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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKKa-dependent noncanonical NF-κB activation
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Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKKa-dependent noncanonical NF-κB activation

机译：EB病毒潜伏感染膜蛋白1 TRAF结合位点诱导NIK / IKKa依赖的非规范性NF-κB激活

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摘要

Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced NF-Κb activation is important for infected cell survival. LMP1 activates NF-Κb, in part, by engaging tumor necrosis factor (TNF) receptor-associated factors (TRAFs), which also mediate NF-Κb activation from LTβR and CD40. LTβR and CD40 activation of p100/NF-Κb2 is now known to be NIK/IKKα-dependent and IKKβ/IKKγ independent. In the experiments described here, we found that EBV LMP1 induced p100/NF-Κb2 processing in human lymphoblasts and HEK293 cells. LMP1-induced p100 processing was NIK/IKKα dependent and IKKβ/lKKγ independent. Furthermore, the LMP1 TRAF-binding site was required for p100 processing and p52 nuclear localization, whereas the LMP1 death domain-binding site was not. Moreover, the LMP1 TRAF-binding site preferentially caused RelB nuclear accumulation. In murine embryo fibroblasts (MEFs), IKKβ was essential for LMP1 up-regulation of macrophage inflammatory protein (MIP)-2, TNFα, I-TAC, ELC, MIG, and CXCR4 RNAs. Interestingly, in IKKα knockout MEFs, LMP1 hyperinduced MIP-2, TNFα, and I-TAC expression, consistent with a role for IKKα in down-modulating canonical IKKβ activation or its effects. In contrast, LMP1 failed to up-regulate CXCR4 and MIG RNA in IKKα knockout MEFs, indicating a dependence on noncanonical IKKα activation. Furthermore, LMP1 up-regulation of MIP-2 RNA in MEFs was both IKKβ- and IKKγ-dependent, whereas LMP1 up-regulation of MIG and I-TAC RNA was fully IKKγ independent. Thus, LMP1 induces typical canonical IKKβ IKKγ-dependent, atypical canonical IKKβ-dependent/IKKγ-independent, and noncanonical NIK/IKKα-dependent NF-Κb activations; NIK/IKKα-dependent NF-Κb activation is principally mediated by the LMP1 TRAF-binding site.
机译：爱泼斯坦-巴尔病毒（EBV）潜伏感染膜蛋白1（LMP1）诱导的NF-κb活化对于被感染的细胞存活很重要。 LMP1部分地通过参与肿瘤坏死因子（TNF）受体相关因子（TRAFs）激活NF-κb，该因子也介导LTβR和CD40激活NF-κb。现在已知p100 /NF-Κbb2的LTβR和CD40激活是NIK /IKKα依赖性和IKKβ/IKKγ依赖性的。在此处描述的实验中，我们发现EBV LMP1诱导了人类淋巴母细胞和HEK293细胞中的p100 /NF-κb2加工。 LMP1诱导的p100加工是NIK /IKKα依赖性和IKKβ/1KKγ依赖性的。此外，p100加工和p52核定位需要LMP1 TRAF结合位点，而LMP1死亡域结合位点则不是。此外，LMP1 TRAF结合位点优先引起RelB核积累。在鼠胚成纤维细胞（MEF）中，IKKβ对于巨噬细胞炎症蛋白（MIP）-2，TNFα，I-TAC，ELC，MIG和CXCR4 RNA的LMP1上调至关重要。有趣的是，在IKKα基因敲除的MEF中，LMP1过度诱导了MIP-2，TNFα和I-TAC表达，这与IKKα在下调规范性IKKβ激活或其作用中的作用一致。相反，LMP1不能上调IKKα基因敲除的MEF中的CXCR4和MIG RNA，表明对非规范性IKKα激活的依赖性。此外，MEF中MIP-2 RNA的LMP1上调既依赖IKKβ，也依赖IKKγ，而MIG和I-TAC RNA的LMP1上调完全不依赖IKKγ。因此，LMP1诱导典型的典型IKKβIKKγ依赖性，非典型典型IKKβ依赖性/IKKγ依赖性和非经典NIK /IKKα依赖性NF-κb激活。 NIK /IKKα依赖性的NF-κb激活主要是由LMP1 TRAF结合位点介导的。

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