LMP1 signaling pathway activates IRF4 in latent EBV infection and a positive circuit between PI3K and Src is required.
Oncogene
; 36(16): 2265-2274, 2017 04 20.
Article
em En
| MEDLINE
| ID: mdl-27819673
ABSTRACT
Interferon (IFN) regulatory factors (IRFs) have crucial roles in immune regulation and oncogenesis. We have recently shown that IRF4 is activated through c-Src-mediated tyrosine phosphorylation in virus-transformed cells. However, the intracellular signaling pathway triggering Src activation of IRF4 remains unknown. In this study, we provide evidence that Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) promotes IRF4 phosphorylation and markedly stimulates IRF4 transcriptional activity, and that Src mediates LMP1 activation of IRF4. As to more precise mechanism, we show that LMP1 physically interacts with c-Src, and the phosphatidylinositol 3 kinase (PI3K) subunit P85 mediates their interaction. Depletion of P85 by P85-specific short hairpin RNAs disrupts their interaction and diminishes IRF4 phosphorylation in EBV-transformed cells. Furthermore, we show that Src is upstream of PI3K for activation of both IRF4 and Akt. In turn, inhibition of PI3K kinase activity by the PI3K-speicfic inhibitor LY294002 impairs Src activity. Our results show that LMP1 signaling is responsible for IRF4 activation, and further characterize the IRF4 regulatory network that is a promising therapeutic target for specific hematological malignancies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas da Matriz Viral
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Proteínas Proto-Oncogênicas pp60(c-src)
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Infecções por Vírus Epstein-Barr
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Fatores Reguladores de Interferon
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Classe Ia de Fosfatidilinositol 3-Quinase
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article