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.

项目摘要 该提案的目的是研究CELF 2在抑制干扰素对自身免疫应答中的新作用。 RNA配体。而由非自身病毒RNA诱导的干扰素（IFN）激活抗病毒程序， 病原体，它们的异常表达可引起组织损伤，导致自身免疫。虽然像收费一样 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。自我RNA的识别可能是抑制RNA的失败的结果。 自身RNA配体。通过ADAR 1进行的RNA编辑是一种用于抑制自身RNA配体的途径，但它是一种非特异性的RNA编辑。 可以想象，有许多其他机制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，剪接因子CELF 2的缺失诱导了一个强大的诱导， I型IFN和IFN刺激基因。剪接因子是mRNA加工和后加工所必需的。 转录调控，然而，干扰素反应的异常和选择性剪接的影响， 替补演员我们发现，在CELF 2耗竭过程中诱导的IFN依赖于RIG-I样受体。在这 建议，我们将确定CELF 2介导的抑制IFN激活的机制。CELF 2没有 先前涉及抑制免疫刺激性自身RNA配体。这项研究将描述一个 CELF 2在先天免疫信号传导中的新作用，但也研究了mRNA剪接干扰对 先天免疫这项研究有可能揭示内源性RNA的生物合成机制 激活RLR通路这些发现可能对理解IFN诱导的 免疫病理学和鉴定自身免疫中新的治疗靶点。