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Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles

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 fo...

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Autores principales: Hubbard, Troy D., Murray, Iain A., Bisson, William H., Lahoti, Tejas S., Gowda, Krishne, Amin, Shantu G., Patterson, Andrew D., Perdew, Gary H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522678/
https://www.ncbi.nlm.nih.gov/pubmed/26235394
http://dx.doi.org/10.1038/srep12689
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author Hubbard, Troy D.
Murray, Iain A.
Bisson, William H.
Lahoti, Tejas S.
Gowda, Krishne
Amin, Shantu G.
Patterson, Andrew D.
Perdew, Gary H.
author_facet Hubbard, Troy D.
Murray, Iain A.
Bisson, William H.
Lahoti, Tejas S.
Gowda, Krishne
Amin, Shantu G.
Patterson, Andrew D.
Perdew, Gary H.
author_sort Hubbard, Troy D.
collection PubMed
description 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.
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spelling pubmed-45226782015-08-06 Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles Hubbard, Troy D. Murray, Iain A. Bisson, William H. Lahoti, Tejas S. Gowda, Krishne Amin, Shantu G. Patterson, Andrew D. Perdew, Gary H. Sci Rep Article 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. Nature Publishing Group 2015-08-03 /pmc/articles/PMC4522678/ /pubmed/26235394 http://dx.doi.org/10.1038/srep12689 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Hubbard, Troy D.
Murray, Iain A.
Bisson, William H.
Lahoti, Tejas S.
Gowda, Krishne
Amin, Shantu G.
Patterson, Andrew D.
Perdew, Gary H.
Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title_full Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title_fullStr Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title_full_unstemmed Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title_short Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
title_sort adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522678/
https://www.ncbi.nlm.nih.gov/pubmed/26235394
http://dx.doi.org/10.1038/srep12689
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