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.
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Authors | 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 |
Journal | Mucosal immunology
(Mucosal Immunol)
Vol. 7
Issue 6
Pg. 1312-25
(Nov 2014)
ISSN: 1935-3456 [Electronic] United States |
PMID | 24670424
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interferon Regulatory Factors
- NOD2 protein, human
- Nod2 Signaling Adaptor Protein
- Nod2 protein, mouse
- TNF Receptor-Associated Factor 6
- interferon regulatory factor-4
- Receptor-Interacting Protein Serine-Threonine Kinase 2
- Receptor-Interacting Protein Serine-Threonine Kinases
- Ripk2 protein, mouse
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Topics |
- Animals
- Colon
(immunology, pathology)
- Crohn Disease
(genetics, immunology, pathology)
- Dendritic Cells
(immunology, pathology)
- Down-Regulation
(immunology)
- HEK293 Cells
- Humans
- Inflammation
(genetics, immunology, pathology)
- Interferon Regulatory Factors
(genetics, immunology)
- Mice
- Nod2 Signaling Adaptor Protein
(genetics, immunology)
- Receptor-Interacting Protein Serine-Threonine Kinase 2
- Receptor-Interacting Protein Serine-Threonine Kinases
(genetics, immunology)
- TNF Receptor-Associated Factor 6
(genetics, immunology)
- Ubiquitination
(genetics, immunology)
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