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Ephrin receptor A2 is an epithelial cell receptor for Epstein-Barr virus entry.
Nature Microbiology ( IF 28.3 ) Pub Date : 2018-Feb-01 , DOI: 10.1038/s41564-017-0080-8
Hua Zhang , Yan Li , Hong-Bo Wang , Ao Zhang , Mei-Ling Chen , Zhi-Xin Fang , Xiao-Dong Dong , Shi-Bing Li , Yong Du , Dan Xiong , Jiang-Yi He , Man-Zhi Li , Yan-Min Liu , Ai-Jun Zhou , Qian Zhong , Yi-Xin Zeng , Elliott Kieff , Zhiqiang Zhang , Benjamin E. Gewurz , Bo Zhao , Mu-Sheng Zeng

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.

中文翻译:

Ephrin受体A2是Epstein-Barr病毒进入的上皮细胞受体。

爱泼斯坦-巴尔病毒(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,我们报道了表皮生长因子和Neuropilin 1明显增强了EBV进入鼻咽上皮细胞3的能力。。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(EphA2)对于EBV进入上皮细胞很重要。EphA2短干扰RNA敲低或CRISPR-Cas9敲除显着减少了EBV上皮细胞感染,这主要是通过EphA2互补DNA拯救得以恢复的。EphA2过表达增加上皮细胞EBV感染。可溶性EphA2蛋白,抗EphA2的抗体,可溶性EphA2配体EphrinA1或EphA2抑制剂2,5-二甲基吡咯基苯甲酸有效地阻止了EBV上皮细胞感染。从机理上讲,EphA2与EBV进入蛋白gH / gL和gB相互作用,以促进EBV内在化和融合。EphA2 Ephrin结合结构域和纤连蛋白III型重复结构域对于EphA2介导的EBV感染至关重要,而胞内结构域则是可有可无的。这与卡波济氏肉瘤相关的疱疹病毒通过EphA2感染不同4。两者合计,我们的结果确定EphA2是EBV上皮细胞进入的关键参与者。
更新日期:2018-01-01
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