Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation.
Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation.
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Epstein-Barr 病毒激活 F-box 蛋白 FBXO2，通过靶向糖蛋白 B 进行降解来限制病毒感染性
DOI：
10.1371/journal.ppat.1007208
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Feng L
中科院分区：
文献类型：
--
作者：
Zhang HJ;Tian J;Qi XK;Xiang T;He GP;Zhang H;Yu X;Zhang X;Zhao B;Feng QS;Chen MY;Zeng MS;Zeng YX;Feng L
EB病毒（Epstein-Barr virus，EBV）是一种与淋巴和上皮恶性肿瘤密切相关的人类肿瘤相关病毒，EBV糖蛋白B（gB）通过促进细胞间融合在病毒进入B细胞和上皮细胞中发挥重要作用。EBV gB仅被高甘露糖连接的N-聚糖修饰，主要定位于内质网（ER），质膜（PM）上的水平较低。然而，gB在宿主细胞内调节的机制在很大程度上是未知的。在这里，我们报告的F-盒蛋白2（FBXO 2），SCF泛素连接酶底物接头，优先结合高甘露糖聚糖和衰减EBV感染性靶向N-糖基化gB降解的鉴定。gB具有7个N-糖基化位点，FBXO 2通过其糖结合结构域直接与这些高甘露糖部分结合。这种相互作用通过泛素-蛋白酶体途径促进糖基化gB的降解。FBXO 2的消耗不仅稳定gB，而且促进其从ER到PM的运输，导致增强的膜融合和病毒进入。FBXO 2在上皮细胞中表达，但在B细胞中不表达，并且EBV感染上调FBXO 2水平。总之，我们的研究结果突出了gB的高甘露糖修饰的意义，并揭示了一种新的宿主防御机制，涉及糖蛋白稳态调节。
Epstein-Barr virus (EBV) is a human cancer-related virus closely associated with lymphoid and epithelial malignancies, and EBV glycoprotein B (gB) plays an essential role in viral entry into both B cells and epithelial cells by promoting cell-cell fusion. EBV gB is exclusively modified with high-mannose-linked N-glycans and primarily localizes to the endoplasmic reticulum (ER) with low levels on the plasma membrane (PM). However, the mechanism through which gB is regulated within host cells is largely unknown. Here, we report the identification of F-box only protein 2 (FBXO2), an SCF ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans and attenuates EBV infectivity by targeting N-glycosylated gB for degradation. gB possesses seven N-glycosylation sites, and FBXO2 directly binds to these high-mannose moieties through its sugar-binding domain. The interaction promotes the degradation of glycosylated gB via the ubiquitin-proteasome pathway. Depletion of FBXO2 not only stabilizes gB but also promotes its transport from the ER to the PM, resulting in enhanced membrane fusion and viral entry. FBXO2 is expressed in epithelial cells but not B cells, and EBV infection up-regulates FBXO2 levels. In summary, our findings highlight the significance of high-mannose modification of gB and reveal a novel host defense mechanism involving glycoprotein homeostasis regulation.