微生物与感染
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微生物与感染  2017, Vol. 12 Issue (3): 179-185    
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CRL4在增殖的肝细胞系中上调乙型肝炎病毒抗原的分泌表达
朱园飞1, 2,鱼康康2,邓强1, 2,高月求1
1. 上海中医药大学附属曙光医院细胞免疫研究室,上海 201203; 2. 中国科学院上海巴斯德研究所分子病毒与免疫重点实验室,上海 200032
CRL4 upregulates secretion of hepatitis B virus antigens in proliferating liver cell lines
ZHU Yuanfei1,2, YU Kangkang2, DENG Qiang1,2, GAO Yueqiu1
1.Laboratory of Cellular Immunity, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; 2. Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200032, China
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摘要: 乙型肝炎病毒(hepatitis B virus,HBV)编码的X蛋白(hepatitis B virus X protein,HBx)对HBV感染的起始和维持至关重要。HBx可能作为病毒来源的接头分子,介导Cullin-RING E3泛素连接酶4(cullin-RING ubiquitin E3 ligase 4,CRL4)复合物对染色体外DNA限制因子SMC5/6的降解。最近研究发现CRL4接头分子DNA损伤结合蛋白1(DNA damage-binding protein 1,DDB1)可不依赖与HBx的相互作用而直接上调病毒的表达和复制。本研究基于HBx基因删除(X-null)的HBV重组cccDNA(recombinant covalently closed circular DNA,rcccDNA)模型系统,在多种体外培养肝细胞系中证实上述发现。有意思的是,CRL4刺激rcccDNAX-null转染细胞抗原分泌表达的效应能被血清饥饿实验抵消。应用尾静脉高压注射小鼠模型,同样发现CRL4并不上调rcccDNAX-null在非增殖小鼠肝脏细胞中的表达。以上结果提示,细胞增殖特征与CRL4不依赖HBx上调病毒抗原表达的效应密切相关,有助于HBx生物学意义的准确分析和理解。

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朱园飞1
2
鱼康康2
邓强1
2
高月求1
关键词 乙型肝炎病毒乙型肝炎病毒X蛋白共价闭合环状DNACullin-RING E3泛素连接酶4细胞增殖    
Abstract:Hepatitis B virus (HBV) regulatory protein HBx is required to initiate and maintain productive virus replication. HBx is thought to achieve these functions by hijacking Cullin-RING ubiquitin E3 ligase 4 (CRL4) to target the SMC5/6 complex, a restriction factor for extrachromosomal viral DNA degradation. Studies also indicated that DNA damage-binding protein 1 (DDB1), an adaptor protein within CRL4 complex, may stimulate HBV transcription via a mechanism that does not involve an interaction with HBx. In the present study, using a model system of recombinant covalently closed circular DNA (rcccDNA) of HBV, it was confirmed that CRL4 could upregulate the secretion of HBV antigens in the absence of HBx (rcccDNAX-null) in cultured hepatoma cell lines. However, this effect of CRL4 was abolished by serum deprivation in the cell culture. In addition, it was found that CRL4 failed to stimulate the expression of rcccDNAX-null in non-proliferating hepatocytes in a mouse model with DNA hydrodynamic injection. Thus, the HBx-independent, CRL4-upregulated HBV expression is likely to be closely related to rapid proliferation of cultured hepatoma cell lines. The study thus revealed a previously unappreciated role of CRL4 in HBV virology, and would be helpful for better understanding of the biological significance of HBx.

Key wordsHepatitis B virus    Hepatitis B virus X protein    Covalently closed circular DNA    Cullin-RING ubiquitin E3 ligase 4    Cell proliferation
基金资助:国家自然科学基金(81471950、81672034),上海市科学技术委员会科研计划项目(16401970600)

通讯作者: 高月求,邓强   
引用本文:   
朱园飞1, 2,鱼康康2,邓强1, 2,高月求1. CRL4在增殖的肝细胞系中上调乙型肝炎病毒抗原的分泌表达[J]. 微生物与感染, 2017, 12(3): 179-185.
ZHU Yuanfei1,2, YU Kangkang2, DENG Qiang1,2, GAO Yueqiu1. CRL4 upregulates secretion of hepatitis B virus antigens in proliferating liver cell lines. JOURNAL OF MICROBES AND INFECTIONS, 2017, 12(3): 179-185.
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