title: The enteropathogenic E. coli (EPEC) Tir effector inhibits NF-κB activity by targeting TNFα receptor-associated factors.
abstract: 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.
authors.affiliation: Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Ruchaud-Sparagano
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mühlen
authors.forename: Paul
authors.initials: P
authors.lastname: Dean
authors.forename: Brendan
authors.initials: B
authors.lastname: Kenny
mesh_terms: D054308:Enteropathogenic Escherichia coli / Q000235:genetics / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D044404:Genomic Islands / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D016328:NF-kappa B; C553814:NleB protein, E coli; C556114:NleH protein, E coli; D011956:Receptors, Cell Surface; C109287:Tir protein, E coli; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D037521:Virulence Factors; C506688:Z0986 protein, E coli; D046988:Proteasome Endopeptidase Complex