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.

项目概要 宿主模式识别受体，例如视黄酸诱导基因 I (RIG-I)，感知病毒 RNA 并引发 干扰素介导的先天免疫来限制病毒感染。众所周知，RIG-I 诱导 I 型 通过线粒体抗病毒信号蛋白 (MAVS) 和 TANK 结合激酶 1 表达干扰素 (IFN) （TBK1）。 I 型 IFN 发出危险信号，进一步激活 JAK-STAT 信号通路，诱导 干扰素刺激基因（ISG），从而限制病毒感染。最近的一项研究报告了另一种 RIG-I 信号分支，其中 MAVS 通过直接诱导 STAT1 磷酸化和 ISG 表达 酪氨酸激酶 SYK。 RIG-I-STAT1 信号传导已被证明对于早期宿主防御至关重要。 病毒感染阶段。然而，连接 MAVS 和 SYK 的关键中间信号分子缺失 在此信号级联中，因为 MAVS 不具有基于免疫受体酪氨酸的激活基序 (ITAM) 负责 SYK 绑定和激活。因此，RIG-I-STAT1 中存在知识差距 信号通路。本申请的目的是确定卵巢癌的作用 RIG-I-STAT1 信号通路和宿主中含有免疫反应性抗原结构域 1 (OCIAD1) 防御病毒感染。尽管 RIG-I-STAT1 信号通路最近才建立，但仍有一个 MAVS 和 SYK 之间缺少链接。生物信息分析表明 OCIAD1 具有类似 ITAM 的基序 可以招募并激活SYK。我们的初步数据和之前的研究表明 OCIAD1 与 MAVS。此外，OCIAD1 的缺陷会损害 RIG-I 介导的 STAT1 磷酸化。此外，我们 等人报道甲型流感病毒的 NS2 蛋白与 OCIAD1 相互作用。 NS2 过度表达 阻断 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。目标 1 将确定 OCIAD1 在体内和人类 IAV 感染中的作用 原代细胞。目标 2 将剖析 OCIAD1 如何调节 RIG-I-STAT1 的分子机制 信号传导以及 NS2 如何拮抗该通路。 我们的研究将弥合 RIG-I-STAT1 信号级联中的差距，并确定 NS2 在 颠覆宿主先天免疫反应，这将为逃避宿主的新病毒策略提供见解 国防监视。我们的研究结果不仅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。