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  • Review Article
  • Published:

Novel bacterial ADP-ribosylating toxins: structure and function

Nature Reviews Microbiology volume 12, pages 599–611 (2014)Cite this article

Subjects

Key Points

  • The emergence of bioinformatics has changed how the study of microbial pathogenesis is carried out, which has facilitated the development of 'reverse proteomics' strategies. Researchers no longer need to clinically identify a pathogen before identifying putative virulence factors.

  • These analyses can be used to identify new bacterial ADP-ribosyltransferase toxins (bARTTs) on the basis of conserved function, even when the proteins have novel structural organizations. This strategy has been proven by the identification of putative bARTTs, followed by experimental confirmation of their ADP-ribosyltransferase activity. Several novel protein toxins have been identified and characterized in this manner.

  • New toxins, such as cholix toxin (ChxA), SpyA, HopU1, SpvB and the TcC proteins have been identified using this strategy of reverse proteomics and have been experimentally shown to have the predicted ADP-ribosyltransferase enzymatic activity.

  • However, this strategy still has limitations. Many of the novel toxins have unique substrates or structural or delivery properties that were not predicted by bioinformatic methods. Experimental confirmation of the importance of a putative virulence factor according to Falkow's molecular postulates also needs to be considered.

  • The continuing growth of the family of bacterial ADP-ribosylating toxins should enable greater ability to create 'rules' to properly identify substrates and the structural organization of novel toxins. Extrapolation of this technique to other toxins or families of proteins may greatly improve the field of microbiology.

Abstract

Bacterial ADP-ribosyltransferase toxins (bARTTs) transfer ADP-ribose to eukaryotic proteins to promote bacterial pathogenesis. In this Review, we use prototype bARTTs, such as diphtheria toxin and pertussis toxin, as references for the characterization of several new bARTTs from human, insect and plant pathogens, which were recently identified by bioinformatic analyses. Several of these toxins, including cholix toxin (ChxA) from Vibrio cholerae, SpyA from Streptococcus pyogenes, HopU1 from Pseudomonas syringae and the Tcc toxins from Photorhabdus luminescens, ADP-ribosylate novel substrates and have unique organizations, which distinguish them from the reference toxins. The characterization of these toxins increases our appreciation of the range of structural and functional properties that are possessed by bARTTs and their roles in bacterial pathogenesis.

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Figure 1: Structure–function organization of bacterial ADP-ribosyltransferase toxins.
Figure 2: DT-like cellular intoxication pathways.
Figure 3: Modulation of RHO signalling by bacterial ADP-ribosyltransferase toxins.
Figure 4: TT uses a unique intoxication mechanism.

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References

  1. Aktories, K., Braun, U., Rösener, S., Just, I. & Hall, A. The rho gene product expressed in E. coli is a substrate of botulinum ADP-ribosyltransferase C3. Biochem. Biophys. Res. Commun. 158, 209–213 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Braun, U., Habermann, B., Just, I., Aktories, K. & Vandekerckhove, J. Purification of the 22 kDa protein substrate of botulinum ADP-ribosyltransferase C3 from porcine brain cytosol and its characterization as a GTP-binding protein highly homologous to the rho gene product. FEBS Lett. 243, 70–76 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Cassel, D. & Selinger, Z. Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. Proc. Natl Acad. Sci. USA 74, 3307–3311 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gill, D. M. & Meren, R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc. Natl Acad. Sci. USA 75, 3050–3054 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. West, R. E., Moss, J., Vaughan, M., Liu, T. & Liu, T. Y. Pertussis toxin-catalyzed ADP-ribosylation of transducin. Cysteine 347 is the ADP-ribose acceptor site. J. Biol. Chem. 260, 14428–14430 (1985).

    CAS  PubMed  Google Scholar 

  6. Aktories, K. et al. Botulinum C2 toxin ADP-ribosylates actin. Nature 322, 390–392 (1986).

    Article  CAS  PubMed  Google Scholar 

  7. Holbourn, K. P., Shone, C. C. & Acharya, K. R. A family of killer toxins. FEBS J. 273, 4579–4593 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Hottiger, M. O., Hassa, P. O., Lüscher, B., Schüler, H. & Koch-Nolte, F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem. Sci. 35, 208–219 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Tsuge, H. et al. Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin. Proc. Natl Acad. Sci. USA 105, 7399–7404 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tsurumura, T. et al. Arginine ADP-ribosylation mechanism based on structural snapshots of iota-toxin and actin complex. Proc. Natl Acad. Sci. USA 110, 4267–4272 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Jank, T. & Aktories, K. Strain-alleviation model of ADP-ribosylation. Proc. Natl Acad. Sci. USA 110, 4163–4164 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barth, H. & Aktories, K. New insights into the mode of action of the actin ADP-ribosylating virulence factors Salmonella enterica SpvB and Clostridium botulinum C2 toxin. Eur. J. Cell Biol. 90, 944–950 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Barth, H., Aktories, K., Popoff, M. R. & Stiles, B. G. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol. Mol. Biol. Rev. 68, 373–402 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vogelsgesang, M., Pautsch, A. & Aktories, K. C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins. Naunyn Schmiedebergs Arch. Pharmacol. 374, 347–360 (2007).

    Article  CAS  Google Scholar 

  15. Dueholm, M. S., Albertsen, M., Otzen, D. & Nielsen, P. H. Curli functional amyloid systems are phylogenetically widespread and display large diversity in operon and protein structure. PLoS ONE 7, e51274 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Doxey, A. C. & McConkey, B. J. Prediction of molecular mimicry candidates in human pathogenic bacteria. Virulence 4, 453–466 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Priest, N. K. et al. From genotype to phenotype: can systems biology be used to predict Staphylococcus aureus virulence? Nature Rev. Microbiol. 10, 791–797 (2012).

    Article  CAS  Google Scholar 

  18. Masignani, V. et al. In silico identification of novel bacterial ADP-ribosyltransferases. Int. J. Med. Microbiol. 293, 471–478 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Fieldhouse, R. J., Turgeon, Z., White, D. & Merrill, A. R. Cholera- and anthrax-like toxins are among several new ADP-ribosyltransferases. PLoS Comput. Biol. 6, e1001029 (2010). This paper shows that bioinformatics could be used to discover new toxins using protein-fold homology and amino acid sequence conservation searches; it also characterizes several toxins in silico , several of which were later experimentally confirmed to have ADP-ribosyltransferase activity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Choe, S. et al. The crystal structure of diphtheria toxin. Nature 357, 216–222 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Gill, D. M. & Dinius, L. L. Observations on the structure of diphtheria toxin. J. Biol. Chem. 246, 1485–1491 (1971).

    CAS  PubMed  Google Scholar 

  22. Collier, R. J. & Kandel, J. Structure and activity of diphtheria toxin. I. Thiol-dependent dissociation of a fraction of toxin into enzymically active and inactive fragments. J. Biol. Chem. 246, 1496–1503 (1971).

    CAS  PubMed  Google Scholar 

  23. Gill, D. M. & Pappenheimer, A. M. Jr. Structure–activity relationships in diphtheria toxin. J. Biol. Chem. 246, 1492–1495 (1971).

    CAS  PubMed  Google Scholar 

  24. Zhang, R.-G. et al. The three-dimensional crystal structure of cholera toxin. J. Mol. Biol. 251, 563–573 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Sixma, T. K. et al. Refined structure of Escherichia coli heat-labile enterotoxin, a close relative of cholera toxin. J. Mol. Biol. 230, 890–918 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Blöcker, D. et al. The C terminus of component C2II of Clostridium botulinum C2 toxin is essential for receptor binding. Infect. Immun. 68, 4566–4573 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Schleberger, C., Hochmann, H., Barth, H., Aktories, K. & Schulz, G. E. Structure and action of the binary C2 toxin from Clostridium botulinum. J. Mol. Biol. 364, 705–715 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Aktories, K., Weller, U. & Chhatwal, G. S. Clostridium botulinum type C produces a novel ADP-ribosyltransferase distinct from botulinum C2 toxin. FEBS Lett. 212, 109–113 (1987).

    Article  CAS  PubMed  Google Scholar 

  29. Han, S., Arvai, A. S., Clancy, S. B. & Tainer, J. A. Crystal structure and novel recognition motif of Rho ADP-ribosylating C3 exoenzyme from Clostridium botulinum: structural insights for recognition specificity and catalysis. J. Mol. Biol. 305, 95–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Song, J., Gao, X. & Galan, J. E. Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin. Nature 499, 350–354 (2013). This paper solves the crystal structure of TT, showing its novel A2B5 arrangement and its similarity to PT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lang, A. E. et al. Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering. Science 327, 1139–1142 (2010). This study identifies the substrates of the TcC components of P. luminescens toxin complex proteins and shows that these toxins promote actin polymerization.

    Article  CAS  PubMed  Google Scholar 

  32. Blackburn, M., Golubeva, E., Bowen, D. & Ffrench-Constant, R. H. A. Novel insecticidal toxin from Photorhabdus luminescens, toxin complex a (Tca), and its histopathological effects on the midgut of Manduca sexta. Appl. Environ. Microbiol. 64, 3036–3041 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Han, S. & Tainer, J. The ARTT motif and a unified structural understanding of substrate recognition in ADP-ribosylating bacterial toxins and eukaryotic ADP-ribosyltransferases. Int. J. Med. Microbiol. 291, 523–529 (2002). This paper proposes that toxins could be identified by a core ARTT motif and suggests that substrate specificity is dependent on external protein structure.

    Article  CAS  PubMed  Google Scholar 

  34. Wilson, B. A., Reich, K. A., Weinstein, B. R. & Collier, R. J. Active-site mutations of diphtheria toxin: effects of replacing glutamic acid-148 with aspartic acid, glutamine, or serine. Biochemistry 29, 8643–8651 (1990).

    Article  CAS  PubMed  Google Scholar 

  35. Carroll, S. F. & Collier, R. J. NAD binding site of diphtheria toxin: identification of a residue within the nicotinamide subsite by photochemical modification with NAD. Proc. Natl Acad. Sci. USA 81, 3307–3311 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carroll, S. F. & Collier, R. J. Active site of Pseudomonas aeruginosa exotoxin A. Glutamic acid 553 is photolabeled by NAD and shows functional homology with glutamic acid 148 of diphtheria toxin. J. Biol. Chem. 262, 8707–8711 (1987).

    CAS  PubMed  Google Scholar 

  37. Douglas, D. & Collier, R. Exotoxin A of Pseudomonas aeruginosa: substitution of glutamic acid 553 with aspartic acid drastically reduces toxicity and enzymatic activity. J. Bacteriol. 169, 4967–4971 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bell, C. E. & Eisenberg, D. Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide. Biochemistry 35, 1137–1149 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Oliver, A. W. et al. Crystal structure of the catalytic fragment of murine poly(ADP–ribose) polymerase-2. Nucleic Acids Res. 32, 456–464 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ruf, A., Mennissier de Murcia, J., de Murcia, G. & Schulz, G. E. Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken. Proc. Natl Acad. Sci. USA 93, 7481–7485 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tsuge, H. et al. Crystal structure and site-directed mutagenesis of enzymatic components from Clostridium perfringens iota-toxin. J. Mol. Biol. 325, 471–483 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Domenighini, M. & Rappuoli, R. Three conserved consensus sequences identify the NAD-binding site of ADP-ribosylating enzymes, expressed by eukaryotes, bacteria and T-even bacteriophages. Mol. Microbiol. 21, 667–674 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Roux Jr., E. & Yersin, A. Contribution a l'etude de la diphtherie. Ann. Inst. Pasteur 2, 620–629 (1888).

    Google Scholar 

  44. Eaton, M. D. The purification and concentration of diphtheria toxin. J. Bacteriol. 31, 347 (1936).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Pappenheimer, A. M. Jr. Diphtheria toxin: I. isolation and characterization of a toxic protein from C. diphtheriae filtrates. J. Biol. Chem. 125, 543–553 (1937).

    Google Scholar 

  46. Freeman, V. J. Studies on the virulence of bacteriophage infected strains of C. diphtheriae. J. Bacteriol. 61, 675–688 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Naglich, J. G., Metherall, J. E., Russell, D. W. & Eidels, L. Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69, 1051–1061 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Louie, G. V., Yang, W., Bowman, M. E. & Choe, S. Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor. Mol. Cell 1, 67–78 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Lemichez, E. et al. Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery. Mol. Microbiol. 23, 445–457 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Gordon, V. M., Klimpel, K. R., Arora, N., Henderson, M. A. & Leppla, S. H. Proteolytic activation of bacterial toxins by eukaryotic cells is performed by furin and by additional cellular proteases. Infect. Immun. 63, 82–87 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sandvig, K. & Olsnes, S. Diphtheria toxin entry into cells is facilitated by low pH. J. Cell Biol. 87, 828–832 (1980).

    Article  CAS  PubMed  Google Scholar 

  52. Draper, R. K. & Simon, M. I. The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lysosomal involvement. J. Cell Biol. 87, 849–854 (1980).

    Article  CAS  PubMed  Google Scholar 

  53. Collier, R. J. Effect of diphtheria toxin on protein synthesis: inactivation of one of the transfer factors. J. Mol. Biol. 25, 83–98 (1967).

    Article  CAS  PubMed  Google Scholar 

  54. Honjo, T., Nishizuka, Y., Hayaishi, O. & Kato, I. Diphtheria toxin-dependent adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis. J. Biol. Chem. 243, 3553–3555 (1968).

    CAS  PubMed  Google Scholar 

  55. Van Ness, B. G., Howard, J. B. & Bodley, J. W. ADP-ribosylation of elongation factor 2 by diphtheria toxin. Isolation and properties of the novel ribosyl-amino acid and its hydrolysis products. J. Biol. Chem. 255, 10717–10720 (1980).

    PubMed  Google Scholar 

  56. Su, X., Lin, Z. & Lin, H. The biosynthesis and biological function of diphthamide. Crit. Rev. Biochem. Mol. Biol. 48, 515–521 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Strauss, N. & Hendee, E. D. The effect of diphtheria toxin on the metabolism of HeLa cells. J. Exp. Med. 109, 145–163 (1959).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Taylor, D. et al. Critical movements of a single diphthamide residue of eukaryotic elongation factor 2 monitored by cryo-EM. Microsc. Microanalysis 13, 388–389 (2007).

    Article  Google Scholar 

  59. Liu, S. et al. Diphthamide modification on eukaryotic elongation factor 2 is needed to assure fidelity of mRNA translation and mouse development. Proc. Natl Acad. Sci. USA 109, 13817–13822 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gupta, P. K., Liu, S., Batavia, M. P. & Leppla, S. H. The diphthamide modification on elongation factor-2 renders mammalian cells resistant to ricin. Cell. Microbiol. 10, 1687–1694 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gill, D. M. Bacterial toxins: a table of lethal amounts. Microbiol. Rev. 46, 86–94 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Carroll, S. F. & Collier, R. J. Amino acid sequence homology between the enzymic domains of diphtheria toxin and Pseudomonas aeruginosa exotoxin A. Mol. Microbiol. 2, 293–296 (1988).

    Article  CAS  PubMed  Google Scholar 

  63. Collier, R. J. & McKay, D. B. Crystallization of exotoxin A from Pseudomonas aeruginosa. J. Mol. Biol. 157, 413–415 (1982).

    Article  CAS  PubMed  Google Scholar 

  64. Allured, V. S., Collier, R. J., Carroll, S. F. & McKay, D. B. Structure of exotoxin A of Pseudomonas aeruginosa at 3.0-Angstrom resolution. Proc. Natl Acad. Sci. USA 83, 1320–1324 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kounnas, M. Z. et al. The α2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J. Biol. Chem. 267, 12420–12423 (1992).

    CAS  PubMed  Google Scholar 

  66. Ogata, M., Fryling, C. M., Pastan, I. & FitzGerald, D. J. Cell-mediated cleavage of Pseudomonas exotoxin between Arg279 and Gly280 generates the enzymatically active fragment which translocates to the cytosol. J. Biol. Chem. 267, 25396–25401 (1992).

    CAS  PubMed  Google Scholar 

  67. Fitzgerald, D., Morris, R. E. & Saelinger, C. B. Receptor-mediated internalization of Pseudomonas toxin by mouse fibroblasts. Cell 21, 867–873 (1980).

    Article  CAS  PubMed  Google Scholar 

  68. Weldon, J. E. & Pastan, I. A guide to taming a toxin — recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. FEBS J. 278, 4683–4700 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McKee, M. L. & FitzGerald, D. J. Reduction of furin-nicked Pseudomonas exotoxin A: an unfolding story. Biochemistry 38, 16507–16513 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Iglewski, B. H., Liu, P. V. & Kabat, D. Mechanism of action of Pseudomonas aeruginosa exotoxin A: adenosine diphosphate ribosylation of mammalian elongation factor 2 in vitro and in vivo. Infection Immun. 15, 138–144 (1977).

    CAS  Google Scholar 

  71. Faruque, S. M. et al. Genetic diversity and virulence potential of environmental Vibrio cholerae population in a cholera-endemic area. Proc. Natl Acad. Sci. USA 101, 2123–2128 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Colwell, R. R. Global climate and infectious disease: the cholera paradigm. Science 274, 2025–2031 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Purdy, A. E. et al. Diversity and distribution of cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae. Environ. Microbiol. Rep. 2, 198–207 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Chen, Y., Johnson, J. A., Pusch, G. D., Morris, J. G. & Stine, O. C. The genome of non-O1 Vibrio cholerae NRT36S demonstrates the presence of pathogenic mechanisms that are distinct from those of O1 Vibrio cholerae. Infection Immun. 75, 2645–2647 (2007). This is the first study to identify chxA in strains of Vibrio cholerae that do not express CT using sequence analysis.

    Article  CAS  Google Scholar 

  75. Awasthi, S. P. et al. Novel cholix toxin variants, ADP-ribosylating toxins in Vibrio cholerae non-O1/non-O139 strains, and their pathogenicity. Infect. Immun. 81, 531–541 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jørgensen, R. et al. Cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae. J. Biol. Chem. 283, 10671–10678 (2008). This paper characterizes the structure of ChxA and shows its similarity to other DT-like toxins. It also proposes a new mechanism for DT-like toxin ADP-ribosylation activity.

    Article  PubMed  CAS  Google Scholar 

  77. Fieldhouse, R. J., Jørgensen, R., Lugo, M. R. & Merrill, A. R. The 1.8 Å cholix toxin crystal structure in complex with NAD+ and evidence for a new kinetic model. J. Biol. Chem. 287, 21176–21188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Stover, C. K. et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature 406, 959–964 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Koch, R. Sechster Bericht der deutschen Wissenschaftlichen Commission zur Enforschung der Cholera. Dtsch Med Wochenschr 10, 191–192 (in German) (1884).

    Article  Google Scholar 

  80. Howard-Jones, N. Robert Koch and the cholera vibrio: a centenary. BMJ 288, 379–381 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. De, S. N. Enterotoxicity of bacteria-free culture-filtrate of Vibrio cholerae. Nature 183, 1533–1534 (1959).

    Article  CAS  PubMed  Google Scholar 

  82. Lencer, W. I., Hirst, T. R. & Holmes, R. K. Membrane traffic and the cellular uptake of cholera toxin. Biochim. Biophys. Acta 1450, 177–190 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Eidels, L., Proia, R. & Hart, D. Membrane receptors for bacterial toxins. Microbiol. Rev. 47, 596–620 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ewers, H. & Helenius, A. Lipid-mediated endocytosis. Cold Spring Harb. Perspect. Biol. 3, a004721 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Bobak, D. et al. Mechanism of activation of cholera toxin by ADP-ribosylation factor (ARF): both low- and high-affinity interactions of ARF with guanine nucleotides promote toxin activation. Biochemistry 29, 855–861 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. O'Neal, C. J., Jobling, M. G., Holmes, R. K. & Hol, W. G. J. Structural basis for the activation of cholera toxin by human ARF6-GTP. Science 309, 1093–1096 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Kahn, R. A. & Gilman, A. G. The protein cofactor necessary for ADP-ribosylation of Gs by cholera toxin is itself a GTP binding protein. J. Biol. Chem. 261, 7906–7911 (1986).

    CAS  PubMed  Google Scholar 

  88. Gill, D. M. & Meren, R. ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase. Proc. Natl Acad. Sci. USA 75, 3050–3054 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cassel, D. & Pfeuffer, T. Mechanism of cholera toxin action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc. Natl Acad. Sci. USA 75, 2669–2673 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Moss, J. Activation of adenylate cyclase by heat-labile Escherichia coli enterotoxin: evidence for ADP-ribosyl transferase activity similar to that of choleragen. J. Clin. Invest. 62, 281–285 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chang, P. P., Moss, J., Twiddy, E. M. & Holmes, R. K. Type II heat-labile enterotoxin of Escherichia coli activates adenylate cyclase in human fibroblasts by ADP ribosylation. Infect. Immun. 55, 1854–1858 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kantor, H. S., Tao, P. & Wisdom, C. Action of Escherichia coli enterotoxin: adenylate cyclase behavior of intestinal epithelial cells in culture. Infecti. Immun. 9, 1003–1010 (1974).

    CAS  Google Scholar 

  93. World Health Organization. Immunization, Vaccines and Biologicals: Pertussis [online], (WHO, 2011).

  94. Tamura, M. et al. Subunit structure of islet-activating protein, pertussis toxin, in conformity with the A–B model. Biochemistry 21, 5516–5522 (1982).

    Article  CAS  PubMed  Google Scholar 

  95. Stein, P. E. et al. The crystal structure of pertussis toxin. Structure 2, 45–57 (1994).

    Article  CAS  PubMed  Google Scholar 

  96. Armstrong, G. D., Howard, L. A. & Peppler, M. S. Use of glycosyltransferases to restore pertussis toxin receptor activity to asialoagalactofetuin. J. Biol. Chem. 263, 8677–8684 (1988).

    CAS  PubMed  Google Scholar 

  97. Stein, P. et al. Structure of a pertussis toxin–sugar complex as a model for receptor binding. Nature Struct. Biol. 1, 591–596 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Brennan, M. J., David, J. L., Kenimer, J. G. & Manclark, C. R. Lectin-like binding of pertussis toxin to a 165-kilodalton Chinese hamster ovary cell glycoprotein. J. Biol. Chem. 263, 4895–4899 (1988).

    CAS  PubMed  Google Scholar 

  99. el Bayâ, A., Linnemann, R., von Olleschik-Elbheim, L., Robenek, H. & Schmidt, M. Endocytosis and retrograde transport of pertussis toxin to the Golgi complex as a prerequisite for cellular intoxication. Eur. J. Cell Biol. 73, 40–48 (1997).

    PubMed  Google Scholar 

  100. Burns, D. L. & Manclark, C. R. Role of cysteine 41 of the A subunit of pertussis toxin. J. Biol. Chem. 264, 564–568 (1989).

    CAS  PubMed  Google Scholar 

  101. Antoine, R. & Locht, C. Roles of the disulfide bond and the carboxy-terminal region of the S1 subunit in the assembly and biosynthesis of pertussis toxin. Infection Immun. 58, 1518–1526 (1990).

    CAS  Google Scholar 

  102. Bokoch, G. M., Katada, T., Northup, J. K., Hewlett, E. L. & Gilman, A. G. Identification of the predominant substrate for ADP-ribosylation by islet activating protein. J. Biol. Chem. 258, 2072–2075 (1983).

    CAS  PubMed  Google Scholar 

  103. Katada, T. & Ui, M. Direct modification of the membrane adenylate cyclase system by islet-activating protein due to ADP-ribosylation of a membrane protein. Proc. Natl Acad. Sci. USA 79, 3129–3133 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kurose, H., Katada, T., Amano, T. & Ui, M. Specific uncoupling by islet-activating protein, pertussis toxin, of negative signal transduction via α-adrenergic, cholinergic, and opiate receptors in neuroblastoma x glioma hybrid cells. J. Biol. Chem. 258, 4870–4875 (1983).

    CAS  PubMed  Google Scholar 

  105. Simpson, L. L., Stiles, B. G., Zepeda, H. H. & Wilkins, T. D. Molecular basis for the pathological actions of Clostridium perfringens iota toxin. Infect. Immun. 55, 118–122 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Perelle, S., Gibert, M., Bourlioux, P., Corthier, G. & Popoff, M. R. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect. Immun. 65, 1402–1407 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Simpson, L. L., Stiles, B. G., Zepeda, H. & Wilkins, T. D. Production by Clostridium spiroforme of an iotalike toxin that possesses mono(ADP-ribosyl)transferase activity: identification of a novel class of ADP-ribosyltransferases. Infect. Immun. 57, 255–261 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Aktories, K., Lang, A. E., Schwan, C. & Mannherz, H. G. Actin as target for modification by bacterial protein toxins. FEBS J. 278, 4526–4543 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Young, J. A. T. & Collier, R. J. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 76, 243–265 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Papatheodorou, P. et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc. Natl Acad. Sci. USA 108, 16422–16427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Han, S., Craig, J. A., Putnam, C. D., Carozzi, N. B. & Tainer, J. A. Evolution and mechanism from structures of an ADP-ribosylating toxin and NAD complex. Nature Struct. Biol. 6, 932–936 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Vandekerckhove, J., Schering, B., Bärmann, M. & Aktories, K. Clostridium perfringens iota toxin ADP-ribosylates skeletal muscle actin in Arg-177. FEBS Lett. 225, 48–52 (1987).

    Article  CAS  PubMed  Google Scholar 

  113. Vandekerckhove, J., Schering, B., Bärmann, M. & Aktories, K. Botulinum C2 toxin ADP-ribosylates cytoplasmic β/γ-actin in arginine 177. J. Biol. Chem. 263, 696–700 (1988).

    CAS  PubMed  Google Scholar 

  114. Gülke, I. et al. Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect. Immun. 69, 6004–6011 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Gerding, D. N., Johnson, S., Rupnik, M. & Aktories, K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5, 6–18 (2014).

    Article  Google Scholar 

  116. Schwan, C. et al. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog. 5, e1000626 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Schwan, C. et al. Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. Proc. Natl Acad. Sci. USA 111, 2313–2318 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lesnick, M. L., Reiner, N. E., Fierer, J. & Guiney, D. G. The Salmonella spvB virulence gene encodes an enzyme that ADP-ribosylates actin and destabilizes the cytoskeleton of eukaryotic cells. Mol. Microbiol. 39, 1464–1470 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Otto, H. et al. The spvB gene-product of the Salmonella enterica virulence plasmid is a mono(ADP-ribosyl)transferase. Mol. Microbiol. 37, 1106–1115 (2000). This paper shows that the spvB gene is similar to other mono-ADP-ribosyltransferases using PSI-BLAST protein homology searches.

    Article  CAS  PubMed  Google Scholar 

  120. Braun, M. et al. Characterization of an ADP-ribosyltransferase toxin (AexT) from Aeromonas salmonicida subsp. salmonicida. J. Bacteriol. 184, 1851–1858 (2002). This study uses bioinformatics to show that AexT is similar to ExoS, using sequence similarity, and characterizes the cytotoxic activity of AexT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fehr, D. et al. Aeromonas exoenzyme T of Aeromonas salmonicida is a bifunctional protein that targets the host cytoskeleton. J. Biol. Chem. 282, 28843–28852 (2007). This paper identifies AexT as a bifunctional toxin and characterizes its ADP-ribosyltransferase substrates.

    Article  CAS  PubMed  Google Scholar 

  122. Visschedyk, D. D. et al. Photox, a novel actin-targeting mono-ADP-ribosyltransferase from Photorhabdus luminescens. J. Biol. Chem. 285, 13525–13534 (2010). This paper uses bioinformatics to identify photox using amino acid homology with the previously identified toxin SpvB; it shows structural and functional similarity between photox and other actin-ADP-ribosylating toxins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hochmann, H., Pust, S., von Figura, G., Aktories, K. & Barth, H. Salmonella enterica SpvB ADP-ribosylates actin at position arginine-177. Characterization of the catalytic domain within the SpvB protein and a comparison to binary clostridial actin-ADP-ribosylating toxins. Biochemistry 45, 1271–1277 (2006). This paper shows that SpvB has amino acid residues that are conserved in bacterial actin-ADP-ribosylating toxins, despite not being a binary toxin. It also functionally confirms this conservation by demonstrating actin ADP-ribosylation at Arg177.

    Article  CAS  PubMed  Google Scholar 

  124. Vilches, S. et al. Aeromonas hydrophila AH-3 AexT is an ADP-ribosylating toxin secreted through the type III secretion system. Microb. Pathog. 44, 1–12 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Barbieri, J. T. & Sun, J. in Reviews of Physiology, Biochemistry and Pharmacology Vol. 152 (eds Aktories, K. & Just, I.) 79–92 (Springer Berlin Heidelberg, 2005).

    Book  Google Scholar 

  126. Coburn, J., Dillon, S. T., Iglewski, B. H. & Gill, D. M. Exoenzyme S of Pseudomonas aeruginosa ADP-ribosylates the intermediate filament protein vimentin. Infection Immun. 57, 996–998 (1989).

    CAS  Google Scholar 

  127. Coburn, J., Wyatt, R. T., Iglewski, B. H. & Gill, D. M. Several GTP-binding proteins, including p21c-H-ras, are preferred substrates of Pseudomonas aeruginosa exoenzyme S. J. Biol. Chem. 264, 9004–9008 (1989).

    CAS  PubMed  Google Scholar 

  128. Litvak, Y. & Selinger, Z. Aeromonas salmonicida toxin AexT has a Rho family GTPase-activating protein domain. J. Bacteriol. 189, 2558–2560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rubin, E. J., Gill, D. M., Boquet, P. & Popoff, M. R. Functional modification of a 21-kilodalton G protein when ADP-ribosylated by exoenzyme C3 of Clostridium botulinum. Mol. Cell. Biol. 8, 418–426 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wilde, C., Vogelsgesang, M. & Aktories, K. Rho-specific Bacillus cereus ADP-ribosyltransferase C3cer cloning and characterization. Biochemistry 42, 9694–9702 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Hanna, S. & El-Sibai, M. Signaling networks of Rho GTPases in cell motility. Cell Signall. 25, 1955–1961 (2013).

    Article  CAS  Google Scholar 

  132. Heasman, S. J. & Ridley, A. J. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nature Rev. Mol. Cell Biol. 9, 690–701 (2008).

    Article  CAS  Google Scholar 

  133. Sekine, A., Fujiwara, M. & Narumiya, S. Asparagine residue in the rho gene product is the modification site for botulinum ADP-ribosyltransferase. J. Biol. Chem. 264, 8602–8605 (1989).

    CAS  PubMed  Google Scholar 

  134. Genth, H., Schmidt, M., Gerhard, R., Aktories, K. & Just, I. Activation of phospholipase D1 by ADP-ribosylated RhoA. Biochem. Biophys. Res. Commun. 302, 127–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Genth, H. et al. Entrapment of Rho ADP-ribosylated by Clostridium botulinum C3 exoenzyme in the Rho-guanine nucleotide dissociation inhibitor-1 complex. J. Biol. Chem. 278, 28523–28527 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Barth, H. et al. Neosynthesis and activation of Rho by Escherichia coli cytotoxic necrotizing factor (CNF1) reverse cytopathic effects of ADP-ribosylated Rho. J. Biol. Chem. 274, 27407–27414 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Pautsch, A., Vogelsgesang, M., Tränkle, J., Herrmann, C. & Aktories, K. Crystal structure of the C3bot–RalA complex reveals a novel type of action of a bacterial exoenzyme. EMBO J. 24, 3670–3680 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wilde, C., Chhatwal, G. S., Schmalzing, G., Aktories, K. & Just, I. A. Novel C3-like ADP-ribosyltransferase from Staphylococcus aureus. Modifying RhoE and Rnd3. J. Biol. Chem. 276, 9537–9542 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Molinari, G. et al. Localization of the C3-Like ADP-ribosyltransferase from Staphylococcus aureus during bacterial invasion of mammalian cells. Infect. Immun. 74, 3673–3677 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Fahrer, J. et al. Selective and specific internalization of clostridial C3 ADP-ribosyltransferases into macrophages and monocytes. Cell. Microbiol. 12, 233–247 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Wollein Waldetoft, K. & Råberg, L. To harm or not to harm? On the evolution and expression of virulence in group A streptococci. Trends Microbiol. 22, 7–13 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Ferretti, J. J. et al. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc. Natl Acad. Sci. USA 98, 4658–4663 (2001). This paper proposes, on the basis of sequence data, that the spyA gene encodes a C3-like ADP-ribosyltransferase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Coye, L. H. & Collins, C. M. Identification of SpyA, a novel ADP-ribosyltransferase of Streptococcus pyogenes. Mol. Microbiol. 54, 89–98 (2004). This study characterizes the ADP-ribosyltransferase activity of SpyA and shows that, despite its predicted C3-like activity, SpyA has activity towards different eukaryotic substrates.

    Article  CAS  PubMed  Google Scholar 

  144. Korotkova, N. et al. SpyA is a membrane-bound ADP-ribosyltransferase of Streptococcus pyogenes which modifies a streptococcal peptide, SpyB. Mol. Microbiol. 83, 936–952 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ivaska, J., Pallari, H.-M., Nevo, J. & Eriksson, J. E. Novel functions of vimentin in cell adhesion, migration, and signaling. Exp. Cell Res. 313, 2050–2062 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Eckes, B. et al. Impaired wound healing in embryonic and adult mice lacking vimentin. J. Cell Sci. 113, 2455–2462 (2000).

    CAS  PubMed  Google Scholar 

  147. Icenogle, L. M. et al. Molecular and biological characterization of streptococcal SpyA-mediated ADP-ribosylation of intermediate filament protein vimentin. J. Biol. Chem. 287, 21481–21491 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gohara, R. et al. Phosphorylation of vimentin head domain inhibits interaction with the carboxyl-terminal end of α-helical rod domain studied by surface plasmon resonance measurements. FEBS Lett. 489, 182–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Hoff, J. S., DeWald, M., Moseley, S. L., Collins, C. M. & Voyich, J. M. SpyA, a C3-Like ADP-ribosyltransferase, contributes to virulence in a mouse subcutaneous model of Streptococcus pyogenes infection. Infection Immun. 79, 2404–2411 (2011).

    Article  CAS  Google Scholar 

  150. Guttman, D. S. et al. A functional screen for the type III (Hrp) secretome of the plant pathogen Pseudomonas syringae. Science 295, 1722–1726 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. Petnicki-Ocwieja, T. et al. Genomewide identification of proteins secreted by the Hrp type III protein secretion system of Pseudomonas syringae pv. tomato DC3000. Proc. Natl Acad. Sci. USA 99, 7652–7657 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Lindeberg, M. et al. Closing the circle on the discovery of genes encoding Hrp regulon members and type III secretion system effectors in the genomes of three model Pseudomonas syringae strains. Mol. Plant Microbe Interact. 19, 1151–1158 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Fouts, D. E. et al. Genomewide identification of Pseudomonas syringae pv. tomato DC3000 promoters controlled by the HrpL alternative sigma factor. Proc. Natl Acad. Sci. USA 99, 2275–2280 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Buell, C. R. et al. The complete genome sequence of the Arabidopsis and tomato pathogen Pseudomonas syringae pv. tomato DC3000. Proc. Natl Acad. Sci. USA 100, 10181–10186 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fu, Z. Q. et al. A type III effector ADP-ribosylates RNA-binding proteins and quells plant immunity. Nature 447, 284–288 (2007). This paper identifies the substrate of effector HopU1 ADP-ribosyltransferase activity and shows the unique immunosuppressive phenotype of HopU1 activity.

    Article  CAS  PubMed  Google Scholar 

  156. Jeong, B.R. et al. Structure function analysis of an ADP-ribosyltransferase type III effector and its RNA-binding target in plant immunity. J. Biol. Chem. 286, 43272–43281 (2011). This study solves the crystal structure of HopU1 and shows that unique loops that frame the NAD-binding pocket are necessary for substrate recognition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sun, J. & Barbieri, J. T. Pseudomonas aeruginosa ExoT ADP-ribosylates CT10 regulator of kinase (Crk) proteins. J. Biol. Chem. 278, 32794–32800 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Sun, J., Maresso, A. W., Kim, J. J. & Barbieri, J. T. How bacterial ADP-ribosylating toxins recognize substrates. Nature Struct. Mol. Biol. 11, 868–876 (2004).

    Article  CAS  Google Scholar 

  159. Heintzen, C., Nater, M., Apel, K. & Staiger, D. AtGRP7, a nuclear RNA-binding protein as a component of a circadian-regulated negative feedback loop in Arabidopsis thaliana. Proc. Natl Acad. Sci. USA 94, 8515–8520 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Nicaise, V. et al. Pseudomonas HopU1 modulates plant immune receptor levels by blocking the interaction of their mRNAs with GRP7. EMBO J. 32, 701–712 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jessen, T. H., Oubridge, C., Teo, C. H., Pritchard, C. & Nagai, K. Identification of molecular contacts between the U1, a small nuclear ribonucleoprotein and U1 RNA. EMBO J. 10, 3447–3456 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Burd, C. & Dreyfuss, G. Conserved structures and diversity of functions of RNA-binding proteins. Science 265, 615–621 (1994).

    Article  CAS  PubMed  Google Scholar 

  163. Nagai, K., Oubridge, C., Jessen, T. H., Li, J. & Evans, P. R. Crystal structure of the RNA-binding domain of the U1 small nuclear ribonucleoprotein A. Nature 348, 515–520 (1990).

    Article  CAS  PubMed  Google Scholar 

  164. Lee, A. L. et al. Chemical shift mapping of the RNA-binding interface of the multiple-RBD protein sex-lethal. Biochemistry 36, 14306–14317 (1997).

    Article  CAS  PubMed  Google Scholar 

  165. Schöning, J. C. et al. Auto-regulation of the circadian slave oscillator component AtGRP7 and regulation of its targets is impaired by a single RNA recognition motif point mutation. Plant J. 52, 1119–1130 (2007).

    Article  PubMed  CAS  Google Scholar 

  166. Boller, T. & He, S. Y. Innate immunity in plants: an arms race between pattern recognition receptors in plants and effectors in microbial pathogens. Science 324, 742–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Dodds, P. N. & Rathjen, J. P. Plant immunity: towards an integrated view of plant–pathogen interactions. Nature Rev. Genet. 11, 539–548 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Segonzac, C. & Zipfel, C. Activation of plant pattern-recognition receptors by bacteria. Curr. Opin. Microbiol. 14, 54–61 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Maurice, J. A first step in bringing typhoid fever out of the closet. Lancet 379, 699–700 (2012).

    Article  PubMed  Google Scholar 

  170. Haghjoo, E. & Galán, J. E. Salmonella Typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway. Proc. Natl Acad. Sci. USA 101, 4614–4619 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Spanò, S., Ugalde, J. E. & Galán, J. E. Delivery of a Salmonella Typhi exotoxin from a host intracellular compartment. Cell Host Microbe 3, 30–38 (2008).

    Article  PubMed  CAS  Google Scholar 

  172. Guidi, R. et al. Salmonella enterica delivers its genotoxin through outer membrane vesicles secreted from infected cells. Cell. Microbiol. 15, 2034–2050 (2013).

    Article  CAS  PubMed  Google Scholar 

  173. Forst, S., Dowds, B., Boemare, N. & Stackebrandt, E. Xenorhabdus and Photorhabdus spp.:bugs that kill bugs. Annu. Rev. Microbiol. 51, 47–72 (1997).

    Article  CAS  PubMed  Google Scholar 

  174. Waterfield, N., Hares, M., Ffrench-Constant, R., Wren, B. & Hinchliffe, S. in The Genus Yersinia (eds Perry, R. & Fetherston, J.) 247–257 (Springer, 2007).

    Book  Google Scholar 

  175. Waterfield, N. R., Ciche, T. & Clarke, D. Photorhabdus and a host of hosts. Annu. Rev. Microbiol. 63, 557–574 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Waterfield, N. R., Bowen, D. J., Fetherston, J. D., Perry, R. D. & Ffrench-Constant, R. H. The tc genes of Photorhabdus: a growing family. Trends Microbiol. 9, 185–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Ffrench-Constant, R. & Waterfield, N . in Advances in Applied Microbiology (eds Laskin, A. I., Bennett, J. W., Gadd, G. M. & Sariaslani, S.) 169–183 (Academic Press, 2005).

    Google Scholar 

  178. Gatsogiannis, C. et al. A syringe-like injection mechanism in Photorhabdus luminescens toxins. Nature 495, 520–523 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Ffrench-Constant, R. et al. Photorhabdus: towards a functional genomic analysis of a symbiont and pathogen. FEMS Microbiol. Rev. 26, 433–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. Cassimeris, L., Safer, D., Nachmias, V. T. & Zigmond, S. H. Thymosin β4 sequesters the majority of G-actin in resting human polymorphonuclear leukocytes. J. Cell Biol. 119, 1261–1270 (1992).

    Article  CAS  PubMed  Google Scholar 

  181. Mannherz, H. G. & Hannappel, E. The β-thymosins: intracellular and extracellular activities of a versatile actin binding protein family. Cell. Motil. Cytoskeleton 66, 839–851 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Vetter, I. R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299–1304 (2001).

    Article  CAS  PubMed  Google Scholar 

  183. Meusch, D. et al. Mechanism of Tc toxin action revealed in molecular detail. Nature 508, 61–65 (2014).

    Article  CAS  PubMed  Google Scholar 

  184. Falkow, S. Molecular Koch's postulates applied to microbial pathogenicity. Rev. Infect. Dis. 10 (Suppl. 2) 274–276 (1988). This paper explains the molecular application of Koch's postulates by Falkow for confirmation of the role of putative virulence factors in bacterial pathogenesis.

    Article  Google Scholar 

  185. Falkow, S. Molecular Koch's postulates applied to bacterial pathogenicity — a personal recollection 15 years later. Nature Rev. Microbiol. 2, 67–72 (2004).

    Article  CAS  Google Scholar 

  186. Zheng, L.-L. et al. A comparison of computational methods for identifying virulence factors. PLoS ONE 7, e42517 (2012). This paper shows the functionality and importance of protein amino acid sequence analyses and explains caveats and issues with common search methods.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Jones, D. T. & Swindells, M. B. Getting the most from PSI-BLAST. Trends Biochem. Sci. 27, 161–164 (2002).

    Article  CAS  PubMed  Google Scholar 

  188. Qi, Y., Sadreyev, R. I., Wang, Y., Kim, B. H. & Grishin, N. V. A comprehensive system for evaluation of remote sequence similarity detection. BMC Bioinformatics 8, 314 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Palmiter, R. D. et al. Cell lineage ablation in transgenic mice by cell-specific expression of a toxin gene. Cell 50, 435–443 (1987).

    Article  CAS  PubMed  Google Scholar 

  190. Saito, M. et al. Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice. Nature Biotech. 19, 746–750 (2001).

    Article  CAS  Google Scholar 

  191. Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nature Meth. 2, 419–426 (2005).

    Article  CAS  Google Scholar 

  192. Chaudhary, V. K. et al. A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339, 394–397 (1989).

    Article  CAS  PubMed  Google Scholar 

  193. Pastan, I. Immunotoxins containing Pseudomonas exotoxin A: a short history. Cancer Immunol. Immunother. 52, 338–341 (2003).

    PubMed  Google Scholar 

  194. Kreitman, R. J. & Pastan, I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin. Cancer Res. 17, 6398–6405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kreitman, R. J. et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. New Engl. J. Med. 345, 241–247 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Chaudhary, V. K. et al. Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature 335, 369–372 (1988).

    Article  CAS  PubMed  Google Scholar 

  197. Berger, E. A. & Pastan, I. Immunotoxin complementation of HAART to deplete persisting HIV-infected cell reservoirs. PLoS Pathog. 6, e1000803 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Sarnovsky, R. et al. Initial characterization of an immunotoxin constructed from domains II and III of cholera exotoxin. Cancer Immunol. Immunother. 59, 737–746 (2010).

    Article  CAS  PubMed  Google Scholar 

  199. Francis, J. W. et al. Enhancement of diphtheria toxin potency by replacement of the receptor binding domain with tetanus toxin C-fragment. J. Neurochem. 74, 2528–2536 (2000).

    Article  CAS  PubMed  Google Scholar 

  200. Ahnert-Hilger, G. et al. Differential effects of Rho GTPases on axonal and dendritic development in hippocampal neurones. J. Neurochem. 90, 9–18 (2004).

    Article  CAS  PubMed  Google Scholar 

  201. Bertrand, J., Di Polo, A. & McKerracher, L. Enhanced survival and regeneration of axotomized retinal neurons by repeated delivery of cell-permeable C3-like Rho antagonists. Neurobiol. Dis. 25, 65–72 (2007).

    Article  CAS  PubMed  Google Scholar 

  202. Höltje, M. et al. A 29-amino acid fragment of Clostridium botulinum C3 protein enhances neuronal outgrowth, connectivity, and reinnervation. FASEB J. 23, 1115–1126 (2009).

    Article  PubMed  CAS  Google Scholar 

  203. Bertrand, J., Winton, M. J., Rodriguez-Hernandez, N., Campenot, R. B. & McKerracher, L. Application of Rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J. Neurosci. 25, 1113–1121 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Boato, F. et al. C3 peptide enhances recovery from spinal cord injury by improved regenerative growth of descending fiber tracts. J. Cell Sci. 123, 1652–1662 (2010).

    Article  PubMed  Google Scholar 

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Acknowledgements

N.C.S. and J.T.B. are supported by a US National Institutes of Health (NIH) grant (grant number NIH AI30162). K.A. is supported by the Deutsche Forschungsgemeinschaft (AK6/23-1 and AK6//22-2)

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  1. Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Nathan C. Simon & Joseph T. Barbieri

  2. Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, 79104, Germany

    Klaus Aktories

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J.T.B. is a consultant for Syntaxin Ltd. N.C.S. and K.A. declare no competing interests.

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Glossary

SN1 strain-alleviation mechanism

An electrophilic reaction mechanism that starts with the hydrolytic release of nicotinamide from the NAD donor, followed by formation of an oxocarbenium cation intermediate in a 'strained' conformation. Rotation around the phosphodiester bond forms a second oxocarbenium cation, which results in strain relief and moving of the ribose moiety near to the acceptor residue to complete the ADP-ribose transfer.

P-site

(Peptidyl site). The site on the small ribosomal subunit that holds the tRNA molecule that is linked to the growing end of the polypeptide chain.

Retrograde trafficking

Trafficking of vesicles in a direction from the host cell surface to the ER; for example, trafficking from the Golgi complex to the ER.

ER-associated degradation

(ERAD). A cellular pathway that targets misfolded proteins in the ER for ubiquitylation and subsequent degradation by the proteasome.

Intermediate filament

A filament that is formed by coiled-coil-rich cytoskeletal proteins, such as keratin.

Pattern recognition receptors

(PRRs). Soluble or membrane-associated receptors that are displayed by the metazoan host and can recognize complex molecular patterns on the surface of microorganisms.

Autocrine

A term used to describe the activation of cellular receptors on the same cell that produces the ligand.

Paracrine

A term used to describe the activation of cellular receptors on cells adjacent to the cell that produces the ligand.

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Simon, N., Aktories, K. & Barbieri, J. Novel bacterial ADP-ribosylating toxins: structure and function. Nat Rev Microbiol 12, 599–611 (2014). https://doi.org/10.1038/nrmicro3310

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  • DOI: https://doi.org/10.1038/nrmicro3310

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