Mycolactone subverts immunity by selectively blocking the Sec61 translocon.

Abstract : 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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Journal of Experimental Medicine, Rockefeller University Press, 2016, 213 (13), pp.2885-2896. 〈10.1084/jem.20160662〉
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Ludivine Baron, Anja Onerva Paatero, Jean-David Morel, Francis Impens, Laure Guenin-Macé, et al.. Mycolactone subverts immunity by selectively blocking the Sec61 translocon.. Journal of Experimental Medicine, Rockefeller University Press, 2016, 213 (13), pp.2885-2896. 〈10.1084/jem.20160662〉. 〈pasteur-01432024〉

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