Glucosylation of Rho/Ras Proteins by Lethal Toxin – Implications of Actin Re-Organization and Apoptosis in C. Sordellii-Associated Disease

Clostridium sordellii causes disease in livestock and life-threatening illnesses in humans. Pathogenic C. sordellii strains produce up to seven virulence factors, including lethal toxin (TcsL), hemorrhagic toxin, a hemolysin, a DNAse, a collagenase, and a lysolecithinase cell. TcsL exhibits an A-B toxin-like structure and enters its target cells by receptor-mediated endocytosis. Inside the, TcsL mono-glucosylates low molecular weight GTP-binding proteins of the Ras and Rho families. This article reviews recent progress for (i) re-enforcing (H/K/N)Ras glucosylation and subsequent inhibition of the phosphoinositide 3-kinase (PI3K) / Akt survival signalling pathway as the cause of TcsL-induced apoptotic cell death, and (ii) showing the critical nature of Rac1 glucosylation in the loss of epithelial and endothelial barrier function. Finally, the detection of TcsL-induced glucosylation of Rac1 and (H/K/N)Ras using glucosylation- sensitive antibodies is presented as a new method to track TcsL activity.