Action by large clostridial toxins (LCTs) from Clostridioides difficile includes four steps: (1) receptor-mediated endocytosis, (2) translocation of a catalytic glucosyltransferase domain across the membrane, (3) release of the enzymatic part by auto-proteolysis, and (4) inactivation of Rho family proteins.
[2] Cleavage of toxin B and all other large clostridial cytotoxins, is an autocatalytic process dependent on host cytosolic inositolphosphate cofactors.
[4] Clostridioides difficile infection, caused by the actions of the homologous toxins TcdA and TcdB on colonic epithelial cells is due to binding to target cells which triggers toxin internalization into acidified vesicles, whereupon cryptic segments from within the 1,050-aa translocation domain unfurl and insert into the bounding membrane, creating a transmembrane passageway to the cytosol.
Defective variants exhibit impaired pore formation in planar lipid bilayers and biological membranes, resulting in an inability to intoxicate cells through either apoptotic or necrotic pathways.
[5] Proteolytically processed clostridial cytotoxins A (306 kDa; TC# 1.C.57.1.2) and B (269 kDa; TC# 1.C.57.1.1) are O-glycosyltransferases that modify small GTPases of the Rho family by glucosylation of threonine residues, thereby blocking the action of the GTPases as switches of signal processes such as those mediated by the actin cytoskeleton.