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The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors

Lookup NU author(s): Dr Marie Ruchaud-Sparagano, Dr Paul Dean, Professor Brendan Kenny

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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-kappa B 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-kappa B activation. Indeed, biochemical, imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby Tir interaction with cytoplasm-located TNF alpha 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-kappa B inhibitory capacity linked to Tir's activity being suppressed by undefined EPEC factors. Infections in a disease-relevant intestinal model confirm key NF-kappa B 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-kappa B inhibitory mechanism but also lends itself to speculations on the evolution of EPEC's capacity to inhibit NF-kappa B function.


Publication metadata

Author(s): Ruchaud-Sparagano MH, Mühlen S, Dean P, Kenny B

Publication type: Article

Publication status: Published

Journal: PLoS Pathogens

Year: 2011

Volume: 7

Issue: 12

Print publication date: 01/12/2011

Date deposited: 02/05/2012

ISSN (print): 1553-7366

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.ppat.1002414

DOI: 10.1371/journal.ppat.1002414


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