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

Abstract

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 glucosylationsensitive antibodies is presented as a new method to track TcsL activity.

Cytoprotective effect of the small GTPase RhoB expressed upon treatment of fibroblasts with the Ras‐glucosylating Clostridium sordellii lethal toxin

“…TcsL enters target cells by receptor‐mediated endocytosis and efficaciously mono‐glucosylates (and thereby inactivates) the Ras subtype proteins (H/K/N)Ras and Rap(1/2). TcsL less efficaciously glucosylates Rac1 and Cdc42, while Rho(A/B/C) are not glucosylated [17–19]. Treatment of cells with TcsL results in inhibition of PI3K/Akt‐mediated survival signaling and activation of p38 MAP kinase, with both effects contributing to the initiation of apoptosis of cultured myeloid and epithelial cells [20–23].…”