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.

描述（由适用提供）：病毒感染诱导了由胞质模式识别受体RIG-I和MDA-5介导的先天抗病毒宿主反应，它感知了病毒RNA。 RIG-I/MDA5触发涉及线粒体适配器分子MAV，激酶TBK1/IKKI和转录因子IRF3和IRF7的下游信号传导事件。 IRF3和IRF7直接激活I型干扰素（IFN）A和ß基因的转录，扮演着关键的抗病毒作用。该途径受到关键抑制蛋白的严格调节，该蛋白质在病毒清除时协调抗病毒信号的下调，以确保稳态并防止组织损伤和不受控制的注射。 RIG-I/MDA-5途径激活与抑制之间平衡的失调可能导致I型IFN的不受控制的产生可能导致自身免疫性疾病。税务1BP1首先被鉴定为与A20锌指蛋白相互作用的抗凋亡蛋白。此后，Tax1bp1被表征为A20的适配器分子，这两种蛋白质抑制了炎症信号传导途径中NF-¿B转录因子的刺激诱导的激活。我们已经证明，税务1BP1和A20还协调以抑制RIG-I/MDA-5途径并限制病毒感染触发的I型IFN的激活。然而，尚不清楚税务1bp1的抗凋亡功能在宿主对病毒感染的反应中起作用。还不清楚在呼吸道病毒感染过程中，例如影响力和特定细胞类型的税务1BP1的精确作用在体内，其中税务1BP1可减轻病毒诱导的促炎细胞因子和I型IFN的产生。在初步研究中，我们提供了证据，表明税务1BP1在病毒感染过程中充当Ikki激酶的新底物。 Ikki对税务1BP1的磷酸化触发了病毒感染细胞的蛋白酶体降解和凋亡死亡。因此，税务1BP1缺陷的细胞对病毒诱导的细胞死亡和细胞病变作用高度敏感，这表明税务1BP1的抗凋亡功能被其降解并进一步支持税收1BP1构造抗体信号抗病毒对细胞死亡的概念的概念。推动拟议研究的中心假设是税务1BP1是病毒感染背景下先天抗病毒信号传导和细胞存活的关键调节剂。我们将以特定目的进行实验测试这一假设：（1）确定Ikki诱导的税务1BP1磷酸化和降解的机制；（2）阐明细胞类型特异性税务1BP1在调节中的作用会影响病毒感染。拟议研究的完成将为限制病毒复制至关重要的宿主机制提供重要的见解，并可能为鉴定新型抗病毒药物或疫苗的影响铺平道路以影响感染。