Mycolactone subverts immunity by selectively blocking the Sec61 translocon. - Institut Pasteur Access content directly
Journal Articles Journal of Experimental Medicine Year : 2016

Mycolactone subverts immunity by selectively blocking the Sec61 translocon.

Francis Impens
Nicolas Blanchard


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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Dates and versions

pasteur-01432024 , version 1 (11-01-2017)


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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, 2016, 213 (13), pp.2885-2896. ⟨10.1084/jem.20160662⟩. ⟨pasteur-01432024⟩
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