PreS1BP mediates inhibition of Hepatitis B virus replication by promoting HBx protein degradation

被引:0
作者
Wang, Jun [1 ,2 ]
Yuan, Xiaoxue [2 ,3 ]
Wang, Yun [3 ]
Zhang, Yu [3 ]
Han, Ming [2 ,3 ]
Lu, Hongping [4 ]
Liu, Shunai [2 ,3 ]
Zhang, Yang [2 ]
Ge, Feilin [5 ]
Liu, Yan [6 ]
Cheng, Jun [1 ,4 ]
机构
[1] Peking Univ, Ditan Teaching Hosp, Beijing 100015, Peoples R China
[2] Capital Med Univ, Beijing Ditan Hosp, Inst Infect Dis, Beijing Key Lab Emerging Infect Dis, Beijing 100015, Peoples R China
[3] Capital Med Univ, Beijing Ditan Hosp, Div Liver Dis, Beijing 100015, Peoples R China
[4] Hebei Utu Pharmaceut Co Ltd, Shijiazhuang 052165, Hebei, Peoples R China
[5] Zhengzhou Univ, Dept Chinese Med, Affiliated Hosp 1, Zhengzhou 450052, Peoples R China
[6] Chinese Peoples Liberat Army Gen Hosp, Dept Infect Dis, Med Ctr 5, Beijing 100039, Peoples R China
基金
中国国家自然科学基金;
关键词
PreS1BP; Hepatitis B virus; HBx; Ubiquitination; X-PROTEIN; DNA; INFECTION; CELLS;
D O I
10.1016/j.virusres.2024.199326
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Background: PreS1-binding protein (PreS1BP), recognized as a nucleolar protein and tumor suppressor, influences the replication of various viruses, including vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1). Its role in hepatitis B virus (HBV) replication and the underlying mechanisms, however, remain elusive. Methods: We investigated PreS1BP expression levels in an HBV-replicating cell and animal model and analyzed the impact of its overexpression on viral replication metrics. HBV DNA, covalently closed circular DNA (cccDNA), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), and HBV RNA levels were assessed in HBV-expressing stable cell lines under varying PreS1BP conditions. Furthermore, coimmunoprecipitation and ubiquitination assays were used to detect PreS1BP- hepatitis B virus X protein (HBx) interactions and HBx stability modulated by PreS1BP. Results: Our study revealed a marked decrease in PreS1BP expression in the presence of active HBV replication. Functional assays showed that PreS1BP overexpression significantly inhibited HBV replication and transcription, evidenced by the reduction in HBV DNA, cccDNA, HBsAg, HBcAg, and HBV RNA levels. At the molecular level, PreS1BP facilitated the degradation of HBx in a dose-dependent fashion, whereas siRNA-mediated knockdown of PreS1BP led to an increase in HBx levels. Subsequent investigations uncovered that PreS1BP accelerated HBx protein degradation via K63-linked ubiquitination in a ubiquitin-proteasome system-dependent manner. Coimmunoprecipitation assays further established that PreS1BP enhances the recruitment of the proteasome 20S subunit alpha 3 (PSMA3) for interaction with HBx, thereby fostering its degradation. Conclusions: These findings unveil a previously unidentified mechanism wherein PreS1BP mediates HBx protein degradation through the ubiquitin-proteasome system, consequentially inhibiting HBV replication. This insight positions PreS1BP as a promising therapeutic target for future HBV interventions. Further studies are warranted to explore the clinical applicability of modulating PreS1BP in HBV therapy.
引用
收藏
页数:9
相关论文
共 36 条
  • [1] Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma
    Ali, Ashraf
    Abdel-Hafiz, Hany
    Suhail, Mohd
    Al-Mars, Amany
    Zakaria, Mohammad Khalid
    Fatima, Kaneez
    Ahmad, Sultan
    Azhar, Esam
    Chaudhary, Adeel
    Qadri, Ishtiaq
    [J]. WORLD JOURNAL OF GASTROENTEROLOGY, 2014, 20 (30) : 10238 - 10248
  • [2] Andrisani OM, 1999, INT J ONCOL, V15, P373
  • [3] Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function
    Belloni, Laura
    Pollicino, Teresa
    De Nicola, Francesca
    Guerrieri, Francesca
    Raffa, Giuseppina
    Fanciulli, Maurizio
    Raimondo, Giovanni
    Levrero, Massimo
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (47) : 19975 - 19979
  • [4] Berke JM, 2017, ANTIMICROB AGENTS CH, V61, DOI [10.1128/AAC.00560-17, 10.1128/aac.00560-17]
  • [5] Chromatin remodelling factor BAF155 protects hepatitis B virus X protein (HBx) from ubiquitin-independent proteasomal degradation
    Chen, Huijing
    Zhang, Yi
    Ye, Shuangshuang
    Wu, Qiong
    Lin, Youfen
    Sheng, Kaiqin
    Chen, Wannan
    Lin, Xinjian
    Lin, Xu
    [J]. EMERGING MICROBES & INFECTIONS, 2019, 8 (01) : 1393 - 1405
  • [6] Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx
    Cheng, Sheng-Tao
    Hu, Jie-Li
    Ren, Ji-Hua
    Yu, Hai-Bo
    Zhong, Shan
    Wong, Vincent Kam Wai
    Law, Betty Yuen Kwan
    Chen, Wei-Xian
    Xu, Hong-Mei
    Zhang, Zhen-Zhen
    Cai, Xue-Fei
    Hu, Yuan
    Zhang, Wen-Lu
    Long, Quan-Xin
    Ren, Fang
    Zhou, Hong-Zhong
    Huang, Ai-Long
    Chen, Juan
    [J]. JOURNAL OF HEPATOLOGY, 2021, 74 (03) : 522 - 534
  • [7] Chinese Patent Medicine Liuweiwuling Tablet had Potent Inhibitory Effects on Both Wild-Type and Entecavir-Resistant Hepatitis B Virus (HBV) in vitro and Effectively Suppressed HBV Replication in Mouse Model
    Ge, Fei-lin
    Si, Lan-lan
    Yang, Yan
    Li, Yuan-hua
    Lv, Zhong-lin
    Liu, Wen-hui
    Liao, Hao
    Wang, Jun
    Zou, Jun
    Li, Le
    Li, Hui
    Zhang, Zi-lin
    Wang, Jia-bo
    Lu, Xue-chun
    Xu, Dong-ping
    Bai, Zhao-fang
    Liu, Yan
    Xiao, Xiao-he
    [J]. FRONTIERS IN PHARMACOLOGY, 2021, 12
  • [8] Current treatment guidelines of chronic hepatitis B: The role of nucleos(t)ide analogues and peginterferon
    Ghany, Marc G.
    [J]. BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, 2017, 31 (03) : 299 - 309
  • [9] Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: An intermediate of covalently closed circular DNA formation
    Guo, Haitao
    Jiang, Dong
    Zhou, Tianlun
    Cuconati, Andrea
    Block, Timothy M.
    Guo, Ju-Tao
    [J]. JOURNAL OF VIROLOGY, 2007, 81 (22) : 12472 - 12484
  • [10] Identification and characterization of avihepadnaviruses isolated from exotic anseriformes maintained in captivity
    Guo, HT
    Mason, WS
    Aldrich, CE
    Saputelli, JR
    Miller, DS
    Jilbert, AR
    Newbold, JE
    [J]. JOURNAL OF VIROLOGY, 2005, 79 (05) : 2729 - 2742