title: Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease.
abstract: 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 or D-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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ogura
authors.forename: Ana
authors.initials: A
authors.lastname: Fontalba
authors.forename: Olga
authors.initials: O
authors.lastname: Gutierrez
authors.forename: Fernando
authors.initials: F
authors.lastname: Pons
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Seiichi
authors.initials: S
authors.lastname: Inamura
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Masahito
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foster
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Moran
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernandez-Luna
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry / Q000378:metabolism*; D001412:Bacillus subtilis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics*; D004926:Escherichia coli / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D011994:Recombinant Proteins; D000119:Acetylmuramyl-Alanyl-Isoglutamine