Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1)
Activation of the cJun N-terminal kinase (JNK) pathway by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1)
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DOI：
10.1038/sj.onc.1201694
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发表时间：
1998-04-02
期刊：
影响因子：
8
通讯作者：
Young, LS
中科院分区：
文献类型：
--
作者：
Eliopoulos, AG;Young, LS
eb病毒（EBV）编码的潜伏膜蛋白1 （LMP1）通过胞质c端两个不同的结构域，即CTAR1 （aa 187-231）和CTAR2 （aa 351-386）的表达激活NF-kappa B轴上的信号传导，虽然这种作用是LMP1表达的一些功能后果的原因，但可能存在其他LMP1介导的信号传导途径，这些途径有助于该蛋白的多效性活性。在这项研究中，我提供了LMP1激活激酶级联的证据。因此，我们证明了来自B95.8的LMP1原型在上皮细胞或B细胞来源的细胞中稳定或短暂表达激活了c-Jun n -末端激酶（JNK，也称为应激激活蛋白激酶，SAPK）途径，这一作用被发现是通过CTAR2介导的，而不是CTAR1，来自Cao病毒株的LMP1或来自自然感染狒狒和恒河猴的猿类EBV的LMP1同源物也能够激活JNK。有趣的是，LMP1/CD40嵌合体包括LMP1的n端和跨膜结构域，以及与CTAR1具有共同TRAF结合基序的CD40的细胞质尾部，有效地诱导了JNK，由于NF-kappa B和JNK在表达LMP1的细胞中共激活，我们研究了这两种途径是重叠的还是独立的。我们发现，代谢抑制剂或组成活性突变的I κ B α对NF-kappa B的抑制不会损害LMP1在JNK轴上发出信号的能力，相反，虽然显性负突变的SEK （JNKK）抑制LMP1诱导的JNK激活，但它不影响NF-kappa B，这表明这两种LMP1介导的途径是不同的。
Expression of the oncogenic Epstein-Barr virus (EBV)-encoded Latent Membrane Protein 1 (LMP1) activates signalling on the NF-kappa B axis through two distinct domains in the cytoplasmic C-terminus of the protein, namely CTAR1 (aa 187-231) and CTAR2 (aa 351-386), Whilst this effect is responsible for some of the functional consequences of LMP1 expression, additional LMP1-mediated signalling pathways may exist which contribute to the pleiotropic activities of this protein, In this study me provide evidence of a kinase cascade being activated by LMP1. Thus, we demonstrate that stable or transient expression of the LMP1 prototype from B95.8 in cells of epithelial or B cell origin activates the c-Jun N-terminal kinase (JNK, also known as the stress-activated protein kinase, SAPK) pathway, an effect which was found to be mediated through CTAR2 but not CTAR1, LMP1 from the Cao viral strain or LMP1 homologoues from the simian EBV naturally infecting baboons and rhesus monkeys were also able to activate JNK, This phenomenon translates to induction of AP-1, a transcription factor which is readily activated by growth factors and mitogens, Interestingly, an LMP1/CD40 chimaera comprising of the N-terminus and transmembrane domain of LMP1 and the cytoplasmic tail of CD40 which shares a common TRAF binding motif with CTAR1, effectively induced JNK, As NF-kappa B and JNK are co-activated in LMP1-expressing cells, we investigated whether the two pathways are overlapping or independent, We have found that inhibition of NF-kappa B by metabolic inhibitors or a constitutively active mutated I kappa-B alpha does not impair the ability of LMP1 to signal on the JNK axis, Conversely, whilst a dominant negative mutated SEK (JNKK) inhibited LMP1-induced JNK activation, it did not affect NF-kappa B suggesting that these two LMP1-mediated pathways are divergent.