PMID- 38297280 OWN - NLM STAT- MEDLINE DCOM- 20240202 LR - 20240625 IS - 1743-422X (Electronic) IS - 1743-422X (Linking) VI - 21 IP - 1 DP - 2024 Jan 31 TI - ZNF148 inhibits HBV replication by downregulating RXRalpha transcription. PG - 35 LID - 10.1186/s12985-024-02291-4 [doi] LID - 35 AB - BACKGROUND: Progressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study. METHODS: HepG2-Na(+)/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148's impact on HBV in vivo was investigated using an established rcccDNA mouse model. RESULTS: ZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRalpha) expression by binding to the RXRalpha promoter sequence. RXRalpha binding site mutation or RXRalpha overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model. CONCLUSIONS: ZNF148 inhibited HBV replication by downregulating RXRalpha transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies. CI - (c) 2024. The Author(s). FAU - Yao, Xinyan AU - Yao X AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Xu, Kexin AU - Xu K AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Tao, Nana AU - Tao N AD - Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China. AD - Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China. FAU - Cheng, Shengtao AU - Cheng S AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Chen, Huajian AU - Chen H AD - Department of Clinical Laboratory, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China. FAU - Zhang, Dapeng AU - Zhang D AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Yang, Minli AU - Yang M AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Tan, Ming AU - Tan M AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Yu, Haibo AU - Yu H AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Chen, Peng AU - Chen P AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Zhan, Zongzhu AU - Zhan Z AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - He, Siyi AU - He S AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Li, Ranran AU - Li R AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Wang, Chunduo AU - Wang C AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Wu, Daiqing AU - Wu D AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. DQWoo0611@163.com. FAU - Ren, Jihua AU - Ren J AD - The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chong Yi Building, 1 YiXueYuan Road, Yuzhong District, Chongqing, 400016, China. renjihua2016@cqmu.edu.cn. LA - eng GR - 2022YFA1303600/The National Key Research and Development Program of China/ GR - KJQN202100429/The Scientific and Technological Research Program of the Chongqing Municipal Education Commission/ GR - CSTB2022NSCQ-MSX0864/The Natural Science Foundation Project of Chongqing/ GR - W0040/Future Medical Youth Innovation Team of Chongqing Medical University/ PT - Journal Article DEP - 20240131 PL - England TA - Virol J JT - Virology journal JID - 101231645 RN - 0 (DNA, Viral) RN - 0 (Transcription Factors) RN - 0 (ZNF148 protein, human) RN - 0 (RXRA protein, human) SB - IM EIN - Virol J. 2024 Jun 25;21(1):145. doi: 10.1186/s12985-024-02420-z. PMID: 38918845 MH - Animals MH - Humans MH - Mice MH - DNA, Viral/genetics MH - Hep G2 Cells MH - *Hepatitis B MH - *Hepatitis B virus/physiology MH - Transcription Factors/genetics/metabolism MH - Virus Replication PMC - PMC10832224 OTO - NOTNLM OT - HBV OT - RXRalpha OT - Transcription factor OT - ZNF148 OT - cccDNA COIS- The authors declare no competing interests. EDAT- 2024/02/01 00:42 MHDA- 2024/02/02 06:43 PMCR- 2024/01/31 CRDT- 2024/01/31 23:43 PHST- 2023/11/23 00:00 [received] PHST- 2024/01/08 00:00 [accepted] PHST- 2024/02/02 06:43 [medline] PHST- 2024/02/01 00:42 [pubmed] PHST- 2024/01/31 23:43 [entrez] PHST- 2024/01/31 00:00 [pmc-release] AID - 10.1186/s12985-024-02291-4 [pii] AID - 2291 [pii] AID - 10.1186/s12985-024-02291-4 [doi] PST - epublish SO - Virol J. 2024 Jan 31;21(1):35. doi: 10.1186/s12985-024-02291-4.