The splicing factor CELF2 suppresses RNA ligands sensed by RIG-I-like receptor

项目摘要 这项建议的目标是研究CELF2在抑制干扰素对自身的反应中的一种新的作用。 核糖核酸配体。而由非自身病毒RNA诱导的干扰素则激活抗病毒程序以限制病毒 病原体，其异常表达可引起组织损伤，导致自身免疫。虽然通行费一样 受体和Rig-I样受体通常感知非自身rna，这些感受器也被自身rna激活。 在某些情况下。识别自己的RNA可能是抑制失败的结果 自我核糖核酸配体。ADAR1的RNA编辑是用于抑制自身RNA配体的一种途径，但它是 可以想象，还有许多其他机制可以抑制内源性免疫刺激RNA 配基。我们做了一个令人惊讶的观察，剪接因子CELF2的缺失诱导了强健的诱导 I型干扰素和干扰素刺激基因。剪接因子是mRNA加工和转录后所必需的 转录调控，然而，异常和选择性剪接对干扰素反应的影响是 未得到充分研究。我们发现，在CELF2耗竭过程中诱导的干扰素依赖于Rig-I样受体。在这 建议，我们将确定CELF2介导的抑制干扰素激活的机制。CELF2没有 先前被认为与抑制免疫刺激性自身RNA配体有关。这项研究将描述一个 CELF2在先天免疫信号中的新作用，但也研究了mRNA剪接的扰动对 先天免疫力。这项研究有可能揭示内源RNA的生物发生机制 这激活了RLR通路。这些发现可能对理解干扰素诱导的 自身免疫的免疫病理和寻找新的治疗靶点。

Project Summary The goal of this proposal is to investigate a novel role of CELF2 in suppressing interferon responses to self- RNA ligands. While interferons (IFN) induced by non-self-viral RNA activate an antiviral program to restrict viral pathogens, their aberrant expression can cause tissue damage leading to autoimmunity. Although the toll-like receptors and RIG-I-like receptors normally sense non-self RNA, these sensors are also activated by self-RNA under certain conditions. Recognition of self-RNA can be a consequence of a failure of the suppression of the self-RNA ligands. RNA editing by ADAR1 is one pathway used to suppress self-RNA ligands, but it is conceivable that there are many other mechanisms that suppress endogenous immunostimulatory RNA ligands. We made a surprising observation that the loss of splicing factor CELF2 induced a robust induction of type I IFN and IFN-stimulated genes. Splicing factors are required for mRNA processing and post- transcriptional regulation, however the effect of aberrant and alternative splicing on IFN responses is understudied. We found that IFN induced during CELF2 depletion is dependent on RIG-I-like receptors. In this proposal, we will identify the mechanisms of CELF2-mediated suppression of IFN activation. CELF2 has not been previously implicated in suppressing immunostimulatory self-RNA ligands. This study will describe a novel role for CELF2 in innate immune signaling, but also study the effect of perturbation of mRNA splicing on innate immunity. This study has the potential to uncover mechanisms of the biogenesis of endogenous RNA that activates the RLR pathway. These findings could have a significant impact on understanding IFN-induced immune pathologies and identify new therapeutic targets in autoimmunity.