R9AP is a common receptor for EBV infection in epithelial cells and B cells

作者：Yan Li, Hua Zhang, Cong Sun, Xiao-Dong Dong, Chu Xie, Yuan-Tao Liu, Ruo-Bin Lin, Xiang‐Wei Kong, Zhu-Long Hu, Xiao-Yan Ma, Dan‐Ling Dai, Qianying Zhu, Yuchun Li, Ying Li, Shang-Xin Liu, Yuan Li, Penghui Zhou, Song Gao, Ya‐Ping Tang, Jinying Yang, Ping Han, Andrew T. McGuire, Bo Zhao, Jin‐Xin Bei, Erle S. Robertson, Yi‐Xin Zeng, Qian Zhong, Mu‐Sheng Zeng · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09166-w · 被引用次数：25 · 研究领域：Viral-associated cancers and disorders、Lymphoma Diagnosis and Treatment、Immune Cell Function and Interaction

Epstein–Barr virus (EBV) persistently infects more than 90% of the human population, causing infectious mononucleosis1, susceptibility to autoimmune diseases2 and multiple malignancies of epithelial or B cell-origin3. EBV infects epithelial cells and B cells through interaction between viral glycoproteins and different host receptors4, but it has remained unknown whether a common receptor mediates infection of its two major host cell targets. Here, we establish R9AP as a crucial EBV receptor for entry into epithelial and B cells. R9AP silencing or knockout, R9AP-derived peptide and R9AP monoclonal antibody each significantly inhibit, whereas R9AP overexpression promotes, EBV uptake into both cell types. R9AP binds directly to the EBV glycoprotein gH/gL complex to initiate gH/gL–gB-mediated membrane fusion. Notably, the interaction of R9AP with gH/gL is inhibited by the highly competitive gH/gL-neutralizing antibody AMMO1, which blocks EBV epithelial and B cell entry. Moreover, R9AP mediates viral and cellular membrane fusion in cooperation with EBV gp42–human leukocyte antigen class II or gH/gL–EPHA2 complexes in B cells or epithelial cells, respectively. We propose R9AP as the crucial common receptor of B cells and epithelial cells and a potential prophylactic and vaccine target for EBV. R9AP is a key receptor for entry of Epstein–Barr virus into human epithelial and B cells, and interacts directly with the viral glycoprotein gH/gL complex to mediate virus–host membrane fusi...