A20/TNFAIP3 inhibits NF-κB activation induced by the Kaposi’s sarcoma-associated herpesvirus vFLIP oncoprotein

被引:0
作者
S Sakakibara
G Espigol-Frigole
P Gasperini
T S Uldrick
R Yarchoan
G Tosato
机构
[1] Laboratory of Cellular Oncology,
[2] Center for Cancer Research,undefined
[3] National Cancer Institute,undefined
[4] National Institutes of Health,undefined
[5] HIV and AIDS Malignancy Branch,undefined
[6] Center for Cancer Research,undefined
[7] National Cancer Institute,undefined
[8] National Institutes of Health,undefined
来源
Oncogene | 2013年 / 32卷
关键词
KSHV; NF-κB; vFLIP/K13; endothelial cells; Kaposi’s sarcoma; AIDS;
D O I
暂无
中图分类号
学科分类号
摘要
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.
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页码:1223 / 1232
页数:9
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