Mitochondrial DNA Stress Activation of Interferon Signaling and Lupus Pathology

项目总结 这是一项旨在描述干扰素信号转导的线粒体新途径的新建议。 并探讨其与自身免疫性疾病发病机制的关系。干扰素是一种重要的细胞因子 宿主防御，因为它们在非免疫细胞中激发固有的抗病毒状态，并刺激免疫细胞 和炎症来对抗感染。它们被用于治疗某些自身免疫性疾病，癌症， 和病毒感染，但也牵涉到病理时，慢性或断章取义。在我们的 线粒体DNA(MtDNA)应激与正常线粒体反应的TfAM/-小鼠模型研究 病毒感染后，我们发现线粒体DNA释放到细胞质中，为启动干扰素信号提供增强 抗病毒免疫。这种反应需要线粒体DNA与细胞质核酸传感器cGAS结合， 激活内质网(ER)驻留的蛋白刺突，并通过下游信号上调 干扰素刺激基因(ISGs)和1型干扰素的产生。ISG表达与1型干扰素的增加 信号在自身免疫性疾病系统性红斑狼疮(SLE或狼疮)中起作用。我们的 实验计划将系统地询问关于这种新的先天免疫的关键剩余问题 线粒体改变了信号通路，包括线粒体DNA是如何被cGAS释放和识别的 涉及动力学和自噬，是与人类疾病相关的途径，mtDNA应激 已经被牵连了。该项目的具体目标是：1)确定 CGAS感应线粒体DNA，2)破译线粒体动力学(分裂、融合、自噬)在线粒体DNA中的作用 释放和干扰素信号，包括开发一种创新的线粒体DNA释放试验，以及3)测试是否 线粒体DNA应激介导的干扰素信号在狼疮小鼠模型和人类患者细胞中的病理作用。 意义：该项目的完成将为线粒体DNA应激提供重要的新见解，这是 在许多疾病和衰老中观察到，导致先天性免疫途径激活，并可导致 自身免疫病理通过增加干扰素的产生，即使在没有病毒感染的情况下也是如此。通过定义 涉及的分子机制，如何增强这种反应以增强抗病毒免疫的新进展 或在病理情况下(如在狼疮中)预防，将制成具有治疗潜力的药物。 此外，我们将对线粒体动力学、细胞质等有相当大的基础生物学见解。 核酸识别途径、自噬以及线粒体DNA损伤、修复和修饰的机制。

PROJECT SUMMARY This is a new proposal aimed at characterizing a novel mitochondrial pathway of interferon (IFN) signaling we discovered and to probe its relevance to autoimmune disease pathogenesis. IFNs are essential cytokines for host defense because they provoke intrinsic antiviral states in non-immune cells and stimulate immune cells and inflammation to combat infection. They are used therapeutically for certain autoimmune diseases, cancers, and viral infection, but are also implicated in pathology when produced chronically or out of context. In our studies of a Tfam+/- mouse model of mitochondrial DNA (mtDNA) stress and normal mitochondrial responses to viral infection, we found that mtDNA release into the cytoplasm primes IFN signaling to provide enhanced antiviral immunity. This response requires binding of mtDNA to the cytoplasmic nucleic acid sensor cGAS, activation of the endoplasmic reticulum (ER)-resident protein STING, and downstream signaling to up-regulate interferon-stimulated genes (ISGs) and Type 1 IFN production. ISG expression and increased Type 1 IFN signaling contribute to the autoimmune disease systemic lupus erythematosus (SLE or lupus). Our experimental plan will systematically interrogate key remaining questions regarding this new innate immune signaling pathway, including how mtDNA is released and recognized by cGAS, are altered mitochondrial dynamics and autophagy involved, and is the pathway relevant to human diseases states where mtDNA stress has been implicated. The specific aims of the project are to 1) determine the specificity and mechanism of mtDNA sensing by cGAS, 2) decipher the role of mitochondrial dynamics (fission, fusion, autophagy) in mtDNA release and IFN signaling, including development of an innovative new mtDNA-release assay, and 3) test if mtDNA stress-mediated IFN signaling contributes to lupus pathology in mouse models and human patient cells. Significance: Completion of this project will provide significant new insight into how mtDNA stress, which is observed in many disease conditions and aging, results in innate immune pathway activation and can lead to autoimmune pathology via increased IFN production, even in the absence of a viral infection. By defining the molecular mechanisms involved, new inroads into how to augment this response to enhance antiviral immunity or prevent it under pathological circumstances (e.g. in lupus) will be made that have therapeutic potential. Furthermore, we will gain considerable new basic biology insight into mitochondrial dynamics, cytoplasmic nucleic acid recognition pathways, autophagy, and mechanisms of mtDNA damage, repair and modification.