Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman
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引用次数: 0
摘要
最近,我们对dna感应机制的理解有了新的进展。在几种人类疾病以及细胞培养和动物模型中,线粒体功能障碍、氧化和蛋白酶抑制应激、不稳定和类核处置受损会导致线粒体DNA (mtDNA)从线粒体中释放。线粒体DNA错定位于细胞质和/或细胞外区室可通过结合DNA感应受体(DSRs)触发先天免疫和炎症反应。在这里,我们定义了使mtDNA具有高度免疫原性的特征及其从线粒体释放到细胞质和细胞外区室的机制。我们描述了结合mtDNA的主要DSRs,如环鸟苷-单磷酸腺苷-单磷酸合成酶(cGAS), z - dna结合蛋白1 (ZBP1), NOD-, LRR-和PYD-结构域蛋白3受体(NLRP3),在黑色素瘤2 (AIM2)和toll样受体9 (TLR9)中缺失,以及它们的下游信号级联。我们总结了在血管、代谢、肾脏、肺和神经退行性疾病以及病毒和细菌感染中,mtDNA错定位作为免疫反应驱动信号的主要发现、新颖性和空白。最后,我们定义了诱导或抑制mtDNA释放的常见策略,并提出了推进该领域的挑战。
Mitochondrial DNA signals driving immune responses: Why, How, Where?
There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
期刊介绍:
Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior.
Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.