title: CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion.
abstract: CNF1 toxin is a virulence factor produced by uropathogenic Escherichia coli. Upon cell binding and introduction into the cytosol, CNF1 deamidates glutamine 63 of RhoA (or 61 of Rac and Cdc42), rendering constitutively active these GTPases. Unexpectedly, we measured in bladder cells a transient CNF1-induced activation of Rho GTPases, maximal for Rac. Deactivation of Rac correlated with the increased susceptibility of its deamidated form to ubiquitin/proteasome-mediated degradation. Sensitivity to ubiquitylation could be generalized to other permanent-activated forms of Rac and to its sustained activation by Dbl. Degradation of the toxin-activated Rac allowed both host cell motility and efficient cell invasion by uropathogenic bacteria. CNF1 toxicity thus results from a restricted activation of Rho GTPases through hijacking the host cell proteasomal machinery.
authors.affiliation: INSERM U452, IFR 50, Faculté de Médecine, 28 avenue de Valombrose, 06107, Nice, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Doye
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bossis
authors.forename: René
authors.initials: R
authors.lastname: Clément
authors.forename: Caroline
authors.initials: C
authors.lastname: Buisson-Touati
authors.forename: Gilles
authors.initials: G
authors.lastname: Flatau
authors.forename: Laurent
authors.initials: L
authors.lastname: Gagnoux
authors.forename: Marc
authors.initials: M
authors.lastname: Piechaczyk
authors.forename: Patrice
authors.initials: P
authors.lastname: Boquet
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003603:Cytotoxins / Q000378:metabolism*; D004789:Enzyme Activation; D004926:Escherichia coli / Q000378:metabolism / Q000502:physiology; D029968:Escherichia coli Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D003603:Cytotoxins; D029968:Escherichia coli Proteins; D009097:Multienzyme Complexes; D025801:Ubiquitin; C060296:cytotoxic necrotizing factor type 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein