R9AP is a common receptor for EBV infection in epithelial cells and B cells
Epstein-Barr virus (EBV) persistently infects more than 90% of the human population, causing infectious mononucleosis<sup>1</sup>, susceptibility to autoimmune diseases<sup>2</sup> and multiple malignancies of epithelial or B cell-origin<sup>3</sup>. EBV infects epithelial cells and B cells through interaction between viral glycoproteins and different host receptors<sup>4</sup>, 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.
Authors
- Yuchun Li (ORCID: https://orcid.org/0000-0001-5508-4721)
- Yuan-Tao Liu (ORCID: https://orcid.org/0000-0002-5071-9780)
- Dan‐Ling Dai
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Ping Han (ORCID: https://orcid.org/0000-0001-6097-7794)
- Yan Li (ORCID: https://orcid.org/0000-0002-4655-9577)
- Xiang‐Wei Kong
- Cong Sun (ORCID: https://orcid.org/0000-0003-1786-7420)
- Bo Zhao (ORCID: https://orcid.org/0000-0002-8612-5597)
- Erle S. Robertson (ORCID: https://orcid.org/0000-0002-6088-2979)
- Shang-Xin Liu
- Andrew T. McGuire (ORCID: https://orcid.org/0000-0003-1841-6859)
- Chu Xie (ORCID: https://orcid.org/0000-0003-1206-3124)
- Zhu-Long Hu
- Ya‐Ping Tang (ORCID: https://orcid.org/0000-0002-0445-4072)
- Qian Zhong (ORCID: https://orcid.org/0000-0003-1071-6996)
- Jinying Yang (ORCID: https://orcid.org/0000-0002-6063-9258)
- Jin‐Xin Bei (ORCID: https://orcid.org/0000-0003-1333-407X)
- Mu‐Sheng Zeng (ORCID: https://orcid.org/0000-0003-3509-5591)
- Ruo-Bin Lin
- Yi‐Xin Zeng (ORCID: https://orcid.org/0000-0002-6515-628X)
- Hua Zhang (ORCID: https://orcid.org/0000-0001-8180-5019)
- Ying Li (ORCID: https://orcid.org/0000-0002-1034-2077)
- Yuan Li (ORCID: https://orcid.org/0000-0001-7735-9255)
- Xiaoyan Ma
- Penghui Zhou (ORCID: https://orcid.org/0000-0003-0519-461X)
- Qianying Zhu (ORCID: https://orcid.org/0000-0003-3085-5467)
- Xiao-Dong Dong
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Sun Yat-sen University (CN)
- Fred Hutch Cancer Center (US)
- Sun Yat-sen Memorial Hospital (CN)
- Guangzhou Women and Children Medical Center (CN)
- Sun Yat-sen University Cancer Center (CN)
- Institute of Infection and Immunity (CA)
- University of Pennsylvania (US)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1038/s41586-025-09166-w
- Citations
- 10
- Primary Topic
- Viral-associated cancers and disorders
- Type
- article
- Field-Weighted Citation Impact
- 10.45