 |
Journal articles
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.
Cited literature [30 references]
https://hal-pasteur.archives-ouvertes.fr/pasteur-01432024
Contributor : Marie-Luce Kop <>
Submitted on : Wednesday, January 11, 2017 - 2:24:14 PM
Last modification on : Tuesday, May 25, 2021 - 5:38:01 PM
Long-term archiving on: : Friday, April 14, 2017 - 12:07:48 PM
Contributor : Marie-Luce Kop <>
Submitted on : Wednesday, January 11, 2017 - 2:24:14 PM
Last modification on : Tuesday, May 25, 2021 - 5:38:01 PM
Long-term archiving on: : Friday, April 14, 2017 - 12:07:48 PM
Files
2885.full.pdf
Publication funded by an institution
- PMID 27821549.pdf Files produced by the author(s)
Licence
Distributed under a Creative Commons Attribution - NonCommercial - ShareAlike 4.0 International License