title: A novel motif in the Crohn's disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responses.
abstract: The Crohn's disease and early onset sarcoidosis susceptibility protein, NOD2, coordinates innate immune signaling pathways. Because dysregulation of this coordination can lead to inflammatory disease, maintaining appropriate activation of the NOD2 signaling pathway is paramount in immunologic homeostasis. In this work, we identify the atypical tumor necrosis factor-associated factor (TRAF) family member, TRAF4, as a key negative regulator of NOD2 signaling. TRAF4 inhibits NOD2-induced NF-κB activation and directly binds to NOD2 to inhibit NOD2-induced bacterial killing. We find that two consecutive glutamate residues in NOD2 are required for interaction with TRAF4 and inhibition of NOD2 signaling because mutation of these residues abrogated both TRAF4 binding and inhibition of NOD2. This work identifies a novel negative regulator of NOD2 signaling. Additionally, it defines a TRAF4 binding motif within NOD2 involved in termination of innate immune signaling responses.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Marinis
authors.forename: Craig R
authors.initials: CR
authors.lastname: Homer
authors.forename: Christine
authors.initials: C
authors.lastname: McDonald
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D012480:Salmonella Infections / Q000276:immunology / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053449:TNF Receptor-Associated Factor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human; C506368:Traf4 protein, mouse