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

剪接因子CELF2抑制RIG-I样受体感知的RNA配体

• 批准号: 10654469
• 负责人: Ram Savan
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654469
• 关键词: 7SL RNA; ADAR1; Alternative Splicing; Autoimmunity; Biogenesis; Cells; DNA; Defect; Development; Disease; Failure; Family member; Generations; Genes; Genetic Transcription; Goals; Immune; Immune signaling; Infection; Innate Immune Response; Interferon Activation; Interferon Suppression; Interferon Type I; Interferons; Ligands; Mediating; Messenger RNA; Natural Immunity; Nucleic Acids; Pathogen detection; Pathology; Pathway interactions; Phenotype; Play; Post-Transcriptional Regulation; Proteins; Pseudogenes; RNA; RNA Editing; RNA Splicing; RNA-Binding Proteins; Receptor Activation; Regulation; Reporting; Role; Signal Recognition Particle; Signal Transduction; Testing; Tissues; Toll-like receptors; Viral; Virus Diseases; Work; adaptive immune response; immune RNA; monocyte; new therapeutic target; novel; pathogenic virus; programs; receptor; response; sensor; viral RNA; viral detection

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.

项目概要 本提案的目标是研究 CELF2 在抑制干扰素自我反应中的新作用。 RNA配体。非自体病毒 RNA 诱导的干扰素 (IFN) 会激活抗病毒程序以限制病毒 病原体，其异常表达可导致组织损伤，导致自身免疫。虽然像收费站一样 受体和 RIG-I 样受体通常感知非自身 RNA，这些传感器也被自身 RNA 激活 在某些条件下。自身RNA的识别可能是抑制自身RNA失败的结果 自身RNA配体。 ADAR1 的 RNA 编辑是一种用于抑制自身 RNA 配体的途径，但它 可以想象还有许多其他机制可以抑制内源性免疫刺激RNA 配体。我们做了一个令人惊讶的观察，即剪接因子 CELF2 的丢失诱导了强烈的诱导 I 型 IFN 和 IFN 刺激基因。 mRNA 加工和后处理需要剪接因子 转录调控，然而异常剪接和选择性剪接对 IFN 反应的影响是 待研究。我们发现 CELF2 耗竭期间诱导的 IFN 依赖于 RIG-I 样受体。在这个 提案中，我们将确定 CELF2 介导的 IFN 激活抑制机制。 CELF2还没有 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 在先天免疫信号传导中的新作用，还研究了 mRNA 剪接扰动对 先天免疫。这项研究有可能揭示内源性 RNA 的生物发生机制 激活 RLR 通路。这些发现可能对理解 IFN 诱导的 免疫病理学并确定自身免疫的新治疗靶点。