Unraveling the mechanism of action of a new type III secretion system effector AexU from Aeromonas hydrophila

作者：Sierra Johanna C; Suarez Giovanni; Sha Jian; Baze Wallace B; Foltz Sheri M; Chopra Ashok K^*

来源：Microbial Pathogenesis, 2010, 49(3): 122-134.

DOI：10.1016/j.micpath.2010.05.011

• Aeromonas hydrophila
• T3SS
• AexU
• Site-directed mutagenesis
• ADP-ribosyltransferase activity
• GAP activity
• HeLa Tet-Off cells
• Apoptosis
• Septicemic mouse model of infection

We recently characterized a T3SS effector, AexU, from a diarrheal isolate SSU of Aeromonas hydrophila, which exhibited ADP-ribosyltransferase (ADPRT) activity. Here we provided evidence that AexU also possessed GTPase-activating protein (GAP) activity, which was mainly responsible for host cell apoptosis and disruption of actin filaments. Earlier, we showed that the Delta aexU null mutant was attenuated in a mouse model, and we now demonstrated that while the parental A. hydrophila strain could be detected in the lung, liver, and spleen of infected mice, the Delta aexU mutant was rapidly cleared from these organs resulting in increased survivability of animals. Further, AexU prevented phosphorylation of c-Jun. JNK and I kappa B alpha and inhibited IL-6 and IL-8 secretion from HeLa cells. Our data indicated that AexU operated by inhibiting NF-kappa B and inactivating Rho GTPases. Importantly, however, when the Delta aexU null mutant was complemented with the mutated aexU gene devoid of ADPRT and GAP activities, a higher mortality rate in mice with concomitant increase in the production of pro-inflammatory cytokines/chemokines was noted. These data indicated that either such a mutated AexU is a potent inducer of them or that AexU possesses yet another unknown activity that is modulated by ADPRT and GAP activities and results in this aberrant cytokine/chemokine production responsible for increased animal death.

• 出版日期2010-9