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Nature:线粒体DNA损伤引发抗病毒固有免疫反应

来源:生物谷 2015-02-05 11:02

                                                        
2015年2月5日讯 /生物谷BIOON/ --近日,来自美国耶鲁大学医学院的研究人员著名国际期刊nature在线发表了他们的一项最新研究成果,他们发现在抗病毒天然免疫过程中,线粒体发挥了至关重要的作用。
 
在正常情况下,每个细胞内的线粒体DNA(mtDNA)有成千上万个拷贝,并且被包装成几百个高级结构,称为类核。大量mtDNA结合蛋白TFAM负责调控类核结构,数目以及相互之间的隔离。完全删除mtDNA会严重损伤氧化磷酸化过程,触发钙离子依赖的应激信号以及适应性代谢应答。但是在许多人类疾病以及衰老过程中观察到的细胞对mtDNA不稳定性的应答仍没有被很好地定义。研究人员通过实验证明因TFAM缺陷造成的适度mtDNA应激会参与细胞抗病毒信号途径,增强一系列干扰素刺激基因的表达。在机制上,他们发现mtDNA包装异常会促进mtDNA逃逸到细胞质内,被DNA感受器cGAS捕获,促进STING-IRF3依赖性信号途径,导致干扰素刺激基因表达增加,增强I型干扰素应答,促进细胞对病毒的抵抗效应。除此之外,孢疹病毒能够诱导mtDNA应激,增强感染阶段抗病毒信号途径和I型干扰素应答。
 
综上所述,该研究的结果表明线粒体对天然免疫应答至关重要,mtDNA应激是一种细胞内在的抗病毒信号开关,暗示细胞可能通过监控mtDNA平衡,协同经典病毒感应机制全面启动固有免疫系统的抗病毒功能。(生物谷Bioon.com)
 
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Mitochondrial DNA stress primes the antiviral innate immune response
 
A. Phillip West, William Khoury-Hanold, Matthew Staron, Michal C. Tal, Cristiana M. Pineda,Sabine M. Lang, Megan Bestwick, Brett A. Duguay, Nuno Raimundo, Donna A. MacDuff,Susan M. Kaech, James R. Smiley, Robert E. Means, Akiko Iwasaki & Gerald S. Shadel
 
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids1. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
 

 

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