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.

项目概要/摘要 所有病毒在成功感染的过程中都必须通过细胞泛素 (Ub) 系统。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 和信号转导途径的降解。连续 E1-E2-E3 Ub 连接酶级联的激活结果 一个或多个 Ub 分子与底物蛋白中的赖氨酸残基共价连接。不同的数组 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 的目标蛋白。相反，Ub 可以从修饰的蛋白质中去除，以通过以下方式逆转其影响： 许多去泛素化酶 (DUB) 的活性。所有疱疹病毒都编码与 促进病毒生命周期；然而，对这些物质的活性、特异性和生物学的透彻了解 自然感染期间的病毒 DUB 仍然不完整。我们之前已经证明了保守的 DUB 由鼠巨细胞病毒 (MCMV) 编码，控制感染过程中的炎症和病毒发病机制 在自然宿主中。它通过调节宿主 ER 相关降解 (ERAD) 和其他途径来实现这一点， 控制关键病毒趋化因子的表达和分泌。该研究计划的目标是 确定 MCMV DUB 在自然感染过程中促进发病机制的分子机制 主持人。我们的初步数据得出了这样的总体假设：MCMV DUB 活性同时针对宿主和病毒 逃避先天免疫反应并促进病毒感染的因素。这个假设将通过追求来检验 两个具体目标：1）确定CMV DUB活性调节宿主ERAD和蛋白的机制 感染期间的运输途径，2) 确定 MCMV DUB 的连锁特异性靶底物 体外和感染期间。这些努力将对复杂而新颖的机制产生重要的洞察力。 CMV 去泛素酶在发病机制和宿主反应中的作用，并强调了其潜在效用 靶向 DUB 功能来对抗病毒感染。