The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling
The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling
复制标题
DOI：
10.1038/sj.embor.7400580
复制
发表时间：
2006-01-01
期刊：
影响因子：
7.7
通讯作者：
Cesarman, E
中科院分区：
文献类型：
--
作者：
Guasparri, I;Wu, H;Cesarman, E
以卡波西肉瘤疱疹病毒（KSHV;也称为人疱疹病毒8）感染为特征的原发性渗出性淋巴瘤（PEL）的生存依赖于病毒FADD样白细胞介素-1-β转化酶（FLICE）/半胱天冬酶-8抑制蛋白（vFLIP）的表达。这种作用是通过激活转录因子核因子-κ B（NF-κ B）实现的。肿瘤坏死因子（TNF）受体相关因子（TRAFs）是TNF家族受体和EB病毒癌蛋白潜伏膜蛋白1介导的NF-κ B信号传导的直接介质，因此我们评估了TRAFs在vFLIP信号传导中的作用。在这里，我们报告的TRAF相互作用的基序（PYQLT）在vFLIP，这是不存在于其他FLIP分子的鉴定。我们表明，vFLIP直接结合TRAF 2在体外和在PEL细胞。TRAF 2和TRAF 3是诱导NF-κ B和相关细胞存活以及通过vFLIP的Jun氨基末端激酶磷酸化所必需的，而TRAF 1、TRAF 5和TRAF 6是不稳定的。vFLIP的TRAF相互作用基序内的P93或Q95氨基酸的突变消除了其结合TRAF 2和向NF-κ B发信号的能力。TRAF 2而不是TRAF 3介导vFLIP与I κ B激酶复合物的结合。这些数据表明，vFLIP使用TRAF 2和TRAF 3向NF-κ B发出信号，这对于KSHV相关的淋巴瘤发生至关重要。
Primary effusion lymphomas (PELs) characterized by infection with the Kaposi's sarcoma herpesvirus (KSHV; also called human herpesvirus 8) depend on the expression of the viral FADD-like interleukin-1-beta-converting enzyme (FLICE)/caspase-8-inhibitory protein (vFLIP) for their survival. This effect is achieved by activation of the transcription factor nuclear factor-kappa B (NF-kappa B). Tumour necrosis factor (TNF) receptor-associated factors (TRAFs) are direct mediators of NF-kappa B signalling by TNF family receptors and the Epstein-Barr virus oncoprotein latent membrane protein 1 and so we assessed the role of TRAFs in signalling by vFLIP. Here, we report the identification of a TRAF-interacting motif (PYQLT) in vFLIP, which is not present in other FLIP molecules. We show that vFLIP directly binds to TRAF2 in vitro and in PEL cells. TRAF2 and TRAF3 are required for induction of NF-kappa B and associated cell survival, as well as Jun amino-terminal kinase phosphorylation by vFLIP, whereas TRAF1, TRAF5 and TRAF6 are dispensable. Mutations in the P93 or Q95 amino acids within the TRAF-interacting motif of vFLIP abolish its ability to bind to TRAF2 and to signal to NF-kappa B. TRAF2, but not TRAF3, mediates the association of vFLIP with the I kappa B kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappa B, which is crucial for KSHV-associated lymphomagenesis.