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

• 成果类型: Article
• 署名作者: Li, Yan; Zhang, Hua; Sun, Cong; Dong, Xiao-Dong; Xie, Chu; Liu, Yuan-Tao; Lin, Ruo-Bin; Kong, Xiang-Wei; Hu, Zhu-Long; Ma, Xiao-Yan; Dai, Dan-Ling; Zhu, Qian-Ying; Li, Yu-Chun; Li, Ying; Liu, Shang-Xin; Yuan, Li; Zhou, Peng-Hui; Gao, Song; Tang, Ya-Ping; Yang, Jin-Ying; Han, Ping; McGuire, Andrew T.; Zhao, Bo; Bei, Jin-Xin; Robertson, Erle; Zeng, Yi-Xin; Zhong, Qian; Zeng, Mu-Sheng
• 署名单位: State Key Lab Oncology South China; Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; Guangzhou Medical University; Sun Yat Sen University; Fred Hutchinson Cancer Center; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Pennsylvania; Sun Yat Sen University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3092
• DOI: 10.1038/s41586-025-09166-w
• 发表日期: 2025-08-07
• 关键词: epstein-barr-virus; protein; identification; replication; expression; EXISTENCE; TOPOLOGY; fusion; gp42; a2

摘要

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.