title: Protection from Clostridium difficile toxin B-catalysed Rac1/Cdc42 glucosylation by tauroursodeoxycholic acid-induced Rac1/Cdc42 phosphorylation.
abstract: Toxin A (TcdA) and toxin B (TcdB) are the major virulence factors of Clostridium difficile-associated diarrhoea (CDAD). TcdA and TcdB mono-glucosylate small GTPases of the Rho family, thereby causing actin re-organisation in colonocytes, resulting in the loss of colonic barrier function. The hydrophilic bile acid tauroursodeoxycholic acid (TUDCA) is an approved drug for the treatment of cholestasis and biliary cirrhosis. In this study, TUDCA-induced activation of Akt1 is presented to increase cellular levels of pS71-Rac1/Cdc42 in human hepatocarcinoma (HepG2) cells, showing for the first time that bile acid signalling affects the activity of Rho proteins. Rac1/Cdc42 phosphorylation, in turn, protects Rac1/Cdc42 from TcdB-catalysed glucosylation and reduces the TcdB-induced cytopathic effects in HepG2 cells. The results of this study indicate that TUDCA may prove useful as a therapeutic agent for the treatment of CDAD.
authors.affiliation: Institut für Toxikologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Brandes
authors.forename: Ilona
authors.initials: I
authors.lastname: Schelle
authors.forename: Sophie
authors.initials: S
authors.lastname: Brinkmann
authors.forename: Florian
authors.initials: F
authors.lastname: Schulz
authors.forename: Janett
authors.initials: J
authors.lastname: Schwarz
authors.forename: Ralf
authors.initials: R
authors.lastname: Gerhard
authors.forename: Harald
authors.initials: H
authors.lastname: Genth
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D016360:Clostridioides difficile / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C107953:RAC1 protein, human; C031815:toxB protein, Clostridium difficile; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein