GTPases targetted by bacterial toxins

Abstract

Abstract Members of the GTPase superfamily operate as molecular switches in numerous signal-transduction pathways to control such diverse cellular processes as differentiation, proliferation, and the organization of the actin cytoskeleton. These master regulators are the specific targets of a large array of bacterial protein toxins (Table 1)(1). In an extremely efficient manner, the toxins cause the covalent modification of eukaryotic GTPases, resulting in drastic changes in their biological and biochemical properties. It has been known for many years that eukaryotic GTPases are substrates for numerous distinct bacterial ADP-ribosyltransferases. Diphtheria toxin was the first example of such a bacterial toxin and was shown to elicit its biological activity by ADP-ribosylation of the GTPase elongation factor 2 (2). Other well-known ADP-ribosylating bacterial toxins are cholera toxin (3, 4) the group of heat-labile E. coli enterotoxins (5), and pertussis toxin (6), all of which ADP-ribosylate heterotrimeric G proteins of the Gs and Gi families. More recently, small GTPases belonging to the Rho and Ras subfamilies have also been shown to be targets of bacterial toxins. The group of C3-like transferases, including the prototype Clostridium botulinum exoenzyme C3 (7-9), selectively ADP-ribosylates Rho, rendering it biologically inactive, while Ras appears to be an in vivo target of the ADP-ribosyltransferase exoenzyme S from Pseudomonas aeruginosa. Small GTPases are not only substrates for bacterial ADP-ribosyltransferases, but also serve as targets for toxins that act by monoglucosylation (e.g. the large clostridial toxins) (10) or by deamidation (e.g. cytotoxic necrotizing factors) (11).