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The role of TAX1BP1 in the innate immune response to virus infection

TAX1BP1在病毒感染先天免疫反应中的作用

基本信息

批准号：
8998913
负责人：
EDWARD W HARHAJ
金额：
$ 20.25万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8998913
关键词：
Address Antiviral Agents Apoptotic Attenuated Autoimmune Diseases Autoimmunity Automobile Driving Bioinformatics Cell Death Cell Death Induction Cell Death Signaling Process Cell Survival Cells Cessation of life Collaborations Complex Couples Data Development Down-Regulation Embryo Ensure Enzymes Epidemic Epithelial Cells Equilibrium Event Fibroblasts Foundations Genes Genetic Transcription Goals Health Homeostasis IRF3 gene Immune Immune response Infection Inflammation Inflammatory Influenza Influenza A virus Interferon Type I Interferon-alpha Interferon-beta Interferons Investigation Lead Lung Marshal Mass Spectrum Analysis Mediating Mitochondria Mus Mutagenesis Myelogenous Natural Immunity Nucleic Acids Pathway interactions Pattern recognition receptor Phosphorylation Phosphorylation Site Phosphotransferases Play Principal Investigator Production Proteins Public Health RNA Viruses Receptor Signaling Recruitment Activity Regulation Role Signal Pathway Signal Transduction Staging Stimulus TBK1 gene Testing Tissues Transcription Coactivator Ubiquitin Vaccines Viral Virus Virus Diseases Virus Replication Zinc Fingers adaptive immunity antiviral immunity base cell type cytokine in vivo influenzavirus inhibitor/antagonist insight macrophage novel pandemic disease prevent receptor research study respiratory infection virus respiratory virus response transcription factor ubiquitin-protein ligase viral RNA virology

项目摘要

DESCRIPTION (provided by applicant): Virus infection induces an innate antiviral host response mediated by the cytoplasmic pattern recognition receptors RIG-I and MDA-5 that sense viral RNAs. RIG-I/MDA5 trigger downstream signaling events involving the mitochondrial adaptor molecule MAVS, the kinases TBK1/IKKi and the transcription factors IRF3 and IRF7. IRF3 and IRF7 directly activate the transcription of the type I interferon-(IFN) a and ß genes tha play critical antiviral roles. This pathway is tightly regulated by key inhibitory proteins that orchestrate the downregulation of antiviral signaling upon viral clearance to ensure homeostasis and prevent tissue damage and uncontrolled inflammation. Dysregulation of the balance between activation and inhibition of the RIG-I/MDA-5 pathway may result in the uncontrolled production of type I IFN that may lead to autoimmune disease. TAX1BP1 was first identified as an anti-apoptotic protein that interacts with the A20 zinc finger protein. TAX1BP1 has since been characterized as an adaptor molecule for A20, and together these two proteins inhibit the stimulus-induced activation of the NF-¿B transcription factor in inflammatory signaling pathways. We have demonstrated that TAX1BP1 and A20 also cooperate to inhibit the RIG-I/MDA-5 pathway and restrict the activation of type I IFN triggered by virus infection. However, whether the anti-apoptotic function of TAX1BP1 plays a role in the host response to virus infection is unknown. It is also unclear what the precise roles of TAX1BP1 are in vivo during the course of a respiratory virus infection such as influenza and the specific cell types where TAX1BP1 attenuates viral-induced production of proinflammatory cytokines and type I IFN. In preliminary studies we provide evidence that TAX1BP1 serves as a novel substrate of the IKKi kinase during virus infection. The phosphorylation of TAX1BP1 by IKKi triggers its proteasomal degradation and apoptotic death of virus-infected cells. Consequently, TAX1BP1-deficient cells are highly sensitive to virus-induced cell death and cytopathic effects, suggesting that the anti-apoptotic function of TAX1BP1 is unmasked by its degradation and further supporting the notion that TAX1BP1 couples antiviral signaling to cell death pathways. The central hypothesis driving the proposed investigations is that TAX1BP1 is a key regulator of innate antiviral signaling and cell survival in the context of virus infection. We will test this hypothesis experimentally with te following specific aims: (1) determine the mechanisms of IKKi-induced TAX1BP1 phosphorylation and degradation and; (2) elucidate the role of cell-type specific TAX1BP1 in regulating influenza virus infection. Completion of the proposed studies will provide important insight into the host mechanisms that are essential to restrict virus replication and may pave the way for the identification of novel antiviral drugs or vaccines for influenza infection.