Mechanisms of selective host gene translation regulation in picornavirus infection

小核糖核酸病毒感染中选择性宿主基因翻译调控机制

基本信息

  • 批准号:
    RGPIN-2017-05612
  • 负责人:
  • 金额:
    $ 2.48万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2019
  • 资助国家:
    加拿大
  • 起止时间:
    2019-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

Picornaviral infection causes global shutdown of host gene translation but still maintains essential translation of certain host genes supporting viral replication. In the search for such host cellular mRNAs, the 5'TOP (terminal oligopyrimidine tract) mRNAs are candidates of interest. The 5'TOP motif is defined by a 7-methyl-G cap followed by a C and then a stretch of 4-15 CU at the 5' end of mRNA. The 5'TOP mRNAs (~30% of total cellular mRNAs) encode proteins of translational machinery such as ribosomal proteins and translation initiation and elongation factors. The presence of the 5'TOP motif within these mRNAs has previously been shown to cause its translation repression in conditions of cellular stress, such as starvation, radiation, and heat shock. Surprisingly, we recently found that cellular stress caused by infection of coxsackievirus B3 (CVB3), a member of picornavirus family, induced significantly enhanced expression of eukaryotic translation elongation factor 1A (eEF1A), a 5'TOP mRNA, at both the RNA and protein levels. We also found that this upregulation is parallel with increased viral protein synthesis. However, the underlying mechanism is unknown.****In this program, our Goal is to understand the relationship of selective translation of 5'TOP mRNAs and the enhanced viral infection to unravel the underlying mechanism by which CVB3 evolves to exploit the host gene expression machinery to its own benefit. We hypothesize that CVB3 infection upregulates the eEF1A expression, a 5'TOP mRNA, by epigenetic modification of gene promoter, activation of mTORC1 prosurvival signal pathway and recruiting trans-acting factor of 5'TOP motif; the upregulated eEF1A promotes CVB3 replication by specific interactions with viral RNA and proteins. We will use CVB3/eEF1A as an interaction pair for this study:****Aim 1: To elucidate the mechanism by which CVB3 infection upregulates eEF1A1 transcription.***1.1 To identify potential methylation changes of the eEF1A1 promoter which may enhance transcription.***1.2 To evaluate if upregulation of eEF1A1 transcription occurs via the mTORC1-SP1 signaling pathway.***Aim 2: To elucidate the mechanism by which CVB3 upregulates eEF1A1 translation.***2.1 To test if the first C residue at the 5'cap site enables 5'TOP mRNA binding to the cap-binding protein eEF4E.***2.2 To identify the trans-acting factors that initiate eEF1A1 5'TOP mRNA translation.***Aim 3: To determine the mechanism by which eEF1A1 promotes CVB3 replication.***3.1 To evaluate the potential interaction of eEF1A1 with CVB3 3'UTR and/or 3D RNA polymerase to support CVB3 RNA transcription.***3.2 To determine the potential interaction of eEF1A1 with CVB3 5'UTR to initiate CVB3 translation.***This program will reveal novel mechanisms by which picornavirus CVB3 subverts host machinery to promote viral replication. The results will have wide ranging impact on the fields of virology and gene regulation.**
小核糖核酸病毒感染导致宿主基因翻译的全局关闭,但仍维持某些支持病毒复制的宿主基因的基本翻译。在寻找这样的宿主细胞mrna时,5'TOP(末端寡聚嘧啶通道)mrna是感兴趣的候选者。5‘ top基序由一个7-甲基- g帽、一个C和mRNA 5’末端的一段4-15 CU组成。5'TOP mrna(约占细胞总mrna的30%)编码翻译机制的蛋白质,如核糖体蛋白和翻译起始因子和延伸因子。这些mrna中5'TOP基序的存在已经被证明在细胞应激条件下(如饥饿、辐射和热休克)导致其翻译抑制。令人惊讶的是,我们最近发现,感染柯萨奇病毒B3 (CVB3)引起的细胞应激,在RNA和蛋白质水平上诱导真核翻译延伸因子1A (eEF1A)的5'TOP mRNA的表达显著增强。柯萨奇病毒B3是小核糖核酸病毒家族的一员。我们还发现这种上调与病毒蛋白合成的增加是平行的。然而,其潜在机制尚不清楚。****在这个项目中,我们的目标是了解5'TOP mrna的选择性翻译与增强病毒感染的关系,以揭示CVB3进化利用宿主基因表达机制为自身利益的潜在机制。我们假设CVB3感染通过表观遗传修饰基因启动子,激活mTORC1促生存信号通路和募集5'TOP motif的反式作用因子,上调5'TOP mRNA eEF1A的表达;上调的eEF1A通过与病毒RNA和蛋白质的特异性相互作用促进CVB3复制。我们将使用CVB3/eEF1A作为本研究的相互作用对:****目的1:阐明CVB3感染上调eEF1A1转录的机制***1.1鉴定可能增强转录的eEF1A1启动子的潜在甲基化变化***1.2评估eEF1A1转录的上调是否通过mTORC1-SP1信号通路发生。***目的2:阐明CVB3上调eEF1A1翻译的机制***2.1检验5'cap位点的第一个C残基是否使5'TOP mRNA与帽结合蛋白eEF4E结合。***2.2鉴定启动eEF1A1 5'TOP mRNA翻译的反式作用因子。***目的3:确定eEF1A1促进CVB3复制的机制。***3.1评估eEF1A1与CVB3 3' utr和/或3D RNA聚合酶的潜在相互作用以支持CVB3 RNA转录。***3.2确定eEF1A1与CVB3 5'UTR的潜在相互作用以启动CVB3翻译。***该程序将揭示小核糖核酸病毒CVB3破坏宿主机制以促进病毒复制的新机制。这一结果将对病毒学和基因调控领域产生广泛的影响

项目成果

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Yang, Decheng其他文献

MiR-126 promotes coxsackievirus replication by mediating cross-talk of ERK1/2 and Wnt/β-catenin signal pathways
  • DOI:
    10.1007/s00018-013-1411-4
  • 发表时间:
    2013-12-01
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Ye, Xin;Hemida, Maged Gomaa;Yang, Decheng
  • 通讯作者:
    Yang, Decheng
Specific interaction of HeLa cell proteins with coxsackievirus B3 3′UTR:: La autoantigen binds the 3′ and 5′UTR independently of the poly(A) tail
  • DOI:
    10.1111/j.1462-5822.2007.00904.x
  • 发表时间:
    2007-07-01
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Cheung, Paul;Lim, Travis;Yang, Decheng
  • 通讯作者:
    Yang, Decheng
Role of Coxsackievirus B3-Induced Immune Responses in the Transition from Myocarditis to Dilated Cardiomyopathy and Heart Failure.
Inhibition of coxsackievirus B3 in cell cultures and in mice by peptide-conjugated morpholino oligomers targeting the internal ribosome entry site
  • DOI:
    10.1128/jvi.00900-06
  • 发表时间:
    2006-12-01
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Yuan, Ji;Stein, David A.;Yang, Decheng
  • 通讯作者:
    Yang, Decheng
Identification of a conserved linear epitope on the VP1 protein of serotype O foot-and-mouth disease virus by neutralising monoclonal antibody 8E8
  • DOI:
    10.1016/j.virusres.2010.10.024
  • 发表时间:
    2011-01-01
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Yang, Decheng;Zhang, Chunyuan;Yu, Li
  • 通讯作者:
    Yu, Li

Yang, Decheng的其他文献

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{{ truncateString('Yang, Decheng', 18)}}的其他基金

Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2021
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2020
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2018
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2017
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual

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新型M4受体选择性拮抗剂的研究
  • 批准号:
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Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2021
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2020
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2018
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
Mechanisms of selective host gene translation regulation in picornavirus infection
小核糖核酸病毒感染中选择性宿主基因翻译调控机制
  • 批准号:
    RGPIN-2017-05612
  • 财政年份:
    2017
  • 资助金额:
    $ 2.48万
  • 项目类别:
    Discovery Grants Program - Individual
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MUC5B 在健康和疾病期间对肺巨噬细胞编程的机制
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    9750783
  • 财政年份:
    2016
  • 资助金额:
    $ 2.48万
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Mechanisms of lung macrophage programming by MUC5B during health and disease
MUC5B 在健康和疾病期间对肺巨噬细胞编程的机制
  • 批准号:
    9177013
  • 财政年份:
    2016
  • 资助金额:
    $ 2.48万
  • 项目类别:
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内脏过敏的脊髓小胶质细胞机制
  • 批准号:
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急慢性病毒感染过程中CD8 T细胞凋亡机制
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  • 财政年份:
    2010
  • 资助金额:
    $ 2.48万
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Spinal Microglial Mechanisms of Visceral Hypersensitivity
内脏过敏的脊髓小胶质细胞机制
  • 批准号:
    7790438
  • 财政年份:
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  • 资助金额:
    $ 2.48万
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SELECTIVE MECHANISMS MAINTAINING H-2 POLYMORPHISMS
维持 H-2 多态性的选择性机制
  • 批准号:
    2444678
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