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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的病毒感染操纵多种翻译后修饰（PTM），改变了现有的蛋白质景观创建有利于复制的蜂窝环境。 PTM允许快速调制主机环境通过改变蛋白质丰度，定位和活性。由于它们的动态性质，PTMS代表了理想免疫反应效应子或发起人。我们的数据确定了ADP-核糖基化，蛋白质的修饰 ADP-核糖（ADPR），作为构成抗病毒反应的受感染细胞的快速，免疫样反应这抵消了流感病毒感染。使用尖端的ADPR特异性质谱法，我们具有单氨基酸分辨率的特征确定了数千种对病毒和宿主蛋白的修饰。 ADP-核糖基化与针对多种病毒的抗病毒反应。但是，关于病毒感染如何触发这一点，知之甚少 ADP-核糖基化和聚（ADPR） - 聚合酶（PARPS）的反应或活化机理，酶这种催化为蛋白质添加了ADPR。在这里，我们提出了在流感病毒期间的ADP-核糖基化研究感染。我们将确定特定ADPR修改的功能后果，并基于我们独特 ADP-核苷组数据集，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途径，从而定义在流感病毒感染过程中激活的分子触发因素和PARP。这些实验会阐明ADPR介导的病毒抑制的机制，触发该反应的因素以及如何病毒对抗IT，将ADP-核糖基化作为细胞抗病毒反应的关键方面，也许是完全独立的抗病毒防御部门。