GTPases of the Rho family are known as master regulators of the actin cytoskeleton. Moreover, they are involved in various signal transduction processes, from transcriptional activation, cell cycle progression, and cell transformation to apoptosis. CNFs are cytotoxic for a wide variety of cells, including 3T3 fibroblasts, Chinese hamster ovary cells, Vero cells, HeLa cells, and cell lines of neuronal origin. This implies that a commonly expressed receptor is responsible for the uptake of CNF1. Cultured mammalian cells treated with CNFs are characterized by dramatic changes in actin-containing structures, including stress fibers, lamellipodia, and filopodia. Most striking is the formation of multinucleation in these cells. Rho GTPases are increasingly recognized as essential factors in the development of cancer and metastasis. This fact has initiated a discussion as to whether activation of Rho proteins by CNFs might be involved in tumorigenesis. Moreover, CNF1 increases the expression of the cyclooxygenase 2 (Cox2) gene in fibroblasts. Increased expression of Cox2 is observed in some types of tumors, e.g., colon carcinoma. Lipid-mediators produced by the enzyme are suggested to be responsible for tumor progression.

  • Citation: Schmidt G, Aktories K. 2004. Cytotoxic Necrotizing Factors: Rho-Activating Toxins from , EcoSal Plus 2004; doi:10.1128/ecosalplus.8.7.4

Key Concept Ranking

Bacterial Proteins
0.6277738
Amino Acids
0.5964888
Bacterial Toxins
0.45772833
0.6277738

References

1. Boquet P. 2001. The cytotoxic necrotizing factor 1 (CNF1) from Escherichia coli. Toxicon 39:1673–1680. [PubMed][CrossRef]
2. Horiguchi Y. 2001. Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases. Toxicon 39:1619–1627. [PubMed][CrossRef]
3. Takai Y, Sasaki T, Matozaki T. 2001. Small GTP-binding proteins. Physiol Rev 81:153–208.[PubMed]
4. Symons M, Settleman J. 2000. Rho family GTPases: more than just simple switches. Trends Cell Biol 10:415–419. [PubMed][CrossRef]
5. Takai Y, Kaibuchi K, Kikuchi A, Kawata M. 1992. Small GTP-binding proteins. Int Rev Cytol 133:187–230. [PubMed][CrossRef]
6. Van Aelst L, D’Souza-Schorey C. 1997. Rho GTPases and signaling networks. Genes Dev 11:2295–2322. [PubMed][CrossRef]
7. Bishop AL, Hall A. 2000. Rho GTPases and their effector proteins. Biochem J 348:241–255. [PubMed][CrossRef]
8. Etienne-Manneville S, Hall A. 2002. Rho GTPases in cell biology. Nature 420:629–635. [PubMed][CrossRef]
9. Aktories K, Schmidt G. 2003. A new turn in rho GTPase activation by Escherichia coli cytotoxic necrotizing factors. Trends Microbiol 11:152–155. [PubMed][CrossRef]
10. Sekine A, Fujiwara M, Narumiya S. 1989. Asparagine residue in the rho gene product is the modification site for botulinum ADP-ribosyltransferase. J Biol Chem 264:8602–8605.
11. Busch C, Aktories K. 2000. Microbial toxins and the glucosylation of Rho family GTPases. Curr Opin Struct Biol 10:528–535. [PubMed][CrossRef]
12. Just I, Hofmann F, Aktories K. 2000. Molecular mechanisms of large clostridial cytotoxins, p 307–331. Handbook of Experimental Pharmacology. Springer Verlag, Berlin, Germany.
13. Just I, Selzer J, Wilm M, Von Eichel-Streiber C, Mann M, Aktories K. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500–503. [PubMed][CrossRef]
14. Genth H, Aktories K, Just I. 1999. Monoglucosylation of RhoA at Threonine-37 blocks cytosol-membrane cycling. J Biol Chem 274:29050–29056. [PubMed][CrossRef]
15. Sehr P, Joseph G, Genth H, Just I, Pick E, Aktories K. 1998. Glucosylation and ADP-ribosylation of Rho proteins—effects on nucleotide binding, GTPase activity, and effector-coupling. Biochemistry 37:5296–5304. [PubMed][CrossRef]
16. Horiguchi Y, Inoue N, Masuda M, Kashimoto T, Katahira J, Sugimoto N, Matsuda M. 1997. Bordetella bronchiseptica dermonecrotizing toxin induces reorganization of actin stress fibers through deamidation of Gln-63 of the GTP-binding protein Rho. Proc Natl Acad Sci USA 94:11623–11626. [PubMed][CrossRef]
17. Masuda M, Betancourt L, Matsuzawa T, Kashimoto T, Takao T, Shimonishi Y, Horiguchi Y. 2000. Activation of Rho through a cross-link with polyamines catalyzed by Bordetella dermonecrotizing toxin. EMBO J 19:521–530. [PubMed][CrossRef]
18. Galan JE, Fu Y. 2000. Modulation of actin cytoskeleton by Salmonella GTPase activating protein SptP. Methods Enzymol 325:496–504. [PubMed][CrossRef]
19. Stender S, Friebel A, Linder S, Rohde M, Mirold S, Hardt W-D. 2000. Identification of SopE2 from Salmonella typhimurium, a conserved guanine nucleotide exchange factor for Cdc42 of the host cell. Mol Microbiol 36:1206–1221. [PubMed][CrossRef]
20. Caprioli A, Falbo V, Roda LG, Ruggeri FM, Zona C. 1983. Partial purification and characterization of an Escherichia coli toxic factor that induces morphological cell alterations. Infect Immun 39:1300–1306.[PubMed]
21. Oswald E, de Rycke J, Guillot JF, Boivin R. 1989. Cytotoxic effect of multinucleation in HeLa cell cultures associated with the presence of Vir plasmid in Escherichia coli strains. FEMS Microbiol Lett 58:95–100. [CrossRef]
22. Oswald E, Sugai M, Labigne A, Wu HC, Fiorentini C, Boquet P, O’Brien AD. 1994. Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Proc Natl Acad Sci USA 91:3814–3818. [PubMed][CrossRef]
23. de Rycke J, Guillot JF, Boivin R. 1987. Cytotoxins in non-enterotoxigenic strains of Escherichia coli isolated from feces of diarrheic calves. Vet Microbiol 15:137–150. [PubMed][CrossRef]
24. de Rycke J, González EA, Blanco J, Oswald E, Blanco M, Boivin R. 1990. Evidence for two types of cytotoxic necrotizing factor in human and animal clinical isolates of Escherichia coli. J Clin Microbiol 28:694–699.[PubMed]
25. Oswald E, de Rycke J. 1990. A single protein of 110 kDa is associated with the multinucleating and necrotizing activity coded by the Vir plasmid of Escherichia coli. FEMS Microbiol Lett 68:279–284. [CrossRef]
26. Lockman HA, Gillespie RA, Baker BD, Shakhnovich E. 2002. Yersinia pseudotuberculosis produces a cytotoxic necrotizing factor. Infect Immun 70:2708–2714. [PubMed][CrossRef]
27. Lemichez E, Flatau G, Bruzzone M, Boquet P, Gauthier M. 1997. Molecular localization of the Escherichia coli cytotoxic necrotizing factor CNF1 cell-binding and catalytic domains. Mol Microbiol 24:1061–1070. [PubMed][CrossRef]
28. Pei S, Doye A, Boquet P. 2001. Mutation of specific acidic residues of the CNF1 T domain into lysine alters cell membrane translocation of the toxin. Mol Microbiol 41:1237–1247. [PubMed][CrossRef]
29. Chung JW, Hong SJ, Kim KJ, Goti D, Stins MF, Shin S, Dawson VL, Dawson TM, Kim KS. 2003. 37 kDa laminin receptor precusor modulates cytotoxic necrotizing factor 1-mediated RhoA activation and bacterial uptake. J Biol Chem 278:16857–16862. [PubMed][CrossRef]
30. Contamin S, Galmiche A, Doye A, Flatau G, Benmerah A, Boquet P. 2000. The p21 Rho-activating toxin cytotoxic necrotizing factor 1 is endocytosed by a clathrin-independent mechanism and enters the cytosol by an acidic-dependent membrane translocation step. Mol Biol Cell 11:1775–1787.[PubMed]
31. Fiorentini C, Fabbri A, Flatau G, Donelli G, Matarrese P, Lemichez E, Falzano L, Boquet P. 1997. Escherichia coli cytotoxic necrotizing factor 1 (CNF1), a toxin that activates the Rho GTPase. J Biol Chem 272:19532–19537. [PubMed][CrossRef]
32. Flatau G, Lemichez E, Gauthier M, Chardin P, Paris S, Fiorentini C, Boquet P. 1997. Toxin-induced activation of the G protein p21 Rho by deamidation of glutamine. Nature 387:729–733. [PubMed][CrossRef]
33. Schmidt G, Sehr P, Wilm M, Selzer J. Mann M, Aktories K. 1997. Gln63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor 1. Nature 387:725–729. [PubMed][CrossRef]
34. Lerm M, Selzer J, Hoffmeyer A, Rapp UR, Aktories K, Schmidt G. 1999. Deamidation of Cdc42 and Rac by Escherichia coli cytotoxic necrotizing factor 1: activation of c-Jun N-terminal kinase in HeLa cells. Infect Immun 67:496–503.[PubMed]
35. Flatau G, Landraud L, Boquet P, Bruzzone M, Munro P. 2000. Deamidation of RhoA glutamine 63 by the Escherichia coli CNF1 toxin requires a short sequence of the GTPase switch 2 domain. Biochem Biophys Res Commun 267:588–592. [PubMed][CrossRef]
36. Lerm M, Schmidt G, Goehring U-M, Schirmer J, Aktories K. 1999. Identification of the region of Rho involved in substrate recognition by Escherichia coli cytotoxic necrotizing factor 1 (CNF1)*. J Biol Chem 274:28999–29004. [PubMed][CrossRef]
37. Schmidt G, Selzer J, Lerm M, Aktories K. 1998. The Rho-deamidating cytotoxic-necrotizing factor CNF1 from Escherichia coli possesses transglutaminase activity—cysteine-866 and histidine-881 are essential for enzyme activity. J Biol Chem 273:13669–13674. [CrossRef]
38. Kashimoto T, Katahira J, Cornejo WR, Masuda M, Fukuoh A, Matsuzawa T, Ohnishi T, Horiguchi Y. 1999. Identification of functional domains of Bordetella dermonecrotizing toxin. Infect Immun 67:3727–3732.[PubMed]
39. Schmidt G, Goehring U-M, Schirmer J, Lerm M, Aktories K. 1999. Identification of the C-terminal part of Bordetella dermonecrotic toxin as a transglutaminase for Rho GTPases. J Biol Chem 274:31875–31881. [PubMed][CrossRef]
40. Horiguchi Y, Nakai T, Kume K. 1989. Purification and characterization of Bordetella bronchiseptica dermonecrotic toxin. Microb Pathog 6:361–368. [PubMed][CrossRef]
41. Schmidt G, Goehring U-M, Schirmer J, Uttenweiler-Joseph S, Wilm M, Lohmann M, Giese A, Schmalzing G, Aktories K. 2001. Lysine and polyamines are substrates for transglutamination of Rho by the Bordetella dermonecrotic toxin. Infect Immun 69:7663–7670. [PubMed][CrossRef]
42. Denko N, Langland R, Barton M, Lieberman MA. 1997. Uncoupling of S-phase and mitosis by recombinant cytotoxic necrotizing factor 2 (CNF2). Exp Cell Res 234:132–138. [CrossRef]
43. Doye A, Mettouchi A, Bossis G, Clément R, Buisson-Touati C, Flatau G, Gagnoux L, Piechaczyk M, Boquet P, Lemichez E. 2002. CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell 111:553–564. [PubMed][CrossRef]
44. Lerm M, Pop M, Fritz G, Aktories K, Schmidt G. 2002. Proteasomal degradation of cytotoxic necrotizing factor 1-activated Rac. Infect Immun 70:4053–4058. [PubMed][CrossRef]
45. Buetow L, Flatau G, Chiu K, Boquet P, Ghosh P. 2001. Structure of the Rho-activating domain of Escherichia coli cytotoxic necrotizing factor 1. Nat Struct Biol 8:584–588. [PubMed][CrossRef]
46. Pedersen LC, Yee VC, Bishop PD, Trong IL, Teller DC, Stenkamp RE. 1994. Transglutaminase factor XIII uses proteinase-like catalytic triad to crosslink macromolecules. Protein Sci 3:1131–1135. [PubMed][CrossRef]
47. Rippere-Lampe KE, O’Brien AD, Conran R, Lockman HA. 2001. Mutation of the gene encoding cytotoxic necrotizing factor type 1 (cnf1) attenuates the virulence of uropathogenic Escherichia coli. Infect Immun 69:3954–3964. [PubMed][CrossRef]
48. Rippere-Lampe KE, Lang M, Ceri H, Olson M, Lockman HA, O’Brien AD. 2001. Cytotoxic necrotizing factor type 1-positive Escherichia coli causes increased inflammation and tissue damage to the prostate in a rat prostatitis model. Infect Immun 69:6515–6519. [PubMed][CrossRef]
49. Fournout S, Dozois CM, Odin M, Desautels C, Pérès S, Hérault F, Daigle F, Segafredo C, Laffitte J, Oswald E, Fairbrother JM, Oswald IP. 2000. Lack of a role of cytotoxic necrotizing factor 1 toxin from Escherichia coli in bacterial pathogenicity and host cytokine response in infected germfree piglets. Infect Immun 68:839–847. [PubMed][CrossRef]
50. Khan NA, Wang Y, Kim KJ, Chung JW, Wass CA, Kim KS. 2002. Cytotoxic necrotizing factor-1 contributes to Escherichia coli K1 invasion of the central nervous system. J Biol Chem 277:15607–15612. [PubMed][CrossRef]
51. Gerhard R, Schmidt G, Hofmann F, Aktories K. 1998. Activation of Rho GTPases by Escherichia coli cytotoxic necrotizing factor 1 increases intestinal permeability in Caco-2 cells. Infect Immun 66:5125–5131.[PubMed]
52. Hopkins AM, Walsh SV, Verkade P, Boquet P, Nusrat A. 2003. Constitutive activation of Rho proteins by CNF-1 influences tight junction structure and epithelial barrier function. J Cell Sci 116:725–742. [PubMed][CrossRef]
53. Malorni W, Quaranta MG, Straface E, Falzano L, Fabbri A, Viora M, Fiorentini C. 2003. The Rac-activating toxin cytotoxic necrotizing factor 1 oversees NK cell-mediated activity by regulating the actin/microtubule interplay. J Immunol 171:4195–4202.[PubMed]
54. Brest P, Mograbi B, Hofmann V, Loubat A, Rossi B, Auberger P, Hofmann P. 2003. Rho GTPase is activated by cytotoxic necrotizing factor 1 in peripheral blood T lymphocytes: potential cytotoxicity for intestinal epithelial cells. Infect Immun 71:1161–1169. [PubMed][CrossRef]
55. Thomas W, Ascott ZK, Harmey D, Slice LW, Rozengurt E, Lax AJ. 2001. Cytotoxic necrotizing factor from Escherichia coli induces RhoA-dependent expression of the cyclooxygenase-2 gene. Infect Immun 69:6839–6845. [PubMed][CrossRef]
56. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM. 1996. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803–809. [PubMed][CrossRef]
57. Lax AJ, Thomas W. 2002. How bacteria could cause cancer: one step at a time. Trends Microbiol 10:293–299. [PubMed][CrossRef]
ecosalplus.8.7.4.citations
ecosalplus/1/1
content/journal/ecosalplus/10.1128/ecosalplus.8.7.4
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/ecosalplus/10.1128/ecosalplus.8.7.4
2004-04-12
2017-03-26

Abstract:

This article reviews the toxins called cytotoxic necrotizing factors (CNFs), which cause activation of Rho GTPases. It describes their modes of action, structure-function relationships, and roles in disease. Rho GTPases, the targets of CNFs, belong to the Ras superfamily of low molecular mass GTPases and act as molecular switches in various signaling pathways. Low molecular mass GTPases of the Rho family are known as master regulators of the actin cytoskeleton. Moreover, they are involved in various signal transduction processes, from transcriptional activation, cell cycle progression, and cell transformation to apoptosis. CNFs are cytotoxic for a wide variety of cells, including 3T3 fibroblasts, Chinese hamster ovary cells, Vero cells, HeLa cells, and cell lines of neuronal origin. This implies that a commonly expressed receptor is responsible for the uptake of CNF1. Cultured mammalian cells treated with CNFs are characterized by dramatic changes in actin-containing structures, including stress fibers, lamellipodia, and filopodia. Most striking is the formation of multinucleation in these cells. Rho GTPases are increasingly recognized as essential factors in the development of cancer and metastasis. This fact has initiated a discussion as to whether activation of Rho proteins by CNFs might be involved in tumorigenesis. Moreover, CNF1 increases the expression of the cyclooxygenase 2 (Cox2) gene in fibroblasts. Increased expression of Cox2 is observed in some types of tumors, e.g., colon carcinoma. Lipid-mediators produced by the enzyme are suggested to be responsible for tumor progression.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Comment has been disabled for this content
Submit comment
Close
Comment moderation successfully completed

Figures

Image of Figure 1
Figure 1

A large variety of bacterial toxins target small GTPases of the Rho family. C3-like exoenzymes ADP ribosylate RhoA at asparagine 41, inhibiting the biological functions of the GTPase. All members of the Rho subfamily are glucosylated by large clostridial cytotoxins (e.g., toxins A and B). Recently, it was shown that the outer protein T (YopT) is a member of a new family of cysteine proteases that cleave RhoA in front of the isoprenylated cysteine at the C terminus, blocking membrane binding and inactivating the GTPase. Rho is constitutively activated by CNF1 and -2 of The CNF1-related DNT from species, which transglutaminates glutamine 63 of RhoA, activates the GTPase. Rho proteins are not exclusively covalently modified by bacterial toxins. Some bacterial effectors, like SptP, exoenzyme S (ExoS), and outer protein E (YopE), modulate the activities of Rho GTPases by acting as regulatory proteins with GAP activity or with GEF functions ( SopE).

Citation: Schmidt G, Aktories K. 2004. Cytotoxic Necrotizing Factors: Rho-Activating Toxins from , EcoSal Plus 2004; doi:10.1128/ecosalplus.8.7.4
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Glutamine 63 of RhoA (Gln 61 of Rac and Cdc42) is essential for the hydrolysis of bound GTP. CNF and DNT deamidate this glutamine residue, creating glutamic acid, and the GTP-hydrolyzing activity of the GTPase is blocked. In the presence of primary amines, the toxins can polyaminate Rho at the same residue, thereby also blocking hydrolysis of GTP. Polyamination is the preferred activity of DNT, whereas CNF is a much better deamidase.

Citation: Schmidt G, Aktories K. 2004. Cytotoxic Necrotizing Factors: Rho-Activating Toxins from , EcoSal Plus 2004; doi:10.1128/ecosalplus.8.7.4
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

CNF and DNT consist of 1,014 and 1,451 amino acids, respectively. The toxins show homology within their catalytic domains (ΔCNF, amino acids 709 to 1014, and ΔDNT, amino acids 1136 to 1451), which are located at the C termini of the proteins. The highest sequence similarity is observed in a stretch of 64 amino acid residues which covers residues 1250 through 1314 of DNT, showing ~45% sequence identity, whereas the amino acid sequence of the whole catalytic domain of DNT is only ~13% identical with the sequence of the catalytic domain of CNF1. Cysteine 866 and histidine 881 are essential for enzyme activity in CNF1. As deduced from the crystal structure, a third “catalytic” residue appears to be valine 833.

Citation: Schmidt G, Aktories K. 2004. Cytotoxic Necrotizing Factors: Rho-Activating Toxins from , EcoSal Plus 2004; doi:10.1128/ecosalplus.8.7.4
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error