Preferential translation of host cell factors by hantavirus nucleocapsid protein
Preferential translation of host cell factors by hantavirus nucleocapsid protein
批准号:
9292026
负责人:
Mohammad A Mir
金额:
$42.9万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-02-06 至 2021-07-31
关键词:
5&apos Untranslated RegionsAffinityAntiviral AgentsAntiviral ResponseApplications GrantsBindingBinding ProteinsBinding SitesBunyaviridaeCategoriesCellsComplexCytoplasmDataDimerizationDiseaseDrug DesignEnsureFamilyGene ExpressionGenetic TranslationGoalsGuanosine TriphosphateHantavirusHumanInfectionInitiator CodonInitiator tRNAIntegration Host FactorsInterruptionMediatingMessenger RNAMethionineMolecularNucleocapsid ProteinsOpen Reading FramesOrthobunyavirusPathogenesisPathway interactionsPeptide Initiation FactorsPhosphorylationPlayPopulationProtein BiosynthesisProteinsRNA VirusesRPS19 geneRegulationReportingRibosomal ProteinsRibosomesRoleTestingTherapeutic InterventionTranscriptTranslatingTranslationsTrinucleotide RepeatsUntranslated RegionsViralViral ProteinsVirusVirus ReplicationWestern Blottingaerosolizedbasedimergel electrophoresisinfected vector rodentinsightmembermutantnew therapeutic targetpathogenpreventprotein activationprotein kinase Rtranslational approachtwo-dimensional
中文摘要
摘要:汉坦病毒是布尼亚病毒科的成员,包膜呈阴性。
链RNA病毒和A类病原体通过
受感染啮齿动物宿主的雾化排泄物。汉坦病毒已经进化出一种独特的
优先翻译他们的mRNAs的翻译机制。这项优惠
翻译是由汉坦病毒核衣壳蛋白(N-蛋白)进行的,它
与mRNA5‘帽和核糖体蛋白S19(RPS19)特异性结合,RPS19是一种结构性的
40S核糖体亚基的组成部分。此外,一种三聚体N-蛋白质分子
特异性地与高度保守的三联体重复序列(UAGUAGUAG)结合
病毒mRNA5‘非编码区。我们的结果表明N蛋白相关的核糖体是
选择性负载病毒5‘端非编码区以促进病毒转录本的翻译
宿主细胞胞质,其中细胞转录竞争相同的翻译
机械设备。有趣的是,我们的初步数据显示,N-蛋白质介导的翻译
策略也支持某些宿主细胞因子由未知的
机制。利用多方面的实验途径,我们将确定其机制
通过N蛋白介导的翻译选择性地翻译某些宿主细胞的mRNAs
策略。我们将确定宿主细胞因子的优先翻译是否起到了
在病毒复制中的作用。作为抗病毒反应,宿主细胞暂时关闭宿主
翻译机器为病毒蛋白质的合成制造障碍。这
抗病毒反应是由蛋白激酶R(PKR)的激活触发的,PKR
使其下游靶基因eif2α磷酸化,导致翻译关停。我们的
初步结果表明,N-蛋白抑制病毒感染细胞中PKR的激活
确保在感染过程中持续合成病毒蛋白质。我们将测试
N蛋白需要内源性宿主细胞因子辅助的假说
抑制PKR抗病毒反应。这些研究将揭示治疗的新靶点。
汉坦病毒病的干预。
英文摘要
Abstract: Hantaviruses, members of the Bunyaviridae family are enveloped negative
strand RNA viruses and category A pathogens that are transmitted to humans through
aerosolized excreta of infected rodent hosts. Hantaviruses have evolved a unique
translation mechanism for the preferential translation of their mRNAs. This preferential
translation is carried out by hantavirus nucleocapsid protein (N-protein) which
specifically binds to the mRNA 5' cap and ribosomal protein S19 (RPS19), a structural
component of the 40S ribosomal subunit. In addition, a trimeric N-protein molecule
specifically binds to a highly conserved triplet repeat sequence (UAGUAGUAG) of the
viral mRNA 5' UTR. Our results suggest that N-protein associated ribosomes are
selectively loaded on viral mRNA 5' UTR to boost the translation of viral transcripts in the
host cell cytoplasm where cellular transcripts are competing for the same translation
machinery. Interestingly, our preliminary data shows that N-protein mediated translation
strategy also favors the translation of certain host cell factors by an unknown
mechanism. Using multifaceted experimental avenues we will determine the mechanism
for the selective translation of certain host cell mRNAs by N-protein mediated translation
strategy. We will determine whether preferential translation of host cell factors plays a
role in virus replication. As antiviral response, host cells transiently shutdown the host
translation machinery to create roadblocks for the synthesis of viral proteins. This
antiviral response is triggered by the activation of protein kinase R (PKR), which
phosphorylates its downstream target eIF2α, causing translational shutdown. Our
preliminary results show that N-protein inhibits PKR activation in virus-infected cells to
ensure continuous synthesis of viral proteins during the course of infection. We will test
the hypothesis that N-protein requires the assistance from endogenous host cell factors
to inhibit PKR antiviral response. These studies will reveal new targets for therapeutic
intervention of hantavirus disease.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1371/journal.ppat.1010007
发表时间:
2021-10
期刊:
PLoS pathogens
影响因子:
6.7
作者:
[Wang Z, Ren S, Li Q, Royster AD, Lin L, Liu S, Ganaie SS, Qiu J, Mir S, Mir MA]
通讯作者:
Mir MA
Demonstrating the mechanism of Nairovirus translation strategy
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批准号:10291623
-
项目类别:
-
资助金额:$42.3万
-
财政年份:2021
-
负责人:Mohammad A Mir
-
依托单位:
Characterization of hantavirus N protein-mediated translation mechanism
-
批准号:8218779
-
项目类别:
-
资助金额:$18.88万
-
财政年份:2012
-
负责人:Mohammad A Mir
-
依托单位:
Characterization of hantavirus N protein-mediated translation mechanism
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批准号:8424961
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项目类别:
-
资助金额:$22.65万
-
财政年份:2012
-
负责人:Mohammad A Mir
-
依托单位:
Identification and characterization of inhibitors for hantavirus replication
-
批准号:8309019
-
项目类别:
-
资助金额:$37.35万
-
财政年份:2011
-
负责人:Mohammad A Mir
-
依托单位:
Identification and characterization of inhibitors for hantavirus replication
-
批准号:8508844
-
项目类别:
-
资助金额:$35.3万
-
财政年份:2011
-
负责人:Mohammad A Mir
-
依托单位:
Identification and characterization of inhibitors for hantavirus replication
-
批准号:8150134
-
项目类别:
-
资助金额:$38.63万
-
财政年份:2011
-
负责人:Mohammad A Mir
-
依托单位:
MECHANICS OF HANTAVIRAL NUCLEOCAPSID PROTEIN MEDIATED TRANSLATION INITIATION OF
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批准号:8168405
-
项目类别:
-
资助金额:$31.35万
-
财政年份:2010
-
负责人:Mohammad A Mir
-
依托单位:
Role of Cellular P-bodies and Hantavirus Nucleocapsid Protein in Viral mRNA "cap
-
批准号:7701441
-
项目类别:
-
资助金额:$22.5万
-
财政年份:2009
-
负责人:Mohammad A Mir
-
依托单位:
Role of Cellular P-bodies and Hantavirus Nucleocapsid Protein in Viral mRNA "cap
-
批准号:7897814
-
项目类别:
-
资助金额:$18.75万
-
财政年份:2009
-
负责人:Mohammad A Mir
-
依托单位:
海外基金