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Nuclear functions co-opted by human rhinovirus during replication in the cytoplasm of infected cells

人鼻病毒在受感染细胞的细胞质中复制过程中选择的核功能

基本信息

批准号：
10298555
负责人：
Paul D Gershon
金额：
$ 46.25万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-02 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298555
关键词：
Address Animal Diseases Antiviral Agents Antiviral Therapy Behavior Biogenesis Cell Line Cell Nucleus Cell physiology Cells Cellular biology Code Common Cold Complement Complex Coxsackie Viruses Cytoplasm Data Data Set Disease Drosophila genus Encephalitis Enterovirus Enterovirus 68 Enterovirus 71 Environment Eukaryota Family Family Picornaviridae Gene Expression Genes Hand, Foot and Mouth Disease Hela Cells Hepatitis Hepatitis A Virus Human Human poliovirus Infection Knowledge Lead Lung Mass Spectrum Analysis Messenger RNA Molecular Molecular Biology Morbidity - disease rate Myocarditis Nonstructural Protein Nuclear Nuclear Pore Nuclear Protein Nuclear Proteins Nuclear RNA Open Reading Frames Paralysed Pattern Peptide Hydrolases Play Poliomyelitis Polyadenylation Pre-mRNA Polyadenylation Factor Process Protein Analysis Protein Family Protein Splicing Proteins Proteome Publications Publishing RNA RNA Sequences RNA Splicing RNA Viruses RNA replication RNA-Binding Proteins Reporting Respiratory Tract Infections Rhinovirus Rhinovirus infection Role Series Structural Protein Structure Symptoms Therapeutic Translations Transport Process Validation Viral Viral Nonstructural Proteins Viral Proteins Virion Virus Virus Replication base cell type cohort experimental study genomic RNA human disease human morbidity insight member novel novel virus pathogen protein distribution protein expression respiratory respiratory virus trafficking transmission process viral RNA virus host interaction

项目摘要

Picornaviruses cause a wide range of significant human and animal diseases, including poliomyelitis, hepatitis, encephalitis, myocarditis, and the common cold. Since they are among the most genetically simple of all RNA viruses, members of the picornavirus family must usurp host cell functions and modify the cytoplasmic environment to facilitate viral translation, RNA replication, and virion biogenesis. Among the many ways that picornaviruses alter host cell functions is by re-localizing them from the nucleus to the cytoplasm where viral replication takes place. The nuclear versus cytoplasmic separation of the major processes that lead to the expression of protein-coding genes in eukaryotes requires a complex transport process that allows RNAs and proteins to move between these two cellular compartments. The Picornaviridae family is one of several virus families that disrupt the nucleo-cytoplasmic trafficking of cells to promote viral replication. Viral proliferation requires the activity of host RNA-binding proteins that normally function in cellular gene expression and are primarily localized to the nucleus. Picornaviruses alter nucleo-cytoplasmic trafficking to exploit these and other nuclear proteins that are subsequently delivered to the cytoplasm to facilitate efficient viral replication. Our recently-published analysis of the nuclear versus cytoplasmic proteome in human rhinovirus-infected cells has established the identities of a large cohort of nuclear proteins that re-localize to the cytoplasm during infection. In this application, state-of-the-art molecular and cell biology experiments are proposed to determine the functional significance of this protein redistribution on human rhinovirus replication, focusing on nuclear RNA binding proteins involved in mRNA splicing/processing and 3’ polyadenylation. A global analysis of protein distribution during rhinovirus infection of different human lung cell lines by quantitative mass spectrometry is also proposed to uncover novel virus-host interactions that may be respiratory cell-type specific. Results from these studies should reveal novel mechanistic insights into how a respiratory virus like human rhinovirus co-opts specific host nuclear functions and how these functions are altered or re-purposed for specific steps in viral replication. Detailed knowledge of such interactions, particularly at essential interfaces between host proteins and viral proteins and/or viral RNA sequences, promises to reveal new targets for antiviral therapies.

小核糖核酸病毒引起广泛的重大人类和动物疾病，包括脊髓灰质炎、肝炎、