Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry
Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry
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肝配蛋白受体 A2 是 Epstein-Barr 病毒进入的上皮细胞受体。
DOI：
10.1038/s41564-017-0080-8
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发表时间：
2018-02-01
影响因子：
28.3
通讯作者：
Zeng, Mu-Sheng
中科院分区：
文献类型：
--
作者：
Zhang, Hua;Li, Yan;Zeng, Mu-Sheng
EB病毒（EBV）与鼻咽癌、10%的胃癌和各种B细胞淋巴瘤有因果关系（1）。EBV感染B细胞和上皮细胞（2）。最近，我们报道表皮生长因子和神经纤毛蛋白1显著增强EBV进入鼻咽上皮细胞（3）。然而，关于EBV如何感染上皮细胞的知识仍然不完整。为了了解EBV感染上皮细胞的机制，我们整合了微阵列和RNA干扰筛选分析，发现Ephrin受体A2（EphA 2）对于EBV进入上皮细胞是重要的。EphA 2短干扰RNA敲除或CRISPR-Cas9敲除显著降低了EBV上皮细胞感染，这主要通过EphA 2互补DNA拯救来恢复。EphA 2过表达增加上皮细胞EBV感染。可溶性EphA 2蛋白、针对EphA 2的抗体、可溶性EphA 2配体EphrinA 1或EphA 2抑制剂2，5-二甲基吡咯基苯甲酸有效地阻断EBV上皮细胞感染。在机制上，EphA 2与EBV进入蛋白gH/gL和gB相互作用以促进EBV内化和融合。EphA 2 Ephrin结合结构域和纤连蛋白III型重复序列结构域是EphA 2介导的EBV感染所必需的，而胞内结构域是EphA 2介导的EBV感染所必需的。这与通过EphA 2的卡波西肉瘤相关疱疹病毒感染不同（4）。总之，我们的结果确定EphA 2作为EBV上皮细胞进入的关键球员。
Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma, 10% of gastric carcinoma and various B cell lymphomas(1). EBV infects both B cells and epithelial cells(2). Recently, we reported that epidermal growth factor and Neuropilin 1 markedly enhanced EBV entry into nasopharyngeal epithelial cells(3). However, knowledge of how EBV infects epithelial cells remains incomplete. To understand the mechanisms through which EBV infects epithelial cells, we integrated microarray and RNA interference screen analyses and found that Ephrin receptor A2 (EphA2) is important for EBV entry into the epithelial cells. EphA2 short interfering RNA knockdown or CRISPR-Cas9 knockout markedly reduced EBV epithelial cell infection, which was mostly restored by EphA2 complementary DNA rescue. EphA2 overexpression increased epithelial cell EBV infection. Soluble EphA2 protein, antibodies against EphA2, soluble EphA2 ligand EphrinA1, or the EphA2 inhibitor 2,5-dimethylpyrrolyl benzoic acid efficiently blocked EBV epithelial cell infection. Mechanistically, EphA2 interacted with EBV entry proteins gH/gL and gB to facilitate EBV internalization and fusion. The EphA2 Ephrin-binding domain and fibronectin type III repeats domain were essential for EphA2-mediated EBV infection, while the intracellular domain was dispensable. This is distinct from Kaposi's sarcoma-associated herpesvirus infection through EphA2(4). Taken together, our results identify EphA2 as a critical player for EBV epithelial cell entry.