Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles.
Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles.
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DOI：
10.1038/srep12689
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发表时间：
2015-08-03
影响因子：
4.6
通讯作者：
Perdew GH
中科院分区：
文献类型：
--
作者：
Hubbard TD;Murray IA;Bisson WH;Lahoti TS;Gowda K;Amin SG;Patterson AD;Perdew GH
芳烃（arylhydrocarbon，AHR）的配体活化对胃肠道的免疫状态具有深远的影响，建立和维持信号网络，促进宿主-微生物在粘膜界面的稳态。然而，负责肠道内这种AHR介导的活化的配体的身份仍有待确定。在这里，我们结合联合收割机在体外配体结合，定量基因表达，蛋白质-DNA相互作用和配体结构的活性分析，在硅片建模的AHR配体结合域，以确定吲哚，微生物色氨酸代谢产物，作为人类AHR选择性激动剂。作为宿主吲哚受体的人AHR可能表现出独特的双分子（2：1）结合化学计量，这在典型的AHR配体中是观察不到的。胃肠道内的人AHR的这种双分子吲哚介导的活化可以为肠道微生物菌群和免疫系统之间的界间信号传导提供基础，以促进肠道内的消化不良。
Ligand activation of the aryl hydrocarbon (AHR) has profound effects upon the immunological status of the gastrointestinal tract, establishing and maintaining signaling networks, which facilitate host-microbe homeostasis at the mucosal interface. However, the identity of the ligand(s) responsible for such AHR-mediated activation within the gut remains to be firmly established. Here, we combine in vitro ligand binding, quantitative gene expression, protein-DNA interaction and ligand structure activity analyses together with in silico modeling of the AHR ligand binding domain to identify indole, a microbial tryptophan metabolite, as a human-AHR selective agonist. Human AHR, acting as a host indole receptor may exhibit a unique bimolecular (2:1) binding stoichiometry not observed with typical AHR ligands. Such bimolecular indole-mediated activation of the human AHR within the gastrointestinal tract may provide a foundation for inter-kingdom signaling between the enteric microflora and the immune system to promote commensalism within the gut.