Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2

By N. Inohara, Y. Ogura, A. Fontalba, O. Gutiérrez, F. Pons, J. Crespo, K. Fukase, S. Inamura, S. Kusumoto, M. Hashimoto and 4 more. Journal of Biological Chemistry, 2003

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NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-l-Ala-d-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of l-Ala for d-Ala ord-isoGln for l-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development.

Subfields: Food Science, Immunology, Microbiology

View Paper: https://www.semanticscholar.org/paper/125d7d04b26106bc327b7c714cab915a0d1834e7

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Citations in the corpus

Nod2 is required for the regulation of commensal microbiota in the intestine (2009, background): “Nod2 has been shown to respond to muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), a moiety of peptidoglycan consisting of N-acetylmuramylL-Ala-D-Glu (8, 9).”
A critical role of RICK/RIP2 polyubiquitination in Nod‐induced NF‐κB activation (2008, methodology): “Two NLR family members, Nod1 and Nod2, play an essential role in the recognition of specific bacterial peptidoglycan (PGN)- related molecules (Chamaillard et al, 2003; Inohara et al, 2003; Girardin et al, 2003a, b).”
Bacterial flagellin is a dominant antigen in Crohn disease. (2004, background): “highlights the potential role of pattern-recognition receptors and their ligands in diseases such as IBD (11).”
The immunological and genetic basis of inflammatory bowel disease (2003, background): “— which encodes an intracellular molecule of the NOD family that is thought to be involved in the recognition of bacteri”
The Drosophila immune system detects bacteria through specific peptidoglycan recognition (2003, background): “It has been shown in mammals that Nod2, a protein involved in intracellular bacterial sensing, recognizes peptidoglycan by detecting a small peptidoglycan motif, the muramyl-dipeptide (MDP”
Dendritic cells in intestinal immune regulation (2008, positive): “Mononuclear cells or macrophages taken from patients with Crohn's disease with NOD2 mutations show impaired NF-κB activation and cytokine production following stimulation with MDP, indicating that chronic intestinal inflammation may be associated with the loss of NOD2 functio”
Nod-like proteins in immunity, inflammation and disease (2006, background): “Nod2 detects muramyl dipeptide, the largest molecular motif common to Gram-negative and Gram-positive bacteri”
Toll-like receptors and innate immunity (2006, background): “Although initial studies identified LPS as a NOD2 ligand [76], it is well established now that NOD1 and NOD2 recognize peptidoglycan-derived peptides, γ-Dglutamyl-meso-diaminopimelic acid (iE-DAP) [77] and muramyl dipeptide (MDP) [78, 79], respectively.”