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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
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.
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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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