Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production
Activation of the p38 mitogen-activated protein kinase pathway by Epstein-Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production
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DOI：
10.1074/jbc.274.23.16085
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发表时间：
1999-06-04
影响因子：
4.8
通讯作者：
Young, LS
中科院分区：
文献类型：
--
作者：
Eliopoulos, AG;Gallagher, NJ;Young, LS
Epstein-Barr 病毒编码的潜伏膜蛋白 1 (LMP1) 是一种多效性蛋白，其活性包括对基因表达以及细胞转化、生长和死亡的影响。 LMP1 已被证明可诱导靶细胞中的核因子 (NF)-kappa B 和 c-Jun NH2 末端激酶/AP-1 活性，在本研究中，我们证明 LMP1 还参与 p38 丝裂原激活蛋白激酶级联反应，导致转录因子 ATF2 的激活。 LMP1 细胞质 COOH 末端的突变分析表明，p38 激活发生在肿瘤坏死因子受体相关因子 (TRAF) 相互作用、近膜 COOH 末端激活区 (CTAR)1 结构域（氨基酸 186-231）和极端肿瘤坏死因子受体相关死亡结构域 (TRADD) 结合 CTAR2 区域（氨基酸 351-386），因为 LMP1 还参与信号传导通过 CTAR1 和 CTAR2 的 NF-kappa B 轴，我们检查了这两条通路是否重叠或独立。我们发现高度特异性抑制剂 SB203580 对 p58 的抑制不会影响 NF-κ B 结合活性。相反，虽然代谢抑制剂 D609 模拟了 NF-κ B 的激活，但它并没有损害 LMP1 在 p38 轴上发出信号的能力，表明这两条 LMP1 介导的途径基本上是独立的。然而，信号的分歧必须发生在 TRAF2 的下游，因为 TRAF2 显性失活突变体阻断了 LMP1 诱导的 NF-kappa B 激活，也抑制了 p38 信号传导。此外，我们发现 p38 抑制显着损害了 LMP1 介导的白介素-g 和 -8 表达。因此，p38 可能在调节 LMP1 的至少一些多效性活性中发挥重要的协同作用。
The Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a pleiotropic protein the activities of which include effects on gene expression and cell transformation, growth, and death. LMP1 has been shown to induce nuclear factor (NF)-kappa B and c-Jun NH2-terminal kinase/AP-1 activities in target cells, and in this study we demonstrate that LMP1 also engages the p38 mitogen-activated protein kinase cascade, leading to activation of the transcription factor ATF2. Mutational analysis of the LMP1 cytoplasmic COOH terminus revealed that p38 activation occurs from both the tumor necrosis factor receptor-associated factor (TRAF)-interacting, membrane proximal COOH-terminal activating region (CTAR)1 domain (amino acids 186-231) and the extreme tumor necrosis factor receptor-associated death domain (TRADD) binding CTAR2 region (amino acids 351-386), Because LMP1 also engages signaling on the NF-kappa B axis through CTAR1 and CTAR2, we have examined whether these two pathways are overlapping or independent. We have found that inhibition of p58 by the highly specific inhibitor SB203580 did not affect NF-kappa B binding activity. Conversely, although the metabolic inhibitor D609 Mocked NF-kappa B activation, it did not impair the ability of LMP1 to signal on the p38 axis, suggesting that these two LMP1-mediated pathways are primarily independent. Divergence of signals must, however, occur downstream of TRAF2 as a dominant negative TRAF2 mutant that blocks LMP1-induced NF-kappa B activation also inhibited p38 signaling, In addition, we have found that p38 inhibition significantly impaired LMP1-mediated interleukin-g and -8 expression. Thus, p38 may play a significant cooperative role in regulating at least some of the pleiotropic activities of LMP1.