The enteropathogenic E. coli (EPEC) Tir effector inhibits NF-κB activity by targeting TNFα receptor-associated factors

Enteropathogenic escherichia coli (epec) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. epec e2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the locus of enterocyte effacement (lee) pathogenicity island. our previous work implied that non-lee-encoded (nle) effectors possess functions that inhibit epithelial anti-microbial and inflammation-inducing responses by blocking nf-κb transcription factor activity. indeed,screens by us and others have identified novel inhibitory mechanisms for nlec and nleh,with key co-operative functions for nleb1 and nlee1. here,we demonstrate that the lee-encoded translocated-intimin receptor (tir) effector has a potent and specific ability to inhibit nf-κb activation. indeed,biochemical,imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby tir interaction with cytoplasm-located tnfα receptor-associated factor (traf) adaptor proteins induces their proteasomal-independent degradation. infection studies support this tir-traf relationship but reveal that tir,like nlec and nleh,has a non-essential contribution in epec's nf-κb inhibitory capacity linked to tir's activity being suppressed by undefined epec factors. infections in a disease-relevant intestinal model confirm key nf-κb inhibitory roles for the nleb1/nlee1 effectors,with other studies providing insights on host targets. the work not only reveals a second intimin-independent property for tir and a novel epec effector-mediated nf-κb inhibitory mechanism but also lends itself to speculations on the evolution of epec's capacity to inhibit nf-κb function. © 2011 ruchaud-sparagano et al.