Host factor RBM25 promotes HBV replication through Yin Yang 1-mediated cccDNA transcription

Yukun Li; Tianhao Mao; Liwei Zheng; Zhao Zhou; Qianqian Jiang; Xinyu Du; Ziyuan Ma; Xin Liu; Ting Zhang; Guochao Wei; Lin Wang; Yongzhen Liu; Xiaojing Zhang; Shourong Liu; Xiangmei Chen; Fengmin Lu

doi:10.1016/j.virs.2025.05.004

June 2025

. doi: 10.1016/j.virs.2025.05.004

Citation: Yukun Li, Tianhao Mao, Liwei Zheng, Zhao Zhou, Qianqian Jiang, Xinyu Du, Ziyuan Ma, Xin Liu, Ting Zhang, Guochao Wei, Lin Wang, Yongzhen Liu, Xiaojing Zhang, Shourong Liu, Xiangmei Chen, Fengmin Lu. Host factor RBM25 promotes HBV replication through Yin Yang 1-mediated cccDNA transcription .VIROLOGICA SINICA, 2025, 40(3) : 374-387. http://dx.doi.org/10.1016/j.virs.2025.05.004

宿主因子RBM25通过YY1介导的cccDNA转录机制促进HBV复制

李玉坤 ^a ,
毛天皓 ^a ,
郑立威 ^a ,
周召 ^a ,
姜倩倩 ^b ,
杜欣雨 ^c ,
马子媛 ^d ,
刘新 ^a ,
张婷 ^a ,
魏国超 ^a ,
王麟 ^a ,
刘永振 ^e ,
张晓静 ^f ,
刘寿荣 ^f ,
陈香梅 ^a,, ,
鲁凤民 ^a,,

a 北京大学基础医学院, 病原生物学系暨感染病研究中心;
b 北京大学人民医院, 北京大学肝病研究所, 丙型肝炎和肝病免疫治疗北京市重点实验室, 非酒精性脂肪性肝病诊断北京市国际科技合作基地;
c 郑州大学精准医学中心, 医学科学院;
d 悉尼大学医学科学学院;
e 南京大学医学院, 模式动物研究所;
f 浙江中医药大学附属杭州西溪医院, 杭州西溪医院肝病科

通讯作者： 陈香梅, xm_chen6176@bjmu.edu.cn; 鲁凤民, lu.fengmin@hsc.pku.edu.cn
收稿日期： 2024-12-03
录用日期： 2025-05-20

摘要

乙型肝炎病毒 (HBV) 感染肝细胞中持续存在的共价闭合环状DNA (cccDNA) 是导致慢性乙肝(CHB)难以治愈的关键因素，阐明其转录调控机制对于开发新型治疗策略至关重要。本研究探讨了RBM25在HBV复制中的作用，并系统解析其与cccDNA的相互作用及其对宿主转录因子的调控机制。实验结果显示，在HBV复制和感染细胞模型中，敲减RBM25显著降低HBV DNA、乙型肝炎e抗原(HBeAg)、乙型肝炎表面抗原 (HBsAg)、HBV RNA以及L-HBs的表达水平。通过水压动力注射1.2×HBV质粒构建的HBV复制小鼠模型中也观察到一致的结果。相反，过表达RBM25则显著增强HBV复制。机制研究表明，RBM25通过其RE/RD和PWI结构域与cccDNA结合，并上调YY1的表达及其与cccDNA的结合能力。YY1进一步促进乙酰化组蛋白与cccDNA结合，从而激活HBV转录。此外，HBV core蛋白的积累可诱导RBM25表达上调及核定位，而RBM25的过表达则促进core蛋白的降解。综上，本研究证实宿主因子RBM25通过上调YY1表达促进cccDNA转录和病毒复制，同时揭示了HBV core蛋白与RBM25之间的相互调控作用可能是维持有效复制的潜在机制
- 乙型肝炎病毒
- , 共价闭合环状DNA
- , cccDNA转录
- , RNA结合基序蛋白25
- , 阴阳1
- , 乙酰化组蛋白

Host factor RBM25 promotes HBV replication through Yin Yang 1-mediated cccDNA transcription

Yukun Li ^a ,
Tianhao Mao ^a ,
Liwei Zheng ^a ,
Zhao Zhou ^a ,
Qianqian Jiang ^b ,
Xinyu Du ^c ,
Ziyuan Ma ^d ,
Xin Liu ^a ,
Ting Zhang ^a ,
Guochao Wei ^a ,
Lin Wang ^a ,
Yongzhen Liu ^e ,
Xiaojing Zhang ^f ,
Shourong Liu ^f ,
Xiangmei Chen ^a,, ,
Fengmin Lu ^a,,

a. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, 100191, China;
b. Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, 100044, China;
c. Precision Medicine Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, China;
d. School of Medical Sciences, University of Sydney, Sydney, NSW, 2050, Australia;
e. Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210061, China;
f. Department of Hepatology, Hangzhou Xixi Hospital, Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310023, China

Corresponding author: Xiangmei Chen, xm_chen6176@bjmu.edu.cn Fengmin Lu, lu.fengmin@hsc.pku.edu.cn
Received Date: 03 December 2024
Accepted Date: 20 May 2025

Abstract

The persistence of covalently closed circular DNA (cccDNA) in hepatitis B virus (HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment. Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies. In this study, we investigated the role of RNA binding motif protein 25 (RBM25) in HBV replication, focusing on its interaction with cccDNA and its regulation of host transcription factors. The results demonstrated that RBM25 knockdown markedly inhibited HBV replication, reducing levels of HBV DNA, hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV RNA, and L-HBs in HBV-replicating and infected cell models. Consistent results were observed in a mouse model hydrodynamically injected with 1.2 × HBV plasmid. Conversely, RBM25 overexpression significantly enhanced HBV replication. Mechanistically, RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains. This effect was mediated by increased Yin Yang 1 (YY1) expression, which enhanced acetylation of cccDNA-bound histones, promoting HBV transcription. Furthermore, RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation, while overexpression of RBM25 promoted core protein degradation. In conclusion, this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA. It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25, which helps sustain HBV replication.
- Hepatitis B virus (HBV)
- , Covalently closed circular DNA (cccDNA)
- , cccDNA transcription
- , RNA binding motif protein 25 (RBM25)
- , Yin Yang 1 (YY1)
- , Acetylated histones

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