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

• 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
• 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

 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（由申请人提供）：病毒感染诱导由细胞质模式识别受体 RIG-I 和 MDA-5 介导的先天抗病毒宿主反应，RIG-I/MDA5 感测病毒 RNA，触发涉及线粒体接头分子 MAVS 的下游信号传导事件，激酶 TBK1/IKKi 以及转录因子 IRF3 和 IRF7 直接激活 I 型转录。干扰素 (IFN) a 和 ß 基因发挥重要的抗病毒作用，该通路受到关键抑制蛋白的严格调控，这些蛋白在病毒清除后协调抗病毒信号传导的下调，以确保体内平衡并防止组织损伤和失控的炎症之间的平衡。 RIG-I/MDA-5 途径的激活和抑制可能导致 I 型 IFN 的不受控制的产生，从而可能导致自身免疫性疾病。与 A20 锌指蛋白相互作用的抗凋亡蛋白已被定性为 A20 的接头分子，并且这两种蛋白一起抑制刺激诱导的 NF-¿我们已经证明TAX1BP1和A20也协同抑制RIG-I/MDA-5通路并限制病毒感染引发的I型IFN的激活，但其抗凋亡功能是否有效。 TAX1BP1 在宿主对病毒感染的反应中发挥的作用尚不清楚，还不清楚 TAX1BP1 在流感等呼吸道病毒感染过程中在体内的确切作用以及具体的细胞类型。 TAX1BP1 减弱病毒诱导的促炎细胞因子和 I 型 IFN 的产生，我们提供的证据表明，TAX1BP1 在病毒感染过程中充当 IKKi 激酶的新型底物，IKKi 对 TAX1BP1 的磷酸化会触发其蛋白酶体降解和病毒凋亡。 -经测试，TAX1BP1缺陷细胞对病毒诱导的细胞死亡和细胞病变效应高度敏感，这表明TAX1BP1 的抗凋亡功能因其降解而被暴露，并进一步支持了 TAX1BP1 将抗病毒信号传导与细胞死亡途径结合的观点。我们将通过实验检验这一假设，具体目标如下：(1) 确定 IKKi 诱导的 TAX1BP1 磷酸化和降解的机制；(2)阐明细胞类型特异性 TAX1BP1 在调节流感病毒感染中的作用完成拟议的研究将为限制病毒复制所必需的宿主机制提供重要的见解，并可能为识别新型抗病毒药物或疫苗铺平道路。流感感染。