ADP-ribosylation toxin

Barth H, Blocker D, Aktories K. The uptake machinery of clostridial actin ADP-ribosylating toxins—a cell delivery system for fusion proteins and polypeptide drugs. Naunyn Schmiedebergs Arch Pharmacol 2002 366(6) 501-512. 

Clostridium botulinum C2 toxin The prototype of a binary actin-ADP-ribosylating toxin 155... 

Potent Virulence Factors Directly Attack the Actin Cytoskeleton of Mammalian Cells Actin-ADP-Ribosylating Toxins... 

Figure 2 The actin-ADP-ribosylating toxins, (a) Molecular mode of action. The actin-ADP-ribosylating toxins covalently transfer an ADP-ribose moiety from NAD+ onto Arg177 of G-actin in the cytosol of targeted cells. Mono-ADP-ribosylated G-actin acts as a capping protein and inhibits the assembly of nonmodified actin into filaments. Thus, actin polymerization is blocked at the fast-growing ends of actin filaments (plus or barbed ends) but not at the slow growing ends (minus or pointed ends). This effect ultimately increases the critical concentration necessary for actin polymerization and tends to depolymerize F-actin. Finally, all actin within an intoxicated cell becomes trapped as ADP-ribosylated G-actin.

In 1980, C. botulinum C2 toxin was the first binary actin-ADP-ribosylating toxin to be described in the literature. The C2 toxin, produced by C. botulinum types C and D, consists of two nonlinked components... 

Burnette WN (1994) AB5 ADP-ribosylating toxins Comparative anatomy and physiology. In Structure 2 151—158. 

Cholera toxin (CT) and E. coli heat-labile enterotoxin (LT-1 or LT) are members of the AB5 family of ADP-ribosylating toxins (Merritt and Hoi,... 

So far, only two catalytic residues have been identified in SI Glu-129 (Antoine et ai, 1993) and His-35 (Antoine and Locht, 1994). The first residue is conserved in all known ADP-ribosylating toxins, whereas His-35 is only conserved in cholera toxin and a recently identified mosquitocidal toxin produced by Bacillus sphaericus. This residue is not present in diphtheria toxin and exotoxin A (Fig. 1). The absence of this catalytic residue in the latter two toxins may explain their inefficiency in carrying out the NAD -glycohydrolysis reaction, compared to PT and cholera toxin. The acceptor substrate of diphtheria toxin and exotoxin A is diphthamide, a modified histidine residue in EF2. Perhaps this residue may take on some of the functions of the catalytic His residue in the other toxins. 

Ui M (1990) Pertussis toxin as a valuable probe for G-protein involvement in signal transduction. In ADP-ribosylating toxins and G proteins. Insights into signal transduction (Moss J, Vaughan M, eds) pp 45-77. 

Like other bacterial ADP-ribosylating toxins (e.g. diphtheria toxin. Pseudomonas aeruginosa exotoxin A, cholera toxin, pertussis toxin, and C. botulinum C2 toxin (Aktories and Just, 1993)), C3 is a mono-ADP-ribosyltransferase (Aktories et ai, 1988b). Treatment of ADP-ribosylated Rho with phosphodiesterase releases 5 -AMP and not phosphoribosyl-AIVtP, a cleavage product of poly(ADP-ribose) (Aktories et ai, 1988b Rubin ef a/., 1988). Accordingly, thymidine, an inhibitor of poly(ADP-ribose)polymerase, does not block C3-like ADP-ribosyltransferases, and can be included in C3 ADP-ribosylation assays to block poly-ADP-ribosylation reactions. 

Actin-ADP-ribosylating Toxins Cytotoxic Mechanisms of Clostridium botulinum C2 Toxin and Clostridium perfringens lota Toxin... 

Fig. 2. Model of the cytopathic effects of actin ADP-ribosylating toxins. The activated binding component of C. botulinum C2 toxin binds to a receptor of the eukaryotic cell. This induces a binding site for the enzyme component (C2I), Most likely, C2I enters the cell by endocytosis and subsequent translocation. In the cell, G-actin is ADP-ribosylated, which inhibits its polymerization and traps actin in the monomeric form. ADP-ribosylated actin binds in a capping protein-like manner to the barbed ends of filaments to inhibit further polymerization at the fast-growing end of F-acfin. The foxin has no effects on the pointed end of filaments where actin depolymerization takes place. Additionally, ADP-ribosylation may affect functions of complexes of acfin wifh binding proteins as examplified in Fig. 1 (From (Aktories, 1990) with permission)...

Table 2. Effects of actin ADP-ribosylating toxins on the cytoskeleton... 

Aktories K, Wille M, Just I (1992) Clostridial actin-ADP-ribosylating toxins. In Curr. Top. Microbiol. Immunol. 175 97-113... 

Aktories K, Wegner A (1992) Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. In Mol. Microbiol. 6 2905-8... 

Just I, Wille M, Chaponnier C et al. (1993b) Gelsolin-actin complex is target for ADP-ribosylation by Clostridium botulinum C2 toxin in intact human neutrophils. In Eur. J. Pharmacol. Mol. Pharmacol. 246 293-7 Kiefer A, Lerner M, Sehr P et al. (1996) Depolymerization of F-actin by microinjection of ADP-ribosylated skeletal muscle G-actin in PtK2 cells in the absence of the ADP-ribosylating toxin. In A/ted. Microbiol. Immunol. 184 175-80 Mauss S, Chaponnier C, Just I et al. (1990) ADP-ribosylation of actin isoforms by Clostridium botulinum C2 toxin and Clostridium perfringens iota toxin. In Eur. J. Biochem. 194 237-41... 

C. botulinum C2 toxin and C perfringens iota toxin belong to the family of actin-ADP-ribosylating toxins that transfer ADP-ribose from NAD to arginine-177 of actin. This modification results in inhibition of actin polymerization, leading to depolymerization of the microfilament network. Origin, structure, molecular mechanisms and general aspects of the use of this family of toxins is described in chapter 8, 9 and 10. 

Aktories K, Just I (1990) Botulinum C2 Toxin. In ADP-ribosylating toxins and C-proteins, (Moss J, Vaughan M. 79-95 Washington, D.C. American Society for Microbiology. 

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