A20/TNFAIP3 inhibits NF-κB activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein.
Oncogene
; 32(10): 1223-32, 2013 Mar 07.
Article
en En
| MEDLINE
| ID: mdl-22525270
ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP (viral Flice-inhibitory protein) induces transcription of numerous genes through NF-κB activation, including pro-inflammatory cytokines, which contribute to the pathogenesis of Kaposi's sarcoma (KS). In this study, we report that KSHV vFLIP induces the expression of the NF-κB regulatory proteins A20, ABIN-1 and ABIN-3 (A20-binding NF-κB inhibitors) in primary human endothelial cells, and that KS spindle cells express A20 in KS tissue. In reporter assays, A20 strongly impaired vFLIP-induced NF-κB activation in 293T cells, but ABIN-1 and ABIN-3 did not. Mutational analysis established that the C-terminal domain (residues 427-790) is critical for A20 modulation of NF-κB, but the ubiquitin-editing OTU (ovarian tumor) domain is not. In functional assays, A20 inhibited vFLIP-induced expression of the chemokine IP-10, reduced vFLIP-induced cell proliferation and increased IKK1 protein levels. Thus, we demonstrate that A20 negatively regulates NF-κB activation directly induced by KSHV vFLIP. By attenuating excessive and prolonged vFLIP-induced NF-κB activation that could be harmful to KSHV-infected cells, A20 likely has an important role in the pathogenesis of KSHV-associated diseases, in which vFLIP is expressed.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sarcoma de Kaposi
/
Proteínas Virales
/
Proteínas Nucleares
/
FN-kappa B
/
Herpesvirus Humano 8
/
Péptidos y Proteínas de Señalización Intracelular
/
Proteínas de Unión al ADN
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos