Control of HBV replication at the step of core and P protein translation

在核心蛋白和 P 蛋白翻译步骤中控制 HBV 复制

基本信息

  • 批准号:
    8713932
  • 负责人:
  • 金额:
    $ 19.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-06 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV), which causes liver cirrhosis and hepatocellular carcinoma, has a small, compact genome. The only transcript required for genome replication is the 3.5-kb pregenomic (pg) RNA. It serves as the dicistronic mRNA for the translation of both core and P proteins, and also as the genome precursor to be encapsidated and converted by the P protein to double stranded DNA. Since a capsid is assembled from 240 copies of core protein but packages probably just one molecule of P protein, efficient genome replication requires a proper ratio of core / P protein translation. P protein translation involves ribosomal leaky scanning of upstream AUG codons including those of the core gene, but the control mechanisms remain ill defined. Genotype G harbors a unique 36-nt insertion at the 5' end of its core gene, which markedly enhances core protein translation whether in genotype G or when artificially introduced to other genotypes. This increase in core protein translation is rather associated with impaired genome replication in non-G genotypes, most likely due to a corresponding reduction in P protein translation. Paradoxically, deleting the 36nt from genotype G also impaired genome replication. We propose that the unique structural features of genotype G provide a window of opportunity to elucidate the control mechanisms regulating the translation of core vs. P protein. Aim 1 of this R21 grant application will verify the hypothesis that the insertion creates a hairpin structure downstream of core gene AUG to augment translation initiation. Aim 2 will validate a small open reading frame upstream of the core gene (the uORF) as a positive regulator of P protein translation. Aim 3 will investigate why genotype G harbors two nonsense mutations in the precore region. Besides pg RNA, HBV produces another 3.5-kb RNA with about 30-nt extension at the 5' end. This precore (pc) RNA is devoted exclusively to the translation of precore/core protein, the precursor to hepatitis B e antigen (HBeAg). The late stage of chronic HBV infection often selects for the G1896A nonsense mutation in the precore region to abolish HBeAg expression. Curiously, genotype G harbors an extra C1817T nonsense mutation at codon 2. We propose that C1817T enables translational re-initiation at the uORF instead of the core gene, thus redirecting the pc RNA towards P protein translation and rescuing genotype G replication despite the 36-nt insertion. Our studies will clarify translational control of core and P protein expression, and help understand how different HBV genetic variants avoid deviating from an optimal core/P protein ratio required for efficient genome replication.
描述(由申请人提供):导致肝硬化和肝细胞癌的B型肝炎病毒(HBV)基因组小而紧凑。基因组复制所需的唯一转录物是3.5 kb的前基因组(pg)RNA。它作为双顺反子mRNA翻译核心蛋白和P蛋白,也作为基因组前体被P蛋白包裹并转化为双链DNA。由于衣壳是由240个拷贝的核心蛋白组装而成,但包装可能只是一个P蛋白分子,因此有效的基因组复制需要适当的核心/ P蛋白翻译比例。P蛋白翻译涉及 核糖体泄漏扫描上游AUG密码子,包括那些核心基因,但控制机制仍然不明确。基因型G在其核心基因的5'端具有独特的36-nt插入,无论是在基因型G中还是当人工引入到其他基因型中时,其都显著增强核心蛋白的翻译。这种核心蛋白翻译的增加与非G基因型中受损的基因组复制有关,最有可能是由于P蛋白翻译的相应减少。奇怪的是,从基因型G中删除36个核苷酸也会损害基因组复制。我们建议,基因型G的独特结构特征提供了一个机会窗口,以阐明控制机制,调节核心与P蛋白的翻译。这项R21拨款申请的目的1将验证插入在核心基因AUG下游产生发夹结构以增强翻译起始的假设。目的2将验证核心基因上游的一个小的开放阅读框(uORF)作为P蛋白翻译的正调控因子。目的3将研究为什么基因型G在前C区有两个无义突变。除了pg RNA外,HBV还产生另一种3.5kb的RNA,在5'端有约30个核苷酸的延伸。这种前核心(pc)RNA专门用于翻译前核心/核心蛋白,即B e肝炎抗原(HBeAg)的前体。慢性HBV感染晚期常选择前C区G1896 A无义突变来消除HBeAg表达。奇怪的是,基因型G在密码子2处具有额外的C1817 T无义突变。我们提出C1817 T能够在uORF而不是核心基因处重新启动翻译,从而将pc RNA重定向到P蛋白翻译并挽救基因型G复制,尽管插入了36个核苷酸。我们的研究将阐明核心和P蛋白表达的翻译控制,并帮助了解不同的HBV遗传变异如何避免偏离有效基因组复制所需的最佳核心/P蛋白比例。

项目成果

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Jisu Li其他文献

Jisu Li的其他文献

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{{ truncateString('Jisu Li', 18)}}的其他基金

Explore hepatitis B virus preS2 mutants as immune escape mutants
探索乙型肝炎病毒preS2突变体作为免疫逃逸突变体
  • 批准号:
    10572374
  • 财政年份:
    2022
  • 资助金额:
    $ 19.88万
  • 项目类别:
Post-translational regulation of hepatitis B virus large envelope protein
乙型肝炎病毒大包膜蛋白的翻译后调控
  • 批准号:
    10414118
  • 财政年份:
    2021
  • 资助金额:
    $ 19.88万
  • 项目类别:
Post-translational regulation of hepatitis B virus large envelope protein
乙型肝炎病毒大包膜蛋白的翻译后调控
  • 批准号:
    10287803
  • 财政年份:
    2021
  • 资助金额:
    $ 19.88万
  • 项目类别:
Control of HBV replication at the step of core and P protein translation
在核心蛋白和 P 蛋白翻译步骤中控制 HBV 复制
  • 批准号:
    8571336
  • 财政年份:
    2013
  • 资助金额:
    $ 19.88万
  • 项目类别:
Molecular Target(s) for Interruption of HBV Infection
阻断 HBV 感染的分子靶点
  • 批准号:
    6925758
  • 财政年份:
    2005
  • 资助金额:
    $ 19.88万
  • 项目类别:
Molecular Target(s) for Interruption of HBV Infection
阻断 HBV 感染的分子靶点
  • 批准号:
    7363661
  • 财政年份:
    2005
  • 资助金额:
    $ 19.88万
  • 项目类别:
Molecular Target(s) for Interruption of HBV Infection
阻断 HBV 感染的分子靶点
  • 批准号:
    7568192
  • 财政年份:
    2005
  • 资助金额:
    $ 19.88万
  • 项目类别:
Molecular Target(s) for Interruption of HBV Infection
阻断 HBV 感染的分子靶点
  • 批准号:
    7215736
  • 财政年份:
    2005
  • 资助金额:
    $ 19.88万
  • 项目类别:
Molecular Target(s) for Interruption of HBV Infection
阻断 HBV 感染的分子靶点
  • 批准号:
    7054040
  • 财政年份:
    2005
  • 资助金额:
    $ 19.88万
  • 项目类别:
Hepatitis C virus core protein and cell proliferation
丙型肝炎病毒核心蛋白与细胞增殖
  • 批准号:
    6894837
  • 财政年份:
    2004
  • 资助金额:
    $ 19.88万
  • 项目类别:
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