LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-κB activation.
EMBO J
; 30(11): 2115-29, 2011 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-21527913
ABSTRACT
The ubiquitous Epstein Barr virus (EBV) exploits human B-cell development to establish a persistent infection in â¼90% of the world population. Constitutive activation of NF-κB by the viral oncogene latent membrane protein 1 (LMP1) has an important role in persistence, but is a risk factor for EBV-associated lymphomas. Here, we demonstrate that endogenous LMP1 escapes degradation upon accumulation within intraluminal vesicles of multivesicular endosomes and secretion via exosomes. LMP1 associates and traffics with the intracellular tetraspanin CD63 into vesicles that lack MHC II and sustain low cholesterol levels, even in 'cholesterol-trapping' conditions. The lipid-raft anchoring sequence FWLY, nor ubiquitylation of the N-terminus, controls LMP1 sorting into exosomes. Rather, C-terminal modifications that retain LMP1 in Golgi compartments preclude assembly within CD63-enriched domains and/or exosomal discharge leading to NF-κB overstimulation. Interference through shRNAs further proved the antagonizing role of CD63 in LMP1-mediated signalling. Thus, LMP1 exploits CD63-enriched microdomains to restrain downstream NF-κB activation by promoting trafficking in the endosomal-exosomal pathway. CD63 is thus a critical mediator of LMP1 function in- and outside-infected (tumour) cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endossomos
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Glicoproteínas da Membrana de Plaquetas
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Antígenos CD
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Proteínas da Matriz Viral
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NF-kappa B
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Herpesvirus Humano 4
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Exossomos
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Holanda