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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媒传播的高传染性病毒性疾病，死亡率高