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Role of host cell protein TDP2 as VPg unlinkase during picornavirus replication

宿主细胞蛋白 TDP2 在小核糖核酸病毒复制过程中作为 VPg 解链酶的作用

基本信息

批准号：
8673983
负责人：
Bert L Semler
金额：
$ 35.74万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8673983
关键词：
Amino Acid Sequence Animals Antibodies Antiviral Response Area Biological Assay Cell Maturation Cell physiology Cells Cleaved cell Code Common Cold Complementary DNA Coxsackie Viruses DNA Repair Disease Dominant-Negative Mutation Enterovirus Enzymes Escherichia coli Family Family Picornaviridae Frequencies Genomics Goals Growth Hela Cells Hepatitis A Virus Human Human poliovirus In Vitro Infection Internal Ribosome Entry Site Kinetics Laboratories Mammalian Cell Mediating Molecular Biology Myocarditis Pathway interactions Peptides Picornaviridae Infections Poliomyelitis Polioviruses Polyproteins Property Protein Binding Protein Biosynthesis Proteins Public Health RNA RNA Interference RNA Viruses RNA replication Recombinants Regulation Research Rhinovirus Role Signal Transduction Therapeutic Transcriptional Regulation Translations Viral Viral Proteins Virion Virus Virus Receptors chemical synthesis health economics human disease novel public health relevance research study tyrosyl-DNA phosphodiesterase viral RNA virus host interaction

项目摘要

The goal of the proposed research is to uncover the roles(s) in viral replication of a host cell protein recently identified as being VPg unlinkase for the picornavirus family. Picornaviruses are small, positive-strand RNA viruses that cause a wide range of diseases in humans and animals, with significant health and economic repercussions. The importance of these viruses extends beyond their public health implications; as the first mammalian viruses discovered, the study of picornaviruses has had a major impact on viral molecular biology and led to important findings related to cellular receptors for viruses, infectious cDNAs for RNA viruses, internal ribosome entry site (IRES)-driven translation, anti-viral responses of mammalian cells, the maturation of proteins synthesized as polyprotein precursors, chemical synthesis of a virus, and a host of other important research areas. A major theme that has emerged during the last decade is how these viruses with a very limited coding capacity utilize and/or modify host cell functions to complete their replication cycles. One such function is the cellular activity, VPg unlinkase, that removes the small viral peptide (VPg) from the 5' end of picornavirus genomic RNAs by cleaving a protein-nucleotidyl bond prior to or after the onset of viral protein synthesis. The PI's laboratory has recently identified VPg unlinkase from HeLa cells as tyrosyl-DNA phosphodiesterase 2 (TDP2), a host enzyme involved in DNA repair, cell signaling, and transcriptional regulation. This proposal aims to characterize the activity of TDP2/VPg unlinkase in cells infected by enteroviruses (poliovirus or coxsackievirus) and by the closely related human rhinovirus to determine how viral replication is impacted when this activity is down-regulated during infection. The specific aims are: (i) Down-regulate TDP2/VPg unlinkase activity to define its function(s) in picornavirus replication, and (ii) Define the cellular relocalization pathway and protein-binding partners of TDP2/VPg unlinkase in picornavirus-infected cells. The proposed experimental plan will examine the hypothesis that picornaviruses employ TDP2/VPg unlinkase activity to regulate the fate of viral RNAs to carry out specific functions in translation, RNA replication, or assembly into infectious virus particles. Results from the proposed studies may reveal TDP2/VPg unlinkase activity as a novel target for anti-viral therapy directed at human rhinovirus, coxsackievirus, hepatitis A virus, and other picornaviruses responsible for significant human disease sequelae.

本研究的目的是揭示病毒在宿主细胞复制中的作用