Roles of host RNA binding proteins in virus replication

宿主RNA结合蛋白在病毒复制中的作用

• 批准号: 7179793
• 负责人: PETER NAGY
• 金额: $ 17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179793
• 关键词: Affect; Agriculture; Animals; Antiviral Agents; Area; Binding; Biological Assay; Biological Models; Boxing; Cataloging; Catalogs; Cells; Complex; Dengue; Dengue Virus; Development; Disease; Drug Delivery Systems; EF-1alpha; Elongation Factor; Flavivirus; Gene Delivery; Genes; Genetic Recombination; Genome; Genomics; Glyceraldehyde-3-Phosphate Dehydrogenases; Health; Hepatitis A Virus; Hepatitis C virus; Homologous Gene; Human; In Vitro; Integration Host Factors; Knowledge; Laboratories; Lead; Oxidoreductase; Pestivirus; Plants; Play; Positioning Attribute; Proteins; Proteomics; RNA Binding; RNA Helicase; RNA Viruses; RNA replication; RNA-Binding Proteins; RNA-Directed RNA Polymerase; Replication-Associated Process; Research Personnel; Risk; Role; Site; System; Testing; Tomatoes; Tombusvirus; Translations; Viral; Viral Pathogenesis; Viral Physiology; Viral Vaccines; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; Yeast Model System; Yeasts; base; design; in vivo; inorganic phosphate; insight; novel; pathogen; replicase; research study; size; tomato bushy stunt virus; vector; viral RNA; virus host interaction

DESCRIPTION: Plus-stranded RNA viruses, which pose significant risks to human health and cause major losses for agriculture, depend heavily on host factors to replicate in infected cells. The roles of the subverted host factors in virus replication are currently poorly understood due to the lack of tractable virus-host systems. To advance rapidly our understanding of virus-host interactions during viral replication, the investigator has developed the powerful Tomato bushy stunt virus (TBSV)-yeast model system that led to the identification of numerous host factors affecting viral replication. This application is aimed at dissecting the roles of three RNA-binding host proteins: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the p68 DEAD-box RNA helicase homolog Dpb2 and translation elongation factor EF-1alpha (Tef1/2p), all of which bind to TBSV RNA and also known to interact with Hepatitis C virus, West Nile virus, dengue 4 virus and hepatitis A virus RNAs, suggesting that host factors might play similar roles in replication of these viruses. The advantages of tombusviruses for replication studies are numerous, including (i) their simple genomes and robust replication; (ii) similarity of TBSV replicase proteins to proteins of important pathogens, such as HCV, West Nile virus and other flaviviruses and pestiviruses; (iii) availability of in vitro replication assays developed in the Investigator's laboratory; and (iv) the development by the investigator of an efficient yeast-based TBSV replication system. In addition, a recent genome-wide screen including 95% of all yeast genes identified host genes that affected TBSV accumulation. Based on these advances, TBSV is a premium model system to study the roles of host factors in virus replication in eukaryotic hosts. Due to the central role of virus replication in viral pathogenesis, the proposed studies on host RNA-binding proteins involved in virus replication promise to advance our understanding of the viral replication process and to lead to identification of new antiviral targets. These and similar studies are needed urgently, because our current knowledge on host factors involved in virus replication and in viral pathogenesis is incomplete. Knowledge of virus-host interactions and the roles of host RNA-binding proteins might reveal new drug targets and lead to development of novel antiviral strategies. The tractable in vitro and in vivo TBSV system developed by the investigator could prove beneficial to studies of other, less amenable RNA viruses.

产品说明：正链RNA病毒严重依赖宿主因子在感染细胞中复制，对人类健康构成重大风险，并给农业造成重大损失。由于缺乏易处理的病毒-宿主系统，目前对破坏的宿主因子在病毒复制中的作用知之甚少。为了快速推进我们对病毒复制过程中病毒-宿主相互作用的理解，研究人员开发了强大的番茄丛矮病毒（TBSV）-酵母模型系统，该系统导致鉴定了许多影响病毒复制的宿主因素。本申请旨在剖析三种RNA结合宿主蛋白的作用：甘油醛-3-磷酸脱氢酶（GAPDH）、p68 DEAD盒RNA解旋酶同系物Dpb 2和翻译延伸因子EF-1 α（Tf 1/2 p），所有这些都与TBSV RNA结合，并且还已知与丙型肝炎病毒、西尼罗病毒、登革热4型病毒和甲型肝炎病毒RNA相互作用，表明宿主因子在这些病毒的复制中可能起类似的作用。用于复制研究的tombusviruses的优点很多，包括（i）其简单的基因组和稳健的复制;（ii）TBSV复制酶蛋白与重要病原体（例如HCV、西尼罗病毒和其他黄病毒和瘟病毒）的蛋白的相似性;（iii）在研究者的实验室中开发的体外复制测定的可用性;和（iv）研究者开发了有效的基于酵母的TBSV复制系统。此外，最近的全基因组筛选包括95%的所有酵母基因鉴定出影响TBSV积累的宿主基因。TBSV是研究宿主因子在病毒复制中作用的理想模型系统。由于病毒复制在病毒发病机制中的核心作用，对参与病毒复制的宿主RNA结合蛋白的拟议研究有望推进我们对病毒复制过程的理解，并导致新的抗病毒靶点的鉴定。这些和类似的研究是迫切需要的，因为我们目前对病毒复制和病毒发病机制中涉及的宿主因素的知识是不完整的。了解病毒与宿主的相互作用和宿主RNA结合蛋白的作用可能会揭示新的药物靶点，并导致新的抗病毒策略的发展。研究者开发的易处理的体外和体内TBSV系统可以证明对其他不太适合的RNA病毒的研究是有益的。