Role of Deubiquitinases in CMV Pathogenesis

去泛素酶在 CMV 发病机制中的作用

• 批准号: 10730892
• 负责人: Jason W Upton
• 金额: $ 45.6万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730892
• 关键词: Acute; Address; Adult; Antiviral Agents; Biochemical; Biochemistry; Biological; Biological Assay; Biology; Candidate Disease Gene; Cell physiology; Cells; Child; Complex; Cytomegalovirus; Cytomegalovirus Infections; Data; Defect; Deubiquitinating Enzyme; Deubiquitination; Development; Disease; Endoplasmic Reticulum Degradation Pathway; Environment; Enzymes; Family; Genes; Glycoproteins; Goals; Health; Herpesviridae; Human; Immune response; Immunocompromised Host; In Vitro; Infection; Inflammation; Inflammatory Response; Innate Immune Response; Lead; Learning; Life Cycle Stages; Lysine; Modification; Molecular; Murid herpesvirus 1; Pathogenesis; Pathway interactions; Play; Post-Translational Protein Processing; Production; Proteins; Proteomics; Public Health; Quality Control; Research; Role; Route; Scientist; Signal Transduction Pathway; Site-Directed Mutagenesis; Specificity; Students; System; Testing; Therapeutic Intervention; Training; Training Support; Ubiquitin; Ubiquitination; Universities; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; chemokine; combat; enzyme activity; genetic approach; graduate student; human disease; in vivo; in vivo Model; insight; multidisciplinary; novel; novel strategies; protein transport; response; tool; trafficking; ubiquitin isopeptidase; ubiquitin-protein ligase; undergraduate student; virus genetics

Project Summary/Abstract All viruses must navigate the cellular ubiquitin (Ub) system en route to successful infection. Ubiquitin is a versatile posttranslational modification controlling many diverse cellular processes, from protein quality control, trafficking and degradation to signal transduction pathways. Activation of sequential E1-E2-E3 Ub-ligase cascades result in covalent attachment of one or more Ub molecules to lysine residues in substrate proteins. Arrays of different Ub-Ub linkages, in large part, dictate the regulatory role of Ub modification on the stability, localization, or function of target proteins. Conversely, Ub can be removed from modified proteins to reverse its effects through the activities of numerous deubiquitinating enzymes (DUBs). All herpesviruses encode DUBs that are implicated in facilitating the viral life cycle; however, a thorough understanding of the activity, specificity, and biology of these viral DUBs during a natural infection remains incomplete. We have previously shown that the conserved DUB encoded by the murine cytomegalovirus (MCMV) controls inflammation and viral pathogenesis during infection in a natural host. It does so by regulating the host ER-associated degradation (ERAD) and other pathways, to control the expression and secretion of a critical viral chemokine. The objective of this research plan is to determine the molecular mechanisms by which MCMV DUB facilitates pathogenesis during infection in a natural host. Our preliminary data lead to the overall hypothesis that MCMV DUB activity targets both host and viral factors to evade innate immune responses and facilitate viral infection. This hypothesis will be tested by pursuing two specific aims: 1) determine the mechanisms of CMV DUB activity regulating host ERAD and protein trafficking pathways during infection and 2) determine the linkage specificity target substrates of the MCMV DUB in vitro and during infection. These efforts will yield significant mechanistic insight into the complex and novel role CMV deubiquitinases play in pathogenesis and host responses, and underscore the potential utility of targeting DUB functions to combat viral infections.

项目总结/摘要 所有病毒都必须通过细胞泛素（Ub）系统才能成功感染。泛素是一种多功能的 翻译后修饰控制许多不同的细胞过程，从蛋白质质量控制，运输 和降解到信号转导途径。连续E1-E2-E3 Ub连接酶级联的激活结果 在一个或多个Ub分子与底物蛋白中的赖氨酸残基的共价连接中。一系列不同的 Ub-Ub连接在很大程度上决定了Ub修饰对稳定性、定位或功能的调节作用。 目标蛋白质。相反，Ub可以从修饰的蛋白质中去除，以逆转其作用。 许多去泛素化酶（DUBs）的活性。所有疱疹病毒都编码DUB， 促进病毒的生命周期;然而，对这些病毒的活性、特异性和生物学的透彻理解， 在自然感染期间的病毒DUBs仍然是不完整的。我们以前已经证明，保守的DUB 由鼠巨细胞病毒（MCMV）编码，控制感染期间的炎症和病毒发病机制 在一个自然的主机。它通过调节宿主ER相关降解（ERAD）和其他途径， 控制一种关键的病毒趋化因子的表达和分泌。本研究计划的目标是 确定MCMV DUB在自然感染期间促进发病的分子机制， 主持人我们的初步数据导致了MCMV DUB活性靶向宿主和病毒的总体假设 逃避先天免疫反应和促进病毒感染的因素。这一假设将通过追踪 两个具体目标：1）确定CMV DUB活性调节宿主ERAD和蛋白质的机制 2）确定MCMV DUB的连接特异性靶底物 在体外和感染期间。这些努力将产生重要的机械洞察复杂和新颖的 CMV去泛素化酶在发病机制和宿主反应中的作用，并强调了 靶向DUB功能以对抗病毒感染。