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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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Detalles Bibliográficos
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
Descripción
Sumario: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.