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: 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)

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

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)