Role of OCIAD1 in RIG-I-mediated STAT1 signaling pathway

OCIAD1 在 RIG-I 介导的 STAT1 信号通路中的作用

• 批准号: 10554293
• 负责人: Shitao Li
• 金额: $ 19万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554293
• 关键词: Antigens; Antiviral Agents; Autoimmune Diseases; Binding; Bioinformatics; Cells; Data; Economic Burden; Epithelial Cells; Gene Expression; Genes; Goals; Health; Host Defense; Human; ITAM; Immunity; Impairment; Infection; Influenza; Influenza A virus; Innate Immune Response; Integration Host Factors; Interferon Type I; Interferons; Knockout Mice; Knowledge; Link; Literature; Malignant neoplasm of ovary; Mediating; Mitochondria; Molecular; Natural Immunity; Nucleic Acids; Pathway interactions; Pattern recognition receptor; Phosphorylation; Protein Tyrosine Kinase; Proteins; Reporting; Role; STAT1 gene; SYK gene; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; TANK-binding kinase 1; Testing; Tracheal Epithelium; Tretinoin; Viral; Viral Proteins; Virulence; Virus; Virus Diseases; Virus Replication; cytokine; design; immunoreactivity; in vivo; influenzavirus; insight; novel; overexpression; recruit; response; viral RNA

Project summary Host pattern recognition receptors, such as retinoic acid-induced gene I (RIG-I), sense viral RNA and elicit interferon-mediated innate immunity to restrict viral infection. It is well-established that RIG-I induces type I interferon (IFN) expression via the mitochondrial antiviral signaling protein (MAVS) and TANK-binding kinase 1 (TBK1). Type I IFN acts a danger signal and further activates the JAK-STAT signaling pathway to induce interferon-stimulated genes (ISGs), thereby limiting viral infection. A recent study reported another RIG-I signaling branch, in which MAVS directly induces STAT1 phosphorylation and ISG expression through the tyrosine kinase SYK. The RIG-I-STAT1 signaling has been shown to be critical for host defense at the early stage of viral infection. However, the critical intermediate signal molecule(s) linking MAVS and SYK is missing in this signal cascade because MAVS does not have the immunoreceptor tyrosine-based activation motif (ITAM) responsible for SYK binding and activation. Thus, there is a knowledge gap in the RIG-I-STAT1 signaling pathway. The objective in this application is to determine the role of the ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) in the RIG-I-STAT1 signaling pathway and host defense to viral infection. Although the RIG-I-STAT1 signaling pathway is established recently, there is a missing link between MAVS and SYK. Bioinformatic analysis showed that OCIAD1 had an ITAM-like motif that can recruit and activate SYK. Our preliminary data and previous studies showed that OCIAD1 interacted with MAVS. Furthermore, deficiency of OCIAD1 impaired RIG-I-mediated STAT1 phosphorylation. In addition, we and others reported that the NS2 protein of influenza A virus interacted with OCIAD1. Overexpression of NS2 blocked STAT1 phosphorylation. Thus, based on the existing literature and our preliminary data, we hypothesize that OCIAD1 recruits SYK to the MAVS signalosome and activates STAT1 phosphorylation in the RIG-I-STAT1 signaling pathway. Furthermore, influenza NS2 suppresses the RIG-I-STAT1 signaling pathway by antagonizing OCIAD1. Aim 1 will determine the role of OCIAD1 in IAV infection in vivo and in human primary cells. Aim 2 will dissect the molecular mechanisms of how OCIAD1 regulates the RIG-I-STAT1 signaling and how NS2 antagonizes this pathway. Our study will bridge the gaps in the RIG-I-STAT1 signaling cascades and determine a potential role of NS2 in subversion of host innate immune response, which will provide insights on a new viral strategy for evading host defense surveillance. The findings in our study will not only help develop effective antiviral therapeutics but will also deepen our understanding of host innate immune responses to viruses.

项目总结 宿主模式识别受体，如维甲酸诱导基因I(RIG-I)，感知病毒RNA并诱导 干扰素介导的先天免疫以限制病毒感染。公认的是，RIG-I诱导I型 干扰素通过线粒体抗病毒信号蛋白(MAVS)和坦克结合蛋白1的表达 (待定1)。I型干扰素发挥危险信号作用，进一步激活JAK-STAT信号通路，诱导 干扰素刺激基因(ISGs)，从而限制病毒感染。最近的一项研究报告了另一台RIG-I 信号分支，其中MAV直接诱导STAT1的磷酸化和ISG的表达 酪氨酸激酶SYK。RIG-I-STAT1信号在早期被证明是宿主防御的关键 病毒感染阶段。然而，连接小牛和SYK的关键中间信号分子(S)缺失 在这个信号级联中，因为MAV没有基于酪氨酸的免疫受体激活基序 (ITAM)负责SYK绑定和激活。因此，在RIG-I-STAT1中存在知识缺口 信号通路。这项应用的目的是确定卵巢癌的作用 RIG-I-STAT1信号通路中含有1的免疫活性抗原域(OCIAD1)与宿主 对病毒感染的防御。虽然RIG-I-STAT1信号通路是最近建立的，但有一个 缺少小牛和SYK之间的链接。生物信息学分析表明，OCIAD1具有一个类似ITAM的基序 可以招募和激活SYK。我们的初步数据和先前的研究表明，OCIAD1与 小牛。此外，OCIAD1的缺失还损害了RIG-I介导的STAT1的磷酸化。此外，我们 另有报道称，甲型流感病毒的NS2蛋白与OCIAD1相互作用。NS2基因的过度表达 阻断STAT1的磷酸化。因此，根据现有的文献和我们的初步数据，我们 假设OCIAD1将SYK招募到MAVS信号体，并激活STAT1磷酸化 RIG-I-STAT1信号通路。此外，流感NS2抑制RIG-I-STAT1信号通路 通过对抗OCIAD1。目的1确定OCIAD1在体内和人体内IAV感染中的作用 原生细胞。目标2将剖析OCIAD1如何调节RIG-I-STAT1的分子机制 以及NS2是如何拮抗这一途径的。 我们的研究将弥合RIG-I-STAT1信号级联中的空白，并确定NS2在 颠覆宿主的先天免疫反应，这将为逃避宿主的新病毒策略提供见解 国防监视系统。我们研究中的发现不仅将有助于开发有效的抗病毒疗法，而且将 也加深了我们对宿主对病毒的先天免疫反应的理解。