title: NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6.
abstract: It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
authors.affiliation: 1] Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan [2] Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [3] Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: 1] Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA [2] Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Asano
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: G
authors.initials: G
authors.lastname: Meng
authors.affiliation: Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: I J
authors.initials: IJ
authors.lastname: Fuss
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kitani
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: W
authors.initials: W
authors.lastname: Strober
mesh_terms: D000818:Animals; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology*; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D053473:Nod2 Signaling Adaptor Protein; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048029:TNF Receptor-Associated Factor 6; D000099218:Interferon Regulatory Factor-4; C429018:NOD2 protein, human; C495945:Nod2 protein, mouse; C506255:Ripk2 protein, mouse