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:2020
- 资助国家:加拿大
- 起止时间:2020-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:
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面关闭,但仍维持某些支持病毒复制的宿主基因的必要翻译。在寻找这样的宿主细胞mRNA时,5 'TOP(末端寡嘧啶段)mRNA是感兴趣的候选者。5 'TOP基序由7-甲基-G帽、随后的C和随后在mRNA的5'末端的4-15个CU的延伸段限定。5 'TOP mRNA(约占总细胞mRNA的30%)编码翻译机制的蛋白质,如核糖体蛋白和翻译起始和延伸因子。这些mRNA中5 'TOP基序的存在先前已显示在细胞应激条件下(如饥饿、辐射和热休克)引起其翻译抑制。我们最近发现,柯萨奇病毒B3(coxsackievirusB 3,CVB 3)感染引起的细胞应激可诱导真核细胞翻译延伸因子1A(eEF 1A)在RNA和蛋白水平的表达显著增强。我们还发现,这种上调与病毒蛋白质合成增加平行。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的病毒感染的关系,以解开CVB 3进化以利用宿主基因表达机制为自己谋取利益的潜在机制。我们推测CVB 3感染通过基因启动子的表观遗传修饰、mTORC 1促生存信号通路的激活和募集5 'TOP基序的反式作用因子上调eEF 1A的表达;上调的eEF 1A通过与病毒RNA和蛋白质的特异性相互作用促进CVB 3的复制。我们将使用CVB 3/eEF 1A作为本研究的相互作用对:
目的1:阐明CVB 3感染上调eEF 1A 1转录的机制。
1.1确定eEF 1A 1启动子可能增强转录的潜在甲基化变化。
1.2评价eEF 1A 1转录是否通过mTORC 1-SP1信号通路上调。
目的2:阐明CVB 3上调eEF 1A 1翻译的机制。
2.1测试5 '帽位点的第一个C残基是否能够使5' TOP mRNA与帽结合蛋白eEF 4 E结合。
2.2鉴定启动eEF 1A 1 5 'TOP mRNA翻译的反式作用因子。
目的3:研究eEF 1A 1促进CVB 3复制的机制。
3.1评价eEF 1A 1与CVB 3 3 'UTR和/或3D RNA聚合酶的相互作用,以支持CVB 3 RNA转录。
3.2确定eEF 1A 1与CVB 3 5 'UTR的潜在相互作用以启动CVB 3翻译。
该计划将揭示小核糖核酸病毒CVB 3颠覆宿主机制以促进病毒复制的新机制。其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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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.
- DOI:
10.3390/ijms24097717 - 发表时间:
2023-04-23 - 期刊:
- 影响因子:5.6
- 作者:
Yip, Fione;Lai, Brian;Yang, Decheng - 通讯作者:
Yang, Decheng
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:2019
- 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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$ 2.48万 - 项目类别:
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