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

• 批准号: 10684733
• 负责人: Paul D Gershon
• 金额: $ 46.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/10684733
• 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; Foot Diseases; Gene Expression; Genes; Hand' s disease; Hela Cells; Hepatitis; Hepatitis A Virus; Human; Human poliovirus; Infection; Knowledge; Lung; Mass Spectrum Analysis; Messenger RNA; Molecular; Molecular Biology; Morbidity - disease rate; Mouth Diseases; Myocarditis; Nonstructural Protein; Nuclear; Nuclear Pore; Nuclear Protein; Nuclear Proteins; Nuclear RNA; Open Reading Frames; Paralysed; Pattern; Peptide Hydrolases; Play; Poliomyelitis; Poly A; Polyadenylation; Pre-mRNA Polyadenylation Factor; Process; Proliferating; 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; Symptoms; Translations; Transport Process; Validation; Viral; Viral Nonstructural Proteins; Viral Proteins; Virion; Virus; Virus Replication; 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

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、 脑炎心肌炎和普通感冒因为它们是所有RNA中遗传最简单的 病毒，小核糖核酸病毒家族的成员必须篡夺宿主细胞的功能，并修改细胞质 在一些实施方案中，病毒载体可以是促进病毒翻译、RNA复制和病毒体生物发生的环境。在众多方式中， 小核糖核酸病毒改变宿主细胞功能的方法是将它们从细胞核重新定位到细胞质， 进行复制。细胞核与细胞质分离的主要过程，导致 真核生物中蛋白质编码基因的表达需要一个复杂的转运过程， 蛋白质在这两个细胞区室之间移动。小核糖核酸病毒科是几种病毒之一， 破坏细胞的核质运输以促进病毒复制的家族。病毒增殖 需要宿主RNA结合蛋白的活性，这些蛋白通常在细胞基因表达中起作用， 主要定位于细胞核。小核糖核酸病毒改变核质运输，以利用这些和其他 随后被递送到细胞质以促进有效的病毒复制的核蛋白。我们 最近发表的对人鼻病毒感染细胞中细胞核与细胞质蛋白质组的分析， 确定了在感染期间重新定位到细胞质的大量核蛋白的身份。 在本申请中，提出了最先进的分子和细胞生物学实验来确定细胞的生物学特性。 这种蛋白质重新分布对人鼻病毒复制的功能意义，重点是核RNA 参与mRNA剪接/加工和3'聚腺苷酸化的结合蛋白。蛋白质的全球分析 还通过定量质谱法测定了不同人肺细胞系在鼻病毒感染期间的分布， 提出揭示新的病毒-宿主相互作用，可能是呼吸道细胞类型特异性的。从这些 研究应该揭示呼吸道病毒（如人类鼻病毒）如何选择 特定的宿主核功能以及这些功能如何被改变或重新用于病毒感染的特定步骤。 复制的对这种相互作用的详细了解，特别是在宿主蛋白质之间的重要界面 以及病毒蛋白和/或病毒RNA序列，有望揭示抗病毒治疗的新靶点。