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In this study, we show that mycolactone directly targets the \u03b1 subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single\u2013amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61\u03b1. 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 Sec61\u03b1 in mycolactone-treated T cells rescued their homing potential and effector functions. Furthermore, when expressed in macrophages, the mycolactone-resistant mutant restored IFN-\u03b3 receptor\u2013mediated 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.<\/jats:p>","DOI":"10.1084\/jem.20160662","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T15:07:38Z","timestamp":1478531258000},"page":"2885-2896","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":135,"title":["Mycolactone subverts immunity by selectively blocking the Sec61 translocon"],"prefix":"10.1084","volume":"213","author":[{"given":"Ludivine","family":"Baron","sequence":"first","affiliation":[{"name":"Unit\u00e9 d\u2019Immunobiologie de l\u2019Infection, Institut Pasteur, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U1221, 75015 Paris, France 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