Dissecting ADP-ribosylation as an innate immune response countering influenza virus replication

剖析 ADP-核糖基化作为对抗流感病毒复制的先天免疫反应

• 批准号: 10493284
• 负责人: Andrew Mehle
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493284
• 关键词: ADP ribosylation; Adenosine Diphosphate Ribose; Amino Acids; Antiviral Response; COVID-19 pandemic; Cells; Complex; Coronavirus; Data; Data Set; Double-Stranded RNA; Ensure; Environment; Enzymes; Event; Genes; Genomics; Goals; Immune; Immune response; Infection; Influenza; Innate Immune Response; Integration Host Factors; Interferons; Invaded; Knowledge; Link; Maps; Mass Spectrum Analysis; Mediating; Modification; Molecular; Molecular Profiling; Natural Immunity; Nature; Pathway interactions; Play; Poly Adenosine Diphosphate Ribose; Polymerase; Post-Translational Protein Processing; Process; Production; Proteins; Proteome; Resolution; Ribonucleoproteins; Role; Signal Transduction; Site; Stress; Techniques; Therapeutic Intervention; Time; Transcriptional Regulation; Translations; Up-Regulation; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; antagonist; arm; combat; dynamic system; experimental study; influenza infection; influenzavirus; insight; member; new therapeutic target; novel; pathogen; response; therapeutic development

ABSTRACT Viral infections manipulate diverse post-translational modifications (PTMs), altering existing protein landscapes to create cellular environments favorable to replication. PTMs allow for rapid modulation of host environments by altering protein abundance, localization, and activity. Because of their dynamic nature, PTMs typify ideal immune response effectors or initiators. Our data identifies ADP-ribosylation, the modification of proteins with ADP-ribose (ADPr), as a rapid, immune-like response from infected cells that constitutes an antiviral response that counters influenza virus infection. Using cutting-edge ADPr-specific mass spectrometry approaches, we have characterized with single amino acid resolution the ADP-ribosylome during influenza virus infection and identified thousands of modifications on viral and host proteins. ADP-ribosylation has been associated with antiviral responses against multiple viruses. However, little is known about how viral infections trigger this response or the activiral mechanism(s) of ADP-ribosylation and poly(ADPr)-polymerases (PARPs), the enzymes that catalyze addition of ADPr to proteins. Here, we propose studies of ADP-ribosylation during influenza virus infection. We will identify the functional consequences of specific ADPr modifications, and building on our unique ADP-ribosylome dataset, investigate how ADP-ribosylation alters the function of specific viral and host proteins. We will interrogate the cellular pathways responsible for initiating ADP-ribosylation responses, defining the molecular triggers and PARPs that are activated during influenza virus infection. These experiments will elucidate the mechanisms of ADPr-mediated viral inhibition, the factors that trigger this response, and how viruses counter it, establishing ADP-ribosylation as a key aspect of cellular antiviral responses and perhaps as an entirely independent arm of antiviral defenses.

摘要 病毒感染操纵不同的翻译后修饰（PTM），改变现有的蛋白质景观 创造有利于复制的细胞环境。PTM允许快速调节主机环境 通过改变蛋白质丰度、定位和活性。由于其动态特性，PTM代表理想的 免疫应答效应物或引发物。我们的数据确定了ADP-核糖基化，即蛋白质的修饰， ADP-核糖（ADPr），作为来自感染细胞的快速免疫样反应，构成抗病毒反应 对抗流感病毒感染。使用尖端的ADPr特异性质谱方法，我们 已经用单个氨基酸解析表征了流感病毒感染期间的ADP-核糖基体， 在病毒和宿主蛋白上发现了数千种修饰。ADP-核糖基化与 对多种病毒的抗病毒反应。然而，人们对病毒感染如何引发这一点知之甚少 ADP-核糖基化和聚（ADPr）-聚合酶（PARP）的活性应答或活性病毒机制，所述酶 催化ADPr与蛋白质的结合在这里，我们提出了研究ADP-核糖基化在流感病毒 感染我们将确定特定ADPr修饰的功能后果，并建立在我们独特的 ADP-核糖基组数据集，研究ADP-核糖基化如何改变特定病毒和宿主蛋白的功能。 我们将询问负责启动ADP-核糖基化反应的细胞通路， 在流感病毒感染期间被激活的分子触发物和PARP。这些实验将 阐明ADPr介导的病毒抑制机制，触发这种反应的因素，以及如何 病毒对抗它，建立ADP-核糖基化作为细胞抗病毒反应的一个关键方面， 一个完全独立的抗病毒防御系统