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Membrane Association Dictates Ligand Specificity for the Innate Immune Receptor NOD2
ACS Chemical Biology ( IF 4 ) Pub Date : 2017-07-25 00:00:00 , DOI: 10.1021/acschembio.7b00469
Amy K. Schaefer 1 , James E. Melnyk 1 , Michael M. Baksh 2 , Klare M. Lazor 1 , M. G. Finn 2 , Catherine Leimkuhler Grimes 1, 3
Affiliation  

The human gut must regulate its immune response to resident and pathogenic bacteria, numbering in the trillions. The peptidoglycan component of the bacterial cell wall is a dense and rigid structure that consists of polymeric carbohydrates and highly cross-linked peptides which offers protection from the host and surrounding environment. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a human membrane-associated innate immune receptor found in the gut epithelium and mutated in an estimated 30% of Crohn’s disease patients, binds to peptidoglycan fragments and initiates an immune response. Using a combination of chemical synthesis, advanced analytical assays, and protein biochemistry, we tested the binding of a variety of synthetic peptidoglycan fragments to wild-type (WT)-NOD2. Only when the protein was presented in the native membrane did binding measurements correlate with a NOD2-dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) response, supporting the hypothesis that the native-membrane environment confers ligand specificity to the NOD2 receptor for NF-κB signaling. While N-acetyl-muramyl dipeptide (MDP) has been thought to be the minimal peptidoglycan fragment necessary to activate a NOD2-dependent immune response, we found that fragments with and without the dipeptide moiety are capable of binding and activating a NOD2-dependent NF-κB response, suggesting that the carbohydrate moiety of the peptidoglycan fragments is the minimal functional epitope. This work highlights the necessity of studying NOD2-ligand binding in systems that resemble the receptor’s natural environment, as the cellular membrane and/or NOD2 interacting partners appear to play a crucial role in ligand binding and in triggering an innate immune response.

中文翻译:

膜协会决定天然免疫受体NOD2的配体特异性。

人类的肠道必须调节其对常驻细菌和致病细菌的免疫反应,其数量达数万亿。细菌细胞壁的肽聚糖成分是致密而刚性的结构,由聚合的碳水化合物和高度交联的肽组成,可提供对宿主和周围环境的保护。含核苷酸结合的寡聚化域蛋白2(NOD2)是一种人类膜相关的先天免疫受体,在肠道上皮细胞中发现并在大约30%的克罗恩病患者中发生了突变,与肽聚糖片段结合并启动了免疫反应。使用化学合成,先进的分析方法和蛋白质生物化学的组合,我们测试了各种合成的肽聚糖片段与野生型(WT)-NOD2的结合。仅当蛋白质出现在天然膜中时,结合测量才与活化B细胞的NOD2依赖性核因子κ轻链增强子(NF-κB)反应相关,支持天然膜环境赋予配体的假说对NOD2受体对NF-κB信号传导的特异性。尽管N-乙酰基-村m基二肽(MDP)被认为是激活NOD2依赖性免疫反应所必需的最小肽聚糖片段,我们发现具有和不具有二肽部分的片段均能够结合激活NOD2依赖性NF- κB反应,表明肽聚糖片段的碳水化合物部分是最小的功能表位。这项工作强调了在类似于受体自然环境的系统中研究NOD2-配体结合的必要性,因为细胞膜和/或NOD2相互作用的伴侣似乎在配体结合和触发先天免疫反应中起着关键作用。
更新日期:2017-07-26
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