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: 9054802
• 负责人: Saumendra N Sarkar
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054802
• 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（由适用提供）：由非自身病毒核酸的敏感性引发的宿主先天免疫响应决定了病毒感染引起的大多数疾病的结果。因此，为了有效地对抗病毒疾病，有必要批判性地了解先天免疫调查的控制机制。我们发现干扰素（IFN）刺激的基因寡添氧基二苯基合成酶（OASL）可以差异地控制针对RNA和DNA病毒的宿主反应。该提案将检验以下假设：OASL对不同的敏感性和对RNA和DNA病毒的敏感性和结果进行调节，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。我们发现，人OASL通过模仿RIG-I配体多辅解蛋白之一来感知RNA传感器，RIG-I。这，OASL增强了RIG-I信号介导的IFN诱导，并针对多种RNA病毒感染发挥了强大的抗病毒活性。因此，人类细胞中OASL的遗传消融或小鼠中的OASL2降低了RIG-I介导的IFN诱导，并增强对各种RNA病毒感染的敏感性（Zhu等，2014，免疫。40：936-48）。另一方面，OASL或OASL2缺陷型细胞对IFN对DNA传感器，CGAS激活以及随之而来的DNA病毒复制的反应增强。我们的初始结果表明，通过与CGA的直接相互作用，OASL可能会对CGAS信号进行负调节。由于某些DNA病毒建立了长期感染，因此OASL对CGAS信号的负调控的主要意义之一可能是在DNA病毒感染过程中限制注射。该提案的目的是通过三个独立的特定目的确定OASL介导的先天免疫信号传导调制的分子机制：（1）确定RIG-I信号增强的分子机制，以及OASL的RIG-I特性的变化； （2）确定通过DNA传感器CGA诱导的OASL介导的IFN诱导的机理和后果； （3）使用两个模型RNA（VSV）和DNA（HSV）病毒定义OASL在抗病毒反应中的体内作用。这项研究强调了人类OASL的独特活性，并确定了其功能的机械基础，该活动将通过靶向OASL-Pathway来指导针对特定病毒感染的理论策略的未来发展。