Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability
Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability
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DOI：
10.1016/j.virol.2006.10.046
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发表时间：
2007-04-10
期刊：
影响因子：
3.7
通讯作者：
Longnecker, Richard
中科院分区：
文献类型：
--
作者：
Ikeda, Masato;Longnecker, Richard
EB病毒潜伏膜蛋白2 A(LMP2 A)通过功能模拟B细胞受体(BCR)诱导的信号改变正常B细胞的发育，在调节病毒潜伏期和EBV致病过程中发挥关键作用。LMP2A与Nedd4家族泛素蛋白连接酶结合，通过泛素化LMP2A和LMP2A相关蛋白酪氨酸激酶(PTKs)下调LMP2A的活性。由于特定的泛素标签为运输到膜小泡的质膜蛋白提供了内吞的分选信号，我们研究了LMP2A的定位和运输。我们发现LMP2A是通过外体，即小的内吞膜囊分泌的，就像以前对LMP1所证明的那样。有趣的是，用甲基-β-环糊精(MCD)处理细胞，可以从质膜中去除胆固醇，显著增加LMP2A的丰度和LMP2A外体的分泌。胆固醇耗竭也阻断了LMP2A的内吞作用，导致LMP2A在质膜上积聚。LMP2A的磷酸化和泛素化被胆固醇耗竭所阻断。胞外体部分中的LMP2A是泛素化的，而不是磷酸化的。这些结果表明，胆固醇依赖的LMP2A转运决定了LMP2A降解的命运。(C)2006 Elsevier Inc.保留所有权利。
Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) plays a key role in regulating viral latency and EBV pathogenesis by functionally mimicking signals induced by the B cell receptor (BCR) altering normal B cell development. LMP2A specifically associates with Nedd4 family ubiquitin-protein ligases which downmodulate LMP2A activity by ubiquitinating LMP2A and LMP2A-associated protein tyrosine kinases (PTKs). Since specific ubiquitin tags provide an endocytic sorting signal for plasma membrane proteins which traffic to membrane vesicles, we examined LMP2A localization and trafficking. We found that LMP2A is secreted through exosomes, small endocytic membrane vesicles, as previously demonstrated for LMP1. Interestingly, the treatment of cells with methyl-beta-cyclodextrin (MCD), which depletes cholesterol from plasma membrane, dramatically increased LMP2A abundance and LMP2A exosome secretion. Cholesterol depletion also blocked LMP2A endocytosis resulting in the accumulation of LMP2A on plasma membrane. LMP2A phosphorylation and ubiquitination were blocked by cholesterol depletion. LMP2A in the exosomal fraction was ubiquitinated but not phosphorylated. These results indicate that cholesterol-dependent LMP2A trafficking determines the fate of LMP2A degradation. (c) 2006 Elsevier Inc. All rights reserved.