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

T. Watanabe, N. Asano, G. Meng, K. Yamashita, Y. Arai, T. Sakurai, M. Kudo, I. J. Fuss, A. Kitani, T. Shimosegawa, T. Chiba, W. Strober

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27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1312-1325
Number of pages14
JournalMucosal Immunology
Volume7
Issue number6
DOIs
Publication statusPublished - 2014 Nov 25

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Watanabe, T., Asano, N., Meng, G., Yamashita, K., Arai, Y., Sakurai, T., Kudo, M., Fuss, I. J., Kitani, A., Shimosegawa, T., Chiba, T., & Strober, W. (2014). NOD2 downregulates colonic inflammation by IRF4-mediated inhibition of K63-linked polyubiquitination of RICK and TRAF6. Mucosal Immunology, 7(6), 1312-1325. https://doi.org/10.1038/mi.2014.19