Roles of host RNA binding proteins in virus replication

描述：正链RNA病毒对人类健康构成重大威胁，对农业造成重大损失，严重依赖宿主因素在感染细胞中复制。由于缺乏易处理的病毒宿主系统，目前对被破坏的宿主因子在病毒复制中的作用知之甚少。为了快速了解病毒复制过程中病毒与宿主之间的相互作用，研究人员开发了功能强大的番茄丛状矮化病毒(TBSV)-酵母模型系统，该系统导致识别出许多影响病毒复制的宿主因素。这项应用旨在剖析三种RNA结合宿主蛋白的作用：甘油醛-3-磷酸脱氢酶(GAPDH)、p68死盒RNA解旋酶同源物Dpb2和翻译延伸因子EF-1α(Tef1/2p)，所有这些蛋白都与TBSV RNA结合，并已知与丙型肝炎病毒、西尼罗河病毒、登革4型病毒和甲型肝炎病毒RNA相互作用，表明宿主因素在这些病毒的复制中可能发挥类似的作用。番茄病毒用于复制研究的优点有很多，包括(I)它们简单的基因组和强大的复制；(Ii)TBSV复制酶蛋白与重要病原体的蛋白质，如丙型肝炎病毒、西尼罗河病毒和其他黄病毒和鼠疫病毒的相似性；(Iii)研究人员实验室开发的体外复制试验的可用性；以及(Iv)研究人员开发的基于酵母的高效TBSV复制系统。此外，最近的全基因组筛查包括95%的酵母基因，确定了影响TBSV积累的宿主基因。基于这些进展，TBSV是研究宿主因子在真核宿主中病毒复制中的作用的优质模型系统。鉴于病毒复制在病毒致病机制中的核心作用，对参与病毒复制的宿主RNA结合蛋白的研究有望促进我们对病毒复制过程的理解，并导致发现新的抗病毒靶点。这些和类似的研究是迫切需要的，因为我们目前对涉及病毒复制和病毒发病机制的宿主因素的了解是不完整的。了解病毒-宿主相互作用和宿主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开发。研究人员开发的易于处理的体外和体内TBSV系统可能对其他不太容易听话的RNA病毒的研究有利。

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.