Host recognition of bacterial muramyl dipeptide mediated through NOD2
Host recognition of bacterial muramyl dipeptide mediated through NOD2
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DOI：
10.1074/jbc.c200673200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Nuñez, G
中科院分区：
文献类型：
--
作者：
Inohara, N;Ogura, Y;Nuñez, G
NOD2是一种与克罗恩病易感性相关的蛋白质，它对细菌制剂脂多糖和肽聚糖具有反应性，但确切的识别部分仍不清楚。生化和功能分析鉴定为胞壁菌素。二肽(MurNAc-L-ALA-D-IsoGln)来源于肽聚糖，是NOD2识别的细菌的基本结构。用L-丙氨酸代替D-丙氨酸，或用D-异甘氨酸代替L-异甘氨酸，消除了胞壁二肽刺激NOD2的能力，表明是立体选择性识别。到目前为止，Muramyl二肽已被识别，但不能被TLR2或TLR2与TLR1或TLR6共表达。与克罗恩病易感性相关的NOD2突变体缺乏对胞壁二肽的识别能力。值得注意的是，主要疾病相关的L1007fsinsC NOW突变纯合子个体的外周血单核细胞对脂多糖有反应，但对合成的胞壁二肽没有反应。因此，现在介导宿主对来自肽多聚糖的细菌神经肽的反应，这一活性对于预防克罗恩病很重要。由于胞壁二肽是佐剂活性所需的肽聚糖的基本结构，这些结果也对理解佐剂功能和有效的疫苗开发具有重要意义。
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-isoGIn for L-isoGIn eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOW 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 NOW mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOW 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.