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