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: 9240591
• 负责人: Saumendra N Sarkar
• 金额: $ 45.05万
• 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/9240591
• 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; Herpesvirus 1; Host Defense; Human; Human Activities; IRF3 gene; Immune; Immune response; Immune signaling; Immunity; Immunologic Receptors; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; 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; Vitronectin; adaptive immunity; antiviral immunity; base; cell type; combat; dimer; gene induction; in vitro Assay; in vivo; novel; oligoadenylate; public health relevance; receptor; reconstitution; response; sensor; therapeutic development

 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.