CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion.
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.
Doye
Anne
A
INSERM U452, IFR 50, Faculté de Médecine, 28 avenue de Valombrose, 06107, Nice, France.
Mettouchi
Amel
A
Bossis
Guillaume
G
Clément
René
R
Buisson-Touati
Caroline
C
Flatau
Gilles
G
Gagnoux
Laurent
L
Piechaczyk
Marc
M
Boquet
Patrice
P
Lemichez
Emmanuel
E
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
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