TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1
TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1
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DOI：
10.1093/emboj/20.20.5678
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发表时间：
2001-10-15
期刊：
影响因子：
11.4
通讯作者：
Kieser, A
中科院分区：
文献类型：
--
作者：
Schultheiss, U;Püschner, S;Kieser, A
Epstein-Barr病毒的致癌潜伏膜蛋白1（LMP 1）募集肿瘤坏死因子受体（TNFR）相关因子（TRAF）、TNFR相关死亡结构域蛋白（TRADD）和JAK 3以诱导细胞内信号传导途径。LMP 1作为TRADD结合受体的原型，其转化细胞但不诱导凋亡。在这里，我们表明TRAF 6关键介导LMP 1信号p38丝裂原活化蛋白激酶（MAPK）通过MAPK激酶6依赖性途径。此外，NF-kappaB而非c-jun N-末端激酶1（JNK 1）通过LMP 1的诱导涉及TRAF 6。LMP 1 C-末端激活物区域1（CTAR 1）的PxQxT基序和CTAR 2的酪氨酸384一起对于完全p38 MAPK激活和TRAF 6募集到LMP 1信号传导复合物是必需的。显性负性TRADD阻断LMP 1对p38 MAPK的激活。数据表明TRAF 6进入LMP 1复合物是由TRADD和TRAF 2介导的。在TRAF 6敲除的成纤维细胞中，LMP 1对p38 MAPK的显著诱导依赖于TRAF 6的异位表达。我们描述了TRAF 6作为TRADD和TRAF 2下游转化癌基因的重要信号传导介质的新作用。
The oncogenic latent membrane protein 1 (LMP1) of the Epstein-Barr virus recruits tumor necrosis factor-receptor (TNFR) -associated factors (TRAFs), the TNFR-associated death domain protein (TRADD) and JAK3 to induce intracellular signaling pathways. LMP1 serves as the prototype of a TRADD-binding receptor that transforms cells but does not induce apoptosis. Here we show that TRAF6 critically mediates LMP1 signaling to p38 mitogen-activated protein kinase (MAPK) via a MAPK kinase 6-dependent pathway. In addition, NF-kappaB but not c-jun N-terminal kinase 1 (JNK1) induction by LMP1 involves TRAF6. The PxQxT motif of the LMP1 C-terminal activator region 1 (CTAR1) and tyrosine 384 of CTAR2 together are essential for full p38 MAPK activation and for TRAF6 recruitment to the LMP1 signaling complex. Dominant-negative TRADD blocks p38 MAPK activation by LMP1. The data suggest that entry of TRAF6 into the LMP1 complex is mediated by TRADD and TRAF2. In TRAF6-knockout fibroblasts, significant induction of p38 MAPK by LMP1 is dependent on the ectopic expression of TRAF6. We describe a novel role of TRAF6 as an essential signaling mediator of a transforming oncogene, downstream of TRADD and TRAF2.