Mycolactone subverts immunity by selectively blocking the Sec61 translocon.
J Exp Med
; 213(13): 2885-2896, 2016 12 12.
Article
en En
| MEDLINE
| ID: mdl-27821549
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_buruli_ulcer
Asunto principal:
Linfocitos T
/
Transducción de Señal
/
Receptores de Interferón
/
Macrólidos
/
Canales de Translocación SEC
Límite:
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2016
Tipo del documento:
Article
País de afiliación:
Francia