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Mycolactone subverts immunity by selectively blocking the Sec61 translocon
Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit o...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154940/ https://www.ncbi.nlm.nih.gov/pubmed/27821549 http://dx.doi.org/10.1084/jem.20160662 |
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author | Baron, Ludivine Paatero, Anja Onerva Morel, Jean-David Impens, Francis Guenin-Macé, Laure Saint-Auret, Sarah Blanchard, Nicolas Dillmann, Rabea Niang, Fatoumata Pellegrini, Sandra Taunton, Jack Paavilainen, Ville O. Demangel, Caroline |
author_facet | Baron, Ludivine Paatero, Anja Onerva Morel, Jean-David Impens, Francis Guenin-Macé, Laure Saint-Auret, Sarah Blanchard, Nicolas Dillmann, Rabea Niang, Fatoumata Pellegrini, Sandra Taunton, Jack Paavilainen, Ville O. Demangel, Caroline |
author_sort | Baron, Ludivine |
collection | PubMed |
description | Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single–amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α. Quantitative proteomics reveals that during T cell activation, mycolactone-mediated Sec61 blockade affects a selective subset of secretory proteins including key signal-transmitting receptors and adhesion molecules. Expression of mutant Sec61α in mycolactone-treated T cells rescued their homing potential and effector functions. Furthermore, when expressed in macrophages, the mycolactone-resistant mutant restored IFN-γ receptor–mediated antimicrobial responses. Thus, our data provide definitive genetic evidence that Sec61 is the host receptor mediating the diverse immunomodulatory effects of mycolactone and identify Sec61 as a novel regulator of immune cell functions. |
format | Online Article Text |
id | pubmed-5154940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51549402017-06-12 Mycolactone subverts immunity by selectively blocking the Sec61 translocon Baron, Ludivine Paatero, Anja Onerva Morel, Jean-David Impens, Francis Guenin-Macé, Laure Saint-Auret, Sarah Blanchard, Nicolas Dillmann, Rabea Niang, Fatoumata Pellegrini, Sandra Taunton, Jack Paavilainen, Ville O. Demangel, Caroline J Exp Med Research Articles Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single–amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α. Quantitative proteomics reveals that during T cell activation, mycolactone-mediated Sec61 blockade affects a selective subset of secretory proteins including key signal-transmitting receptors and adhesion molecules. Expression of mutant Sec61α in mycolactone-treated T cells rescued their homing potential and effector functions. Furthermore, when expressed in macrophages, the mycolactone-resistant mutant restored IFN-γ receptor–mediated antimicrobial responses. Thus, our data provide definitive genetic evidence that Sec61 is the host receptor mediating the diverse immunomodulatory effects of mycolactone and identify Sec61 as a novel regulator of immune cell functions. The Rockefeller University Press 2016-12-12 /pmc/articles/PMC5154940/ /pubmed/27821549 http://dx.doi.org/10.1084/jem.20160662 Text en © 2016 Baron et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Baron, Ludivine Paatero, Anja Onerva Morel, Jean-David Impens, Francis Guenin-Macé, Laure Saint-Auret, Sarah Blanchard, Nicolas Dillmann, Rabea Niang, Fatoumata Pellegrini, Sandra Taunton, Jack Paavilainen, Ville O. Demangel, Caroline Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title | Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title_full | Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title_fullStr | Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title_full_unstemmed | Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title_short | Mycolactone subverts immunity by selectively blocking the Sec61 translocon |
title_sort | mycolactone subverts immunity by selectively blocking the sec61 translocon |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154940/ https://www.ncbi.nlm.nih.gov/pubmed/27821549 http://dx.doi.org/10.1084/jem.20160662 |
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