HBV核心蛋白在细胞质，核和核仁室之间流动

StephenW

HBV Core Protein Is in Flux between Cytoplasmic, Nuclear, and Nucleolar Compartments
Smita Nair  1 , Adam Zlotnick  2
Affiliations
Affiliations

    1
    Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
    2
    Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA [email protected].

    PMID: 33563815 DOI: 10.1128/mBio.03514-20

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Abstract

Hepatitis B virus (HBV) core protein (Cp) can be found in the nucleus and cytoplasm of infected hepatocytes; however, it preferentially segregates to a specific compartment correlating with disease status. Regulation of this intracellular partitioning of Cp remains obscure. In this paper, we report that cellular compartments are filled and vacated by Cp in a time- and concentration-dependent manner in both transfections and infections. At early times after transfection, Cp, in a dimeric state, preferentially localizes to the nucleolus. Later, the nucleolar compartment is emptied and Cp progresses to being predominantly nuclear, with a large fraction of the protein in an assembled state. Nuclear localization is followed by cell-wide distribution, and then Cp becomes exclusively cytoplasmic. The same trend in Cp movement is seen during an infection. Putative nucleolar retention signals have been identified and appear to be structure dependent. Export of Cp from the nucleus involves the CRM1 exportin. Time-dependent flux can be recapitulated by modifying Cp concentration, suggesting transitions are regulated by reaching a threshold concentration.IMPORTANCE HBV is an endemic virus. More than 250 million people suffer from chronic HBV infection and about 800,000 die from HBV-associated disease each year. HBV is a pararetrovirus; in an infected cell, viral DNA in the nucleus is the template for viral RNA that is packaged in nascent viral capsids in the cytoplasm. Inside those capsids, while resident in cytoplasm, the linear viral RNA is reverse transcribed to form the circular double-stranded DNA (dsDNA) of the mature virus. The HBV core (or capsid) protein plays a role in almost every step of the viral life cycle. Here, we show the core protein appears to follow a programmed, sequential localization from cytoplasmic translation then into the nucleolus, to the nucleus, and back to the cytoplasm. Localization is primarily a function of time, core protein concentration, and assembly. This has important implications for our understanding of the mechanisms of antivirals that target HBV capsid assembly.

Keywords: CRM1; capsid; importin; nucleolar retention; nucleolin; virus assembly.

Copyright © 2021 Nair and Zlotnick.

StephenW

HBV核心蛋白在细胞质，核和核仁室之间流动
Smita Nair 1，Adam Zlotnick 2
隶属关系
隶属关系

    1个
    印第安纳大学，分子和细胞生物化学，美国印第安纳州布卢明顿。
    2
    印第安纳大学，分子和细胞生物化学，美国印第安纳州布卢明顿，azlotnic @ indiana.edu。

    PMID：33563815 DOI：10.1128 / mBio.03514-20

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抽象的

乙型肝炎病毒（HBV）核心蛋白（Cp）可以在感染的肝细胞的细胞核和细胞质中找到。但是，它优先隔离到与疾病状态相关的特定区域。 Cp的这种细胞内分配的调节仍然不清楚。在本文中，我们报道了在转染和感染中，Cp以时间和浓度依赖性的方式填充和腾出了细胞室。在转染后的早期，Cp以二聚体状态优先定位在核仁上。后来，核仁区被排空，Cp逐渐发展为主要为核，大部分蛋白质处于组装状态。核定位之后是全细胞分布，然后Cp变成仅胞质的。在感染期间，可以看到Cp运动的相同趋势。推定的核仁保留信号已被鉴定，并且似乎是结构依赖性的。从核中输出Cp涉及CRM1出口蛋白。可以通过改变Cp浓度来概括时间相关的通量，这表明转变可以通过达到阈值浓度来调节。每年有超过2.5亿人患有慢性HBV感染，每年约有80万人死于HBV相关疾病。乙肝病毒是一种副逆转录病毒。在被感染的细胞中，细胞核中的病毒DNA是病毒RNA的模板，包装在细胞质的新生病毒衣壳中。在这些衣壳内部，线性病毒RNA驻留在细胞质中时被逆转录，形成成熟病毒的环状双链DNA（dsDNA）。 HBV核心（或衣壳）蛋白几乎在病毒生命周期的每个步骤中都发挥着作用。在这里，我们显示核心蛋白似乎遵循从细胞质翻译到核仁，细胞核和细胞质的程序化，顺序定位。定位主要是时间，核心蛋白浓度和组装的函数。这对于我们对靶向HBV衣壳装配的抗病毒药物机制的理解具有重要意义。

关键字：CRM1；衣壳进口核仁保留核仁素病毒程序集。

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