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 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.
Unité d'Immunobiologie de l'Infection, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France.
Ludivine
L
Baron
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
Anja Onerva
0000-0003-2193-2483
AO
Paatero
Unité d'Immunobiologie de l'Infection, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France.
Jean-David
0000-0002-7122-9924
JD
Morel
Unité des Interactions Bactéries-Cellules, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U604, Institut National de la Recherche Agronomique, Unité sous-contrat 2020, 75015 Paris, France.
Francis
0000-0003-2886-9616
F
Impens
Unité d'Immunobiologie de l'Infection, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France.
Laure
0000-0002-9791-5308
L
Guenin-Macé
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7509, École européenne de Chimie, Polymères et Matériaux, Université de Strasbourg, 67087 Strasbourg, France.
Sarah
S
Saint-Auret
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7509, École européenne de Chimie, Polymères et Matériaux, Université de Strasbourg, 67087 Strasbourg, France.
Nicolas
0000-0002-3097-0548
N
Blanchard
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
Rabea
0000-0003-2863-4948
R
Dillmann
Unité d'Immunobiologie de l'Infection, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France.
Fatoumata
F
Niang
Unité de Signalisation des Cytokines, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France.
Sandra
0000-0001-5837-7589
S
Pellegrini
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158.
Jack
J
Taunton
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
Ville O
0000-0002-3160-7767
VO
Paavilainen
Unité d'Immunobiologie de l'Infection, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U1221, 75015 Paris, France demangel@pasteur.fr ville.paavilainen@helsinki.fi.
Caroline
0000-0001-7848-586X
C
Demangel
D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D018942:Macrolides / Q000494:pharmacology*; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D000069816:SEC Translocation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000096743:Interferon gamma Receptor
D018942:Macrolides; D017471:Receptors, Interferon; D000069816:SEC Translocation Channels; D000096743:Interferon gamma Receptor; C000613244:SEC61A1 protein, human; C117218:mycolactone