Differential modulation of RIG-I and cGAS signaling by OASL and its role in antiviral response

OASL 对 RIG-I 和 cGAS 信号传导的差异调节及其在抗病毒反应中的作用

• 批准号: 9263213
• 负责人: Saumendra N Sarkar
• 金额: $ 4.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263213
• 关键词: ATP phosphohydrolase; Ablation; Antiviral Agents; Antiviral Response; Binding; Biochemical; Biological Assay; Cause of Death; Cells; Complement; Coupled; Cyclic GMP; DNA; DNA Binding; DNA Virus Infections; DNA Viruses; Detection; Dimerization; Disease; Future; Genes; Genetic; Goals; Health; Herpesvirus 1; Host Defense; Human; Human Activities; IRF3 gene; Immune; Immune response; Immunity; Immunologic Receptors; In Vitro; Infection; Inflammation; Inflammatory; Integration Host Factors; Interferon Type I; Interferons; Ligands; Ligase; Link; Mediating; Modeling; Molecular; Mus; Mutagenesis; Natural Immunity; Nucleic Acids; Outcome; Pathogenesis; Pathway interactions; Play; Polyubiquitin; Predisposition; Property; Proteins; RNA; RNA Binding; RNA Virus Infections; RNA Viruses; Regulation; Role; Scheme; Shapes; Signal Transduction; Specificity; Structure; Testing; Toll-like receptors; Tretinoin; Vaccination; Vesicular stomatitis Indiana virus; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; adaptive immunity; antiviral immunity; base; cell type; combat; gene induction; in vitro Assay; in vivo; novel; oligoadenylate; receptor; reconstitution; response; sensor; therapeutic development; viral DNA; viral RNA

 DESCRIPTION (provided by applicant): The host innate immune response, initiated by the sensing of non-self viral nucleic acid, determines the outcome of most diseases resulting from viral infection. Therefore, in order to effectively combat viral diseases, it is necessary to critially understand the control mechanisms of the innate immune responses. We have discovered that interferon (IFN)-stimulated gene Oligoadenylate Synthetase-like (OASL) can differentially control the host response against RNA and DNA viruses. This proposal will test the hypothesis that OASL differentially modulates the sensitivity and the outcome of innate immune signaling against RNA and DNA viruses and determine the distinct molecular mechanisms by which OASL controls innate immune signaling in vitro and in vivo. We have found that human OASL sensitizes the RNA-sensor, RIG-I by mimicking one of the RIG-I ligand polyubiquitin. Thus, OASL enhances RIG-I-signaling-mediated IFN induction, and exerts a strong antiviral activity against multiple RNA virus infections. Consequently, genetic ablation of OASL in human cells, or Oasl2 in mice reduces RIG-I-mediated IFN induction and enhances susceptibility to various RNA virus infection (Zhu et al. 2014, Immunity. 40:936-48). On the other hand, the OASL or Oasl2-deficient cells show enhanced IFN response to DNA-sensor, cGAS activation, and consequent lower DNA virus replication. Our initial results indicate that OASL through its direct interaction with cGAS, may negatively regulate the cGAS signaling. As some of the DNA viruses establish long-term infections, one of the major significances of this negative regulation of cGAS signaling by OASL can be to restrict inflammation during DNA virus infections. The goal of this proposal is to determine the molecular mechanisms of OASL-mediated modulation of innate immune signaling through three independent specific aims: (1) determine the molecular mechanism of RIG-I signaling enhancement, and changes of RIG-I properties by OASL; (2) determine the mechanisms and consequences of OASL-mediated modulation of IFN induction through the DNA-sensor cGAS; and (3) define the in vivo role of OASL in antiviral responses using two model RNA (VSV) and DNA (HSV) viruses. Thus, this study highlights the unique activity of human OASL and determines the mechanistic basis of its function that will guide the future development of therapeutic strategies against specific virus infection by targeting the OASL-pathway.

 描述（由申请人提供）：通过感知非自身病毒核酸启动的宿主先天免疫应答决定了大多数病毒感染引起的疾病的结局。因此，为了有效地对抗病毒性疾病，有必要严格了解先天免疫反应的控制机制。我们已经发现，干扰素（IFN）刺激的基因寡腺苷酸合成酶样（OASL）可以不同地控制宿主对RNA和DNA病毒的反应。该提案将检验OASL差异调节针对RNA和DNA病毒的先天免疫信号传导的敏感性和结果的假设，并确定OASL在体外和体内控制先天免疫信号传导的不同分子机制。我们已经发现，人OASL通过模拟RIG-I配体聚泛素之一来敏化RNA传感器RIG-I。因此，OASL增强RIG-I信号传导介导的IFN诱导，并对多种RNA病毒感染发挥强抗病毒活性。因此，人细胞中的OASL或小鼠中的Oasl 2的遗传消除减少了RIG-I介导的IFN诱导并增强了对各种RNA病毒感染的易感性（Zhu等人，2014，Immunity. 40：936-48）。另一方面，OASL或Oasl 2缺陷型细胞显示出对DNA传感器、cGAS活化的增强的IFN应答，以及随之而来的较低的DNA病毒复制。我们的初步结果表明，OASL通过其与cGAS的直接相互作用，可以负调节cGAS信号传导。由于一些DNA病毒建立长期感染，OASL对cGAS信号传导的这种负调节的主要意义之一可能是限制DNA病毒感染期间的炎症。本提案的目的是通过三个独立的具体目标确定OASL介导的先天免疫信号转导调节的分子机制：（1）确定OASL增强RIG-I信号转导的分子机制和RIG-I性质的变化;（2）确定OASL介导的通过DNA传感器cGAS调节IFN诱导的机制和结果;和（3）使用两种模型RNA（VSV）和DNA（HSV）病毒确定OASL在抗病毒应答中的体内作用。因此，本研究强调了人OASL的独特活性，并确定了其功能的机制基础，这将指导未来通过靶向OASL途径开发针对特定病毒感染的治疗策略。