Abstract
Nucleotide oligomerization domain 2 (NOD2) functions as a mammalian cytosolic pathogen recognition molecule, and variants have been associated with risk for Crohn disease. We recently demonstrated that NOD2 functions as an anti-bacterial factor limiting survival of intracellular invasive bacteria. To gain further insight into the mechanism of NOD2 activation and signal transduction, we performed yeast two-hybrid screening. We demonstrate that GRIM-19, a protein with homology to the NADPH dehydrogenase complex, interacts with endogenous NOD2 in HT29 cells. GRIM-19 is required for NF-kappaB activation following NOD2-mediated recognition of bacterial muramyl dipeptide. GRIM-19 also controls pathogen invasion of intestinal epithelial cells. GRIM-19 expression is decreased in inflamed mucosa of patients with inflammatory bowel diseases. GRIM-19 may be a key component in NOD2-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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COS Cells
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Caco-2 Cells
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Cell Line
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Cell Line, Tumor
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Cytosol / metabolism
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Epithelial Cells / metabolism
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Epithelial Cells / microbiology
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Escherichia coli / metabolism
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Genes, Reporter
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Humans
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Immunoblotting
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Immunoprecipitation
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Intestines / microbiology
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / physiology*
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Luciferases / metabolism
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Microscopy, Confocal
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NADH, NADPH Oxidoreductases / chemistry
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NADH, NADPH Oxidoreductases / physiology*
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NF-kappa B / metabolism
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Nod2 Signaling Adaptor Protein
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Plasmids / metabolism
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Protein Binding
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Protein Structure, Tertiary
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RNA, Small Interfering / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Salmonella / metabolism
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Signal Transduction
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Two-Hybrid System Techniques
Substances
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Apoptosis Regulatory Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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NOD2 protein, human
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Nod2 Signaling Adaptor Protein
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RNA, Small Interfering
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Luciferases
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NADH, NADPH Oxidoreductases
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NDUFA13 protein, human