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Preferential translation of host cell factors by hantavirus nucleocapsid protein

汉坦病毒核衣壳蛋白优先翻译宿主细胞因子

基本信息

批准号：
9292026
负责人：
Mohammad A Mir
金额：
$ 42.9万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-06 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292026
关键词：
5&apos Untranslated Regions Affinity Antiviral Agents Antiviral Response Applications Grants Binding Binding Proteins Binding Sites Bunyaviridae Categories Cells Complex Cytoplasm Data Dimerization Disease Drug Design Ensure Family Gene Expression Genetic Translation Goals Guanosine Triphosphate Hantavirus Human Infection Initiator Codon Initiator tRNA Integration Host Factors Interruption Mediating Messenger RNA Methionine Molecular Nucleocapsid Proteins Open Reading Frames Orthobunyavirus Pathogenesis Pathway interactions Peptide Initiation Factors Phosphorylation Play Population Protein Biosynthesis Proteins RNA Viruses RPS19 gene Regulation Reporting Ribosomal Proteins Ribosomes Role Testing Therapeutic Intervention Transcript Translating Translations Trinucleotide Repeats Untranslated Regions Viral Viral Proteins Virus Virus Replication Western Blotting aerosolized base dimer gel electrophoresis infected vector rodent insight member mutant new therapeutic target pathogen prevent protein activation protein kinase R translational approach two-dimensional

项目摘要

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.

摘要：汉坦病毒属布尼亚病毒科，包膜阴性链RNA病毒和A类病原体通过以下途径传播给人类被感染的啮齿类动物的排泄物被雾化。汉坦病毒进化出一种独特的它们的mRNA的优先翻译的翻译机制。这一优惠翻译由汉坦病毒核衣壳蛋白（N蛋白）进行，特异性结合mRNA 5'帽和核糖体蛋白S19（RPS 19）， 40 S核糖体亚基的组成部分。此外，三聚体N蛋白分子特异性地结合到高度保守的三联体重复序列（UAGUAGUAG），病毒mRNA 5' UTR。我们的研究结果表明，N蛋白相关核糖体是选择性地装载在病毒mRNA 5' UTR上，以促进病毒转录物在细胞中的翻译。宿主细胞质，其中细胞转录物竞争相同的翻译机械.有趣的是，我们的初步数据表明，N蛋白介导的翻译，这种策略也有利于某些宿主细胞因子被未知的机制使用多方面的实验途径，我们将确定机制用于通过N-蛋白介导的翻译选择性翻译某些宿主细胞mRNA 战略我们将确定宿主细胞因子的优先翻译是否起作用，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制，为病毒蛋白的合成制造障碍。这抗病毒反应是由蛋白激酶R（PKR）的激活触发的，磷酸化其下游靶eIF 2 α，导致翻译关闭。我们初步结果显示，N蛋白抑制病毒感染细胞中PKR的活化，确保病毒蛋白在感染过程中持续合成。我们将测试 N蛋白需要内源性宿主细胞因子的帮助的假说抑制PKR抗病毒反应。这些研究将揭示新的治疗靶点干预汉坦病毒病。