Bacterial Toxins that Covalently Modify Eukaryotic Proteins by ADP-Ribosylation

Abstract

The study of ADP-ribosylating toxins has advanced our understanding of bacterial pathogenesis and provided insight into the molecular basis of eukaryotic physiology, especially G-protein-coupled signal transduction. The pathology associated with an ADP-ribosylating toxin is due to alterations in the activity of specific eukaryotic proteins. To date, essentially all of the eukaryotic proteins that are ADP-ribosylated by bacterial toxins are nucleotide-binding proteins, most often GTP-binding proteins. Two types of activation have been observed, covalent modification and association with eukaryotic proteins or cofactors. The study of bacterial toxins involves a sequential evolution of knowledge and strategies. First, the toxin is isolated and its catalytic and intoxication mechanisms determined; next, strategies are developed to determine whether the toxin is a useful vaccine candidate by empirically attempting to chemically or genetically inactivate the toxin while retaining its immunogenicity. The final stage in toxin research is to determine whether it can be used as a pharmacological reagent. Continued studies on the eukaryotic mono-ADP ribosylating enzymes should provide new insight into how the posttranslational modification regulates cell physiology, as studies on bacterial ADP-ribosylating toxins have contributed to our understanding of bacterial pathogenesis. Polyacrylamide gel electrophoresis techniques have been used for the measurement of the kinetics of in vivo ADP-ribosylation of eukaryotic proteins by other bacterial toxins. Although ADP-ribosylation of eukaryotic proteins represents the first covalent modification attributed to a bacterial toxin, subsequent studies have identified additional covalent and noncovalent modifications catalyzed by bacterial toxins.