Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway
Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway
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DOI：
10.1038/sj.onc.1207120
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发表时间：
2003-10-23
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;Caamano, JH;Young, LS
致癌性爱泼斯坦-巴尔病毒（EBV）编码的潜伏感染膜蛋白1（LMP 1）组成型激活"经典" NF-κ B途径，其涉及IkappaB激酶（IKK）下游IkappaB α的磷酸化和降解。在这项研究中，我们表明，LMP1还促进蛋白酶体介导的p100 NF-κ B 2的蛋白水解，导致活性p52的产生，其与p65和RelB NF-κ B亚基复合物易位到细胞核。在nf-kb2（-/-）小鼠胚胎成纤维细胞中，LMP1诱导的NF-κ B反式激活减少，表明p100加工有助于LMP1介导的NF-κ B转录效应。这种途径可能在体内起作用，因为LMP1在原发性EBV阳性霍奇金淋巴瘤和鼻咽癌活检组织中的表达与p52的核积聚相关。有趣的是，虽然LMP1激活经典NF-κ B通路的能力在缺乏IKK γ/NEMO（IKK复合物的调节亚基）的细胞中受损，但p100加工仍不受影响。因此，在IKK γ缺失的情况下，p52发生核转位，而p65不发生核转位。这些数据表明，存在一种新的信号通路，调节LMP1表达细胞中的NF-κ B，从而可能在致癌转化和建立持续性EBV感染中发挥作用。
The oncogenic Epstein - Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the 'canonical' NF-kappaB pathway that involves the phosphorylation and degradation of IkappaBalpha downstream of the IkappaB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-kappaB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-kappaB subunits. LMP1-induced NF-kappaB transactivation is reduced in nf-kb2(-/-) mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-kappaB transcriptional effects. This pathway is likely to operate in vivo, as the expression of LMP1 in primary EBV-positive Hodgkin's lymphoma and nasopharyngeal carcinoma biopsies correlates with the nuclear accumulation of p52. Interestingly, while the ability of LMP1 to activate the canonical NF-kappaB pathway is impaired in cells lacking IKKgamma/NEMO, the regulatory subunit of the IKK complex, p100 processing remains unaffected. As a result, nuclear translocation of p52, but not p65, occurs in the absence of IKKgamma. These data point to the existence of a novel signalling pathway that regulates NF-kappaB in LMP1-expressingcells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.