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, Qian-Ying Zhu, Yu-Chun Li, Ying Li, Shang-Xin Liu, Li Yuan, Peng-Hui Zhou, Song Gao, Ya-Ping Tang, Jin-Ying Yang, Ping Han, Andrew T. McGuire, Bo Zhao, Jin-Xin Bei, Erle Robertson, Yi-Xin Zeng, Qian Zhong () and Mu-Sheng Zeng ()
Additional contact information
Yan Li: Sun Yat-sen University Cancer Center
Hua Zhang: Sun Yat-sen University
Cong Sun: Sun Yat-sen University Cancer Center
Xiao-Dong Dong: Sun Yat-sen University Cancer Center
Chu Xie: Sun Yat-sen University Cancer Center
Yuan-Tao Liu: Sun Yat-sen University Cancer Center
Ruo-Bin Lin: Sun Yat-sen University Cancer Center
Xiang-Wei Kong: Sun Yat-sen University Cancer Center
Zhu-Long Hu: Sun Yat-sen University Cancer Center
Xiao-Yan Ma: Sun Yat-sen University Cancer Center
Dan-Ling Dai: Sun Yat-sen University Cancer Center
Qian-Ying Zhu: Sun Yat-sen University Cancer Center
Yu-Chun Li: Sun Yat-sen University
Ying Li: Sun Yat-sen University
Shang-Xin Liu: Sun Yat-sen University Cancer Center
Li Yuan: Sun Yat-sen University Cancer Center
Peng-Hui Zhou: Sun Yat-sen University Cancer Center
Song Gao: Sun Yat-sen University Cancer Center
Ya-Ping Tang: Guangzhou Medical University
Jin-Ying Yang: Guangzhou Medical University
Ping Han: Sun Yat-sen University
Andrew T. McGuire: Fred Hutchinson Cancer Research Center
Bo Zhao: Harvard Medical School
Jin-Xin Bei: Sun Yat-sen University Cancer Center
Erle Robertson: University of Pennsylvania
Yi-Xin Zeng: Sun Yat-sen University Cancer Center
Qian Zhong: Sun Yat-sen University Cancer Center
Mu-Sheng Zeng: Sun Yat-sen University Cancer Center

Nature, 2025, vol. 644, issue 8075, 205-213

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09166-w

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