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: 10410142
• 负责人: Shitao Li
• 金额: $ 22.8万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410142
• 关键词: Antigens; Antiviral Agents; Autoimmune Diseases; Binding; Bioinformatics; Cells; Data; Economic Burden; Epithelial Cells; Gene Expression; Genes; Goals; 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; base; cytokine; design; health economics; 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.

项目摘要 宿主模式识别受体，例如视黄酸诱导的基因I（RIG-I），有义务病毒RNA和引起 干扰素介导的先天免疫可限制病毒感染。瑞格（Rig-i）诱导了I型 干扰素（IFN）通过线粒体抗病毒信号蛋白（MAV）和储罐结合激酶1的表达 （TBK1）。 I型IFN起作用危险信号，并进一步激活JAK-STAT信号传导途径 干扰素刺激的基因（ISG），从而限制了病毒感染。最近的一项研究报道了另一个RIG-I 信号分支，其中MAVS直接诱导STAT1磷酸化和ISG表达 酪氨酸激酶Syk。 rig-i-stat1信号已被证明对于早期的宿主防御至关重要 病毒感染的阶段。但是，连接MAV和SYK的临界中间信号分子缺失 在此信号级联由于MAVS没有免疫受体酪氨酸的激活基序 （ITAM）负责SYK结合和激活。因此，RIG-I-STAT1有一个知识差距 信号通路。本应用的目的是确定卵巢癌的作用 RIG-I-STAT1信号通路中包含1（OCIAD1）的免疫反应性抗原结构域和宿主 对病毒感染的防御。尽管最近建立了RIG-I-STAT1信号通路，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具有类似ITAM的主题 可以招募和激活Syk。我们的初步数据和以前的研究表明，OCIAD1与 小牛。此外，OCIAD1缺乏RIG-I介导的STAT1磷酸化。另外，我们 其他人则报道说，流感A的NS2蛋白与OCIAD1相互作用。 NS2的过表达 阻塞的STAT1磷酸化。因此，根据现有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。 AIM 1将确定OCIAD1在体内和人类IAV感染中的作用 原代细胞。 AIM 2将剖析OCIAD1如何调节RIG-I-STAT1的分子机制 信号传导以及NS2如何拮抗这一途径。 我们的研究将弥合rig-i-stat1信号级联的差距，并确定NS2在 颠覆宿主先天免疫反应，该反应将提供有关逃避宿主的新病毒策略的见解 国防监视。我们研究中的发现不仅将有助于开发有效的抗病毒治疗剂，还将有助于 还加深了我们对宿主对病毒的先天免疫反应的理解。