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Mucosal Immunol. 2014 Nov;7(6):1312-25. doi: 10.1038/mi.2014.19. Epub 2014 Mar 26.

NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6.

Author information

1
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.
2
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.
3
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
4
Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
5
Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan.
6
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
7
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.

PMID:
24670424
PMCID:
PMC4177019
DOI:
10.1038/mi.2014.19
[Indexed for MEDLINE]
Free PMC Article

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