Molecular Biology of Actin-ADP-Ribosylating Toxins

Abstract

The actin cytoskeleton is the target of a large number of toxins. The actin network controls the shape and spatial organization of the cell and contributes to many cell functions, such as movement, cytokinesis, endocytosis, exocytosis and control of intercellular junctions. Its disorganization by toxins leads to important cell dysfunctions and induces the severe lesions which are found in the associated pathologies. Some toxins modify enzymatic regulatory proteins of actin polymerization (Rho family), including: C3 enzyme, which specifically adenosine diphosphate (ADP)—ribosylates Rho (Chap. 11); the large clostridial toxins [Clostridium difficile ToxA and ToxB, C. sordellii heat-labile toxin (LT) and hemorrhagic toxin, and C. novyi Toxα], which monoglucosylate various p21 G-proteins (Chap. 14); and cytotoxic necrotizing factor from Escherichia coli and dermonecrotizing toxin from Bordetella bronchiseptica (Chap. 13), which catalyze the deamidation of Gln-63 in Rho protein. Modification by ADP—ribosylating or glucosylating toxins traps the Rho family proteins in their inactive forms, leading to depolymerization of the actin filaments in cells. In contrast, the deamidation of Gln-63 impairs the Rho guanosine triphosphate (GTP)ase activities, and Rho is permanently active (Flatau et al. 1997; Schmidt et al. 1997). This increases the actin filaments and ruffles and blocks the cytokinesis. Other toxins act directly on the actin monomers by ADP—ribosylation, which is a common mechanism of action for many toxins (Chap. 2); thereby, they cause a complete disorganization of the actin filaments. These toxins, which are called actin-ADP—ribosylating toxins, are produced by bacteria from the Clostridium genus.