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Demonstrating the mechanism of Nairovirus translation strategy

展示内罗病毒翻译策略的机制

基本信息

批准号：
10291623
负责人：
Mohammad A Mir
金额：
$ 42.3万
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：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291623
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Affinity Animals Base Pairing Binding Binding Proteins Binding Sites Black-legged Tick Blood Bunyavirales Category A pathogen Cells Chemicals Complex Crimean Hemorrhagic Fever Crimean-Congo Hemorrhagic Fever Virus Custom Data Development Disease Domestic Animals Engineering Fluorescence Future Genetic Translation Genome Glycoproteins Goals Head Human Individual Infection Internal Ribosome Entry Site Link Mediating Messenger RNA Molecular N Domain Nairovirus Nucleocapsid Proteins Nucleotides Open Reading Frames Patients Peptide Initiation Factors Poly(A) Tail Protein Biosynthesis Proteins Publishing RNA RNA Binding RNA Viruses RNA-Directed RNA Polymerase Randomized Regulation Reporter Reporting Research Proposals Ribosomes Role Structure Testing Therapeutic Intervention Therapeutic Monoclonal Antibodies Ticks Transcript Translations Untranslated Regions Viral Viral Genome Viral Load result Viral Proteins Virus Virus Diseases Virus Replication clinical translation mortality new therapeutic target novel outcome prediction tick population tick-borne translational approach transmission process vector

项目摘要

Abstract: Crimean Congo hemorrhagic fever is a tick born, highly contagious, viral illness with high mortality rates in humans. There is no treatment for this viral disease at present. We recently reported that Crimean Congo hemorrhagic fever virus nucleocapsid protein (CCHFV N protein) has two distinct RNA binding sites in the stalk and head domains. The RNA binding site located in the head domain non-specifically binds to the single strand RNA of viral or nonviral origin. However, the RNA binding site located in the stalk domain specifically binds to the double strand panhandle structure formed by the base pairing of highly conserved and complementary nucleotides at the 5’ and 3’ termini of the viral genome. Interestingly the viral mRNA 5’ UTR also folds into a panhandle-like secondary structure, which is also specifically recognized by the stalk domain of N protein. The interaction between N protein and viral mRNA 5’ UTR facilitates the translation of downstream open reading frame (ORF). The majority of eukaryotic mRNA translation is m7G cap dependent and is initiated by the assembly of eIF4F cap binding complex, composed of three initiation factors eIF4E, eIF4A and eIF4G. Our preliminary data shows that N protein mediated translation strategy does not require the assembly of eIF4F complex but the structural integrity of individual components of this complex is required for this viral translation mechanism. This published data suggests that CHFV N protein highly likely lures the host translation apparatus for the preferential translation of viral mRNA during the course of infection, to boost the translation of viral mRNA in the infected cell. We will use multifaceted experimental avenues to test the hypothesis that CCHFV N protein interacts with the components of eIF4F complex to selectively engage the 40S ribosomal subunits on the viral mRNA 5’ UTR. Since ribosome loading on mRNA is a critical rate limiting step in eukaryotic translation, CCHFV N protein likely helps the viral transcripts at this critical step by selectively engaging the host cell ribosomes on viral mRNA 5’ UTR. This selective ribosome loading likely helps viral transcripts by avoiding the competition from host cell transcripts for the same host translation machinery. We will determine whether CCHFV N protein mediated translation strategy selectively facilitates the translation of viral mRNA during the course of infection.

摘要：克里米亚刚果出血热是一种蜱虫性、高度传染性、病毒性疾病，死亡率高在人类中的比率。目前还没有治疗这种病毒性疾病的方法。我们最近报道了克里米亚刚果出血热病毒核衣壳蛋白（CCHFV N蛋白）在其细胞核中有两个不同的RNA结合位点，茎域和头域。位于头部结构域中的RNA结合位点非特异性地结合至单核苷酸。病毒或非病毒来源RNA链。然而，RNA结合位点特异性地位于茎结构域，与高度保守和保守的碱基配对形成的双链柄状结构结合在病毒基因组的5'和3'末端的互补核苷酸。有趣的是，也折叠成锅柄状二级结构，该结构也被 N蛋白。N蛋白和病毒mRNA 5' UTR之间的相互作用促进了下游转录因子的翻译。开放阅读框（ORF）。大多数真核生物mRNA翻译是m7G帽依赖性的，并且启动于通过组装eIF4F帽结合复合物，由eIF4E、eIF4A和eIF4G三个起始因子组成。我们的初步数据表明，N蛋白介导的翻译策略不需要eIF4F的组装复合物，但这种复合物的各个组分的结构完整性是这种病毒所必需的。翻译机制这一已发表的数据表明，CHFV N蛋白很可能诱导宿主翻译在感染过程中优先翻译病毒mRNA的装置，以促进病毒mRNA在受感染的细胞中。我们将使用多方面的实验途径来测试假设， CCHFV N蛋白与eIF4F复合物的组分相互作用以选择性地接合40S核糖体在病毒mRNA 5'UTR上的亚基。由于核糖体在mRNA上的加载是细胞增殖的关键限速步骤，真核翻译，CCHFV N蛋白可能通过选择性地帮助病毒转录在这个关键步骤接合病毒mRNA 5' UTR上的宿主细胞核糖体。这种选择性的核糖体装载可能有助于病毒通过避免来自宿主细胞转录本的竞争来获得相同的宿主翻译机制。我们将确定CCHFV N蛋白介导的翻译策略是否选择性地促进病毒mRNA在感染过程中。