Mycolactone subverts immunity by selectively blocking the Sec61 translocon.

Ludivine Baron (1) , Anja Onerva Paatero (2) , Jean-David Morel (1) , Francis Impens (3) , Laure Guenin-Macé (1) , Sarah Saint-Auret (4) , Nicolas Blanchard (4) , Rabea Dillmann (2) , Fatoumata Niang (1) , Sandra Pellegrini (5) , Jack Taunton (6) , Ville O Paavilainen (2) , Caroline Demangel (1)

1 Immunobiologie de l'Infection - Immunobiology of Infection
2 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
3 UIBC - Interactions Bactéries-Cellules
4 LCM - Laboratoire de chimie moléculaire
5 Signalisation des Cytokines - Cytokine Signaling
6 UC San Francisco - University of California [San Francisco]

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.

Domains: Life Sciences [q-bio]; Immunology; Biochemistry, Molecular Biology

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⟩