TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the Epstein-Barr virus-encoded latent infection membrane protein 1 but not CD40
TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the Epstein-Barr virus-encoded latent infection membrane protein 1 but not CD40
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DOI：
10.1128/jvi.77.2.1316-1328.2003
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发表时间：
2003-01-01
影响因子：
5.4
通讯作者：
Young, LS
中科院分区：
文献类型：
--
作者：
Eliopoulos, AG;Waites, ER;Young, LS
EB病毒(EBV)编码的潜伏感染膜蛋白1(LMP1)能够以非配体依赖的方式募集肿瘤坏死因子受体相关因子(TRAF)和肿瘤坏死因子受体相关死亡结构域蛋白(Tradd)。因此，LMP1结构性地参与信号通路，如JNK和p38丝裂原激活蛋白激酶(MAPK)，转录因子NF-kappaB，以及JAK/STAT级联，这些活性可能解释了它对细胞表型、生长和转化的许多多效性作用。在这项研究中，我们证明了LMP1的TRAF结合域以一种细胞类型依赖的方式在JNK/AP-1轴上发出信号的能力，这一方式关键地涉及TRAF1和TRAF2。因此，在TRAF1阳性的淋巴瘤细胞中表达这个LMP1结构域可以显著促进JNK的激活，这种激活可以被显性阴性的TRAF2而不是TRAF5所阻断。然而，TRAF1在许多已建立的上皮细胞系和鼻咽癌(NPC)活检标本中缺失。在这些细胞中，LMP1的TRAF结合域对JNK的激活依赖于TRAF1表达的重组。TRAF1在调节TRAF2依赖的JNK信号中的关键作用是LMP1的TRAF结合域，因为在CD40的细胞质尾部有一个同源区域，或者在JNK轴上有一个与TRAF1状态无关的LMP1信号的Tradd相互作用区域。这些数据进一步剖析了LMP1使用的信号成分，并确定了TRAF1作为致癌信号调制器的新角色。
The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-kappaB, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type-dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.