Regulation of cGAS-Mediated Cytosolic DNA Sensing Pathway

项目总结 病毒DNA和泄漏的线粒体DNA(MtDNA)可以触发胞质DNA传感器，环状GMP-AMP 合成酶(CGAS)启动干扰素(IFN)产生的信号级联反应。DNA的异常激活 感觉通路可导致炎症和自身免疫性疾病，如系统性红斑狼疮。 然而，宿主如何限制对病毒dna和mtdna的过度或有害的免疫反应并不是很好。 已澄清。因此，迫切需要确定防止cGAs异常激活的保护机制- 介导的先天免疫。 我们在本申请中的总体目标是阐明主机监管反馈机制，该机制防止 CGAS的过度激活。初步实验确定了补体C1q结合蛋白(C1QBP)，a 蛋白主要在线粒体中表达，与cGAS相关。我们的初步研究发现 C1QBP基因敲除增强DNA诱导的干扰素应答，提示C1QBP负性调节cGAS 发信号。我们的初步研究进一步发现，病毒感染诱导的线粒体应激导致 将C1QBP从线粒体释放到细胞质。基于现有的文献和我们的初步研究 数据，我们提出了以下中心假设：线粒体应激导致C1QBP从 线粒体进入细胞质。胞内C1QBP与cGAS的直接相互作用抑制I型干扰素 表达，从而提供了一种防止先天免疫异常或持续激活的机制 回应。 目的1明确C1QBP在体内外胞浆DNA介导的天然免疫中的作用。 目的2将确定C1QBP限制胞质DNA诱导的cGAs的保护机制 激活。 CGAS活性必须受到严格控制，因为持续的干扰素产生可能导致自身免疫性疾病。 这一探索性的R21应用提出C1QBP作为线粒体基质中的隐藏宿主保护器。什么时候 线粒体受到感染和其他细胞压力的破坏，C1QBP从线粒体释放到 抑制cGAS活性，从而防止mtDNA泄漏引发的过度干扰素反应。本研究 将阐明一种优雅的主持人自律机制，为小说的发展提供基础 传染病和自身免疫性疾病的治疗策略。

Project summary Viral DNA and leaked mitochondrial DNA (mtDNA) can trigger the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS) to initiate the interferon (IFN) production signal cascade. Aberrant activation of the DNA sensing pathway can result in inflammatory and autoimmune diseases, such as systemic lupus erythematosus. However, how host limits excessive or detrimental immune responses to viral DNA and mtDNA is not well elucidated. Thus, it is pressing to define the protective mechanisms that prevent aberrant activation of cGAS- mediated innate immunity. Our overall objective in this application is to elucidate a host regulatory feedback mechanism that prevents cGAS from over-activating. Pilot experiments identified the complement C1q binding protein (C1QBP), a protein predominantly expressed in mitochondria as being associated with cGAS. Our pilot studies found that knockout of C1QBP augmented DNA-induced IFN response, suggesting C1QBP negatively regulates cGAS signaling. Our preliminary studies further discovered that viral infection-induced mitochondrial stress resulted in the release of C1QBP from mitochondria to the cytoplasm. Based on the existing literature and our preliminary data, we propose the following central hypothesis: Mitochondrial stress causes the release of C1QBP from mitochondria into cytosol. Direct interaction between cytosolic C1QBP and cGAS inhibits type I IFN expression, thereby providing a mechanism that prevents aberrant or sustained activation of innate immune responses. Aim 1 will define the role of C1QBP in cytosolic DNA-mediated innate immunity in vitro and in vivo. Aim 2 will determine the protective mechanisms by which C1QBP limits cytosolic DNA-induced cGAS activation. cGAS activity must be tightly regulated because sustained IFN production can lead to autoimmune diseases. This exploratory R21 application proposes C1QBP as a hidden host protector in mitochondria matrix. When mitochondria are damaged by infection and other cellular stresses, C1QBP is released from mitochondria to inhibit cGAS activity, thereby preventing excessive IFN response triggered by the leaked mtDNA. This study will elucidate an elegant host self-regulation mechanism, providing foundations for developing novel therapeutic strategies for infectious and autoimmune diseases.