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

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

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
Available online: 22 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

Electronic Supplementary Material

10.1016j.virs.2025.05.004-ESM.docx
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