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

 描述(申请人提供)：宿主的先天免疫反应，由非自身病毒核酸的感应启动，决定了大多数由病毒感染引起的疾病的结局。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反应的控制机制。我们发现干扰素刺激的基因寡腺苷合成酶样蛋白(OASL)可以不同地控制宿主对RNA和DNA病毒的反应。这一提议将验证OASL对RNA和DNA病毒的天然免疫信号的敏感性和结果的差异性调节的假说，并确定OASL在体外和体内控制天然免疫信号的不同分子机制。我们发现，人类OASL通过模仿RIG-I配体之一的多泛素来敏化RNA传感器RIG-I。因此，OASL增强了RIG-I信号介导的干扰素诱导，并对多种RNA病毒感染具有很强的抗病毒活性。因此，人类细胞中的OASL或小鼠中的OASL2的遗传消融减少了RIG-I介导的干扰素诱导，并增强了对各种RNA病毒感染的敏感性(朱等人。2014年，豁免权。40：936-48)。另一方面，OASL或OASL2缺陷细胞对DNA传感器的干扰素反应增强，cGAS激活，从而降低DNA病毒复制。我们的初步结果表明，OASL通过与cGAS的直接相互作用，可能对cGAS信号进行负向调节。由于一些DNA病毒建立了长期感染，OASL对cGAS信号的这种负调控的主要意义之一是在DNA病毒感染过程中限制炎症。这项建议的目的是通过三个独立的特定目标来确定OASL介导的天然免疫信号调节的分子机制：(1)确定RIG-I信号增强的分子机制，以及OASL对RIG-I性质的改变；(2)确定OASL通过DNA传感器cGAS介导的调节干扰素诱导的机制和后果；以及(3)使用两种模型RNA(VSV)和DNA(HSV)确定OASL在体内抗病毒反应中的作用。因此，本研究强调了人OASL的独特活性，并确定了其作用的机制基础，这将指导未来通过靶向OASL途径来治疗特定病毒感染的策略的发展。

 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.