EBV nuclear antigen 1 hijacks DDX5/BZLF1 axis to facilitate viral lytic replication

Li Yang; Shuyu Xin; Shen Li; Pengfei Cao; Zeyu Sun; Mingjuan Jiang; Yujie Xin; Xiaoling Su; Jing Yang; Jianhong Lu

doi:10.1016/j.virs.2026.03.012

April 2026

. doi: 10.1016/j.virs.2026.03.012

Citation: Li Yang, Shuyu Xin, Shen Li, Pengfei Cao, Zeyu Sun, Mingjuan Jiang, Yujie Xin, Xiaoling Su, Jing Yang, Jianhong Lu. EBV nuclear antigen 1 hijacks DDX5/BZLF1 axis to facilitate viral lytic replication .VIROLOGICA SINICA, 2026, 41(2) : 314-328. http://dx.doi.org/10.1016/j.virs.2026.03.012

EBV核抗原1通过劫持DDX5/BZLF1轴促进病毒裂解复制

杨丽 ^a,b ,
辛舒雨 ^a,b ,
李燊 ^a,b ,
曹鹏飞 ^b ,
孙泽宇 ^c ,
蒋明娟 ^a,b ,
辛玉洁 ^a,b ,
苏小玲 ^c ,
杨静 ^a,b ,
卢建红 ^a,b,d,,

a 医学微生物学系, 湘雅基础医学院, 中南大学, 长沙 410013, 中国;
b 癌变与侵袭原理教育部重点实验室, 卫生部癌变原理重点实验室, 中南大学, 长沙 410078, 中国;
c 传染病重症诊治全国重点实验室, 国家传染病临床医学研究中心, 附属第一医院, 医学院, 浙江大学, 杭州 310003, 中国;
d 微生物学系, 基础医学院, 新疆医科大学, 乌鲁木齐 830017, 中国

通讯作者： 卢建红, jianhlu@csu.edu.cn
收稿日期： 2025-12-17
录用日期： 2026-03-25

摘要

EBV的裂解性复制是上皮恶性肿瘤（如鼻咽癌和胃癌）中病毒传播和致瘤性的关键驱动因素。然而，其潜在的分子机制和有效的治疗策略仍知之甚少。本研究分析了 EBV 核抗原 1（EBNA1）的互作蛋白组，并鉴定出DEAD-box解旋酶5（DDX5）为其新的互作分子。EBNA1的N端区域（第1-88位氨基酸）和DDX5的C端结构域对于两者的结合至关重要。EBNA1通过阻碍 DDX5 K48连接的多聚泛素化介导蛋白酶体降解，从而稳定DDX5蛋白，并促进EBV的裂解复制。此外，DDX5结合于BZLF1（EBV再激活的关键开关）的启动子上，从而反式激活BZLF1以促进病毒的裂解复制。另外，小分子抑制剂 FL118 能够通过促进 DDX5 的降解来阻碍这一过程，揭示了FL118作为一种新型抗病毒药物的潜力。本研究的发现确立了 EBNA1/DDX5/BZLF1 这一新的功能轴，拓展了关于EBNA1在EBV生命周期调控，尤其是裂解性复制过程中作用的认识。该研究也为与 EBV 相关的上皮肿瘤提供了潜在的治疗策略。
- ZNF219
- , PEDV
- , TRAF6
- , P62
- , PEDV S2蛋白
- , 选择性自噬

EBV nuclear antigen 1 hijacks DDX5/BZLF1 axis to facilitate viral lytic replication

Li Yang ^a,b ,
Shuyu Xin ^a,b ,
Shen Li ^a,b ,
Pengfei Cao ^b ,
Zeyu Sun ^c ,
Mingjuan Jiang ^a,b ,
Yujie Xin ^a,b ,
Xiaoling Su ^c ,
Jing Yang ^a,b ,
Jianhong Lu ^a,b,d,,

a. Department of Medical Microbiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha 410013, China;
b. Key Laboratory of Cancer Carcinogenesis and Invasion of Chinese Ministry of Education, NHC Key Laboratory of Carcinogenesis, Central South University, Changsha 410078, China;
c. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China;
d. Department of Microbiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830017, China

Corresponding author: Jianhong Lu, jianhlu@csu.edu.cn
Received Date: 17 December 2025
Accepted Date: 25 March 2026

Abstract

Epstein-Barr virus (EBV) lytic replication is a key driver of viral dissemination and tumorigenicity in epithelial malignancies, such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). However, the underlying molecular mechanism and effective therapeutic strategy remain largely unknown. Here, we analyzed the EBV nuclear antigen 1 (EBNA1) interactome and identified DEAD-box helicase 5 (DDX5) as its novel partner. The N-terminal region (amino acids 1-88) of EBNA1 and the C-terminal domain of DDX5 were crucial for their binding. EBNA1 stabilized the DDX5 protein by impeding its proteasomal degradation via K48-linked polyubiquitin. EBNA1 facilitated EBV lytic replication in a DDX5-dependent manner. Furthermore, DDX5 bound to the promoter of BZLF1, which is the key switch of EBV reactivation, thus transactivating BZLF1 to drive viral lytic replication. Moreover, the small molecule inhibitor FL118 was able to disrupt this process by promoting DDX5 degradation, unveiling FL118 as a new potential antiviral drug. Our findings established a new functional axis of EBNA1/DDX5/BZLF1, adding to the knowledge about the role of EBNA1 in the regulation of EBV life cycle, particularly lytic replication. The study also provided a potential therapeutic strategy for EBV-associated epithelial tumors.
- Epstein-Barr virus (EBV)
- , Epstein-Barr virus nuclear antigen 1 (EBNA1)
- , Dead-box helicase 5 (DDX5)
- , FL118
- , Lytic replication

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