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TRIM9-mediated anti-viral immune pathway

TRIM9介导的抗病毒免疫途径

基本信息

批准号：
8857804
负责人：
Jae U Jung
金额：
$ 41.2万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-05 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857804
关键词：
Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Antiviral Response Binding Biological Assay Bone Marrow Cells Brain CUL1 gene Complex Defense Mechanisms Early Diagnosis Ensure Equilibrium F Box Domain F-Box Proteins Figs - dietary Gene Expression Genes Harvest Histologic Homeostasis IRF3 gene Immune Immune response Immunity Inflammation Inflammatory Inflammatory Response Influenza A virus Interferon Type I Interferons Invaded Lead Measurement Measures Mediating Molecular Mus Mutagenesis Neurons Nuclear Pathway interactions Pattern Pattern recognition receptor Peptides Phase Phosphorylation Production Protein Family Protein Microchips Proteins Receptor Signaling Recruitment Activity Regulation Role Shapes Signal Pathway Signal Transduction Signaling Molecule Splenocyte Staging TBK1 gene TRIM Motif Testing Tetracyclines Tissues Transducin Transgenic Mice Ubiquitination Viral Virus Virus Diseases WD Repeat West Nile virus Yin-Yang base beta-Transducin Repeat-Containing Proteins biodefense cytokine in vivo inhibitor/antagonist meter mouse model novel pathogen prevent protein protein interaction public health relevance response scaffold screening transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The interferon regulatory factors IRF3 and IRF7 are the master transcription factors to sequentially induce the early and late phase of IFN-stimulated genes (ISG) upon TBK1-mediated phosphorylation, which limits viral replication through multiple mechanisms. In addition, the NF-B transcription factor is a critical regulator of the pathogen-induced proinflammatory response and its activity is primarily regulated by the SCF-βTrCP [SKP1-CUL1-F-box-βTrCP (β-transducin repeat-containing protein)] E3 ligase complex-mediated ubiquitination and degradation. Various intracellular restriction factors, including the tripartite motif (TRIM) protein family, cooperate with TBK1, IRF3/7, and NF-B transcription factors to develop effective anti-viral immune responses. From our functional screening of 75 TRIM proteins, we have identified a novel TRIM9 E3 ligase as a major innate yin-yang effector to develop balanced immune responses against viral infection. TRIM9 is primarily expressed in the brain, but its expression is rapidly induced in various other tissues upon viral infection. Our study discovered that TRIM9 interacts with TBK1 and IRF3/7, leading to the robust activation of the type I IFN pathway. On the other hand, TRIM9 binds the WD repeat-containing F-box protein βTrCP of SCF E3 ligase complex in a phosphorylation dependent manner, resulting in the marked suppression of NF-B pathway. Based on these results, we hypothesize that TRIM9 shapes innate immune homeostasis by integrating positive and negative regulation of type I IFN anti-viral and NF-B proinflammatory responses, respectively: as a novel anti-viral factor, the TRIM9 E3 ligase differentially regulates type I IFN and NF-B signaling pathways in a genetically and functionally separable manner, developing well-balanced immune responses against viral infection.

描述（由申请人提供）：干扰素调节因子IRF 3和IRF 7是主转录因子，在TBK 1介导的磷酸化后依次诱导IFN刺激基因（ISG）的早期和晚期，这通过多种机制限制病毒复制。此外，NF-κ B B转录因子是病原体诱导的促炎反应的关键调节因子，其活性主要由SCF-βTrCP [SKP 1-CUL 1-F-box-βTrCP（β-transducin repeat-containing protein）] E3连接酶复合物介导的泛素化和降解调节。各种细胞内限制因子，包括三重基序（TRIM）蛋白家族，与TBK 1、IRF 3/7和NF-κ B B转录因子合作以产生有效的抗病毒免疫应答。从我们对75种TRIM蛋白的功能筛选中，我们已经鉴定出一种新型TRIM 9 E3连接酶作为主要的先天阴阳效应子，以产生针对病毒感染的平衡免疫应答。TRIM 9主要在脑中表达，但在病毒感染后，其表达在各种其他组织中被迅速诱导。我们研究发现TRIM 9与TBK 1和IRF 3/7相互作用，导致I型IFN途径的强烈激活。另一方面，TRIM 9以磷酸化依赖的方式结合SCF E3连接酶复合物的含有WD重复序列的F-box蛋白βTrCP，导致NF-κ B B途径的显著抑制。基于这些结果，我们假设TRIM 9通过整合I型IFN抗病毒和NF-κ B B促炎应答的正向和负向调节分别形成先天免疫稳态：作为一种新的抗病毒因子，TRIM 9 E3连接酶以遗传和功能上可分离的方式差异调节I型IFN和NF-κ B B信号传导途径，产生针对病毒感染的良好平衡的免疫应答。