Doye Anne, Mettouchi Amel, Bossis Guillaume, Clément René, Buisson-Touati Caroline, Flatau Gilles, Gagnoux Laurent, Piechaczyk Marc, Boquet Patrice, Lemichez Emmanuel
INSERM U452, IFR 50, Faculté de Médecine, 28 avenue de Valombrose, 06107, Nice, France.
Cell. 2002 Nov 15;111(4):553-64. doi: 10.1016/s0092-8674(02)01132-7.
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.
细胞毒性坏死因子1（CNF1）毒素是由尿路致病性大肠杆菌产生的一种毒力因子。在与细胞结合并导入胞质溶胶后，CNF1使RhoA的谷氨酰胺63（或Rac和Cdc42的61）脱酰胺，使这些GTP酶组成型激活。出乎意料的是，我们在膀胱细胞中检测到CNF1诱导的Rho GTP酶短暂激活，对Rac的激活作用最大。Rac的失活与其脱酰胺形式对泛素/蛋白酶体介导的降解敏感性增加有关。对泛素化的敏感性可推广到Rac的其他永久激活形式及其由Dbl介导的持续激活。毒素激活的Rac的降解使宿主细胞能够运动，并使尿路致病性细菌有效地侵入细胞。因此，CNF1毒性是通过劫持宿主细胞蛋白酶体机制对Rho GTP酶进行有限激活而产生的。
