West A Phillip, Khoury-Hanold William, Staron Matthew, Tal Michal C, Pineda Cristiana M, Lang Sabine M, Bestwick Megan, Duguay Brett A, Raimundo Nuno, MacDuff Donna A, Kaech Susan M, Smiley James R, Means Robert E, Iwasaki Akiko, Shadel Gerald S
Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2015 Apr 23;520(7548):553-7. doi: 10.1038/nature14156. Epub 2015 Feb 2.
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. 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.
线粒体DNA（mtDNA）通常每个细胞中存在数千个拷贝，并被包装成数百个称为类核的高阶结构。丰富的mtDNA结合蛋白TFAM（线粒体转录因子A）调节类核结构、丰度和分离。完全耗尽mtDNA会严重损害氧化磷酸化，引发钙依赖性应激信号和适应性代谢反应。然而，细胞对mtDNA不稳定性（在许多人类疾病和衰老中观察到的一种生理相关应激）的反应仍不清楚。在这里，我们表明TFAM缺乏引起的适度mtDNA应激会激活胞质抗病毒信号，以增强一部分干扰素刺激基因的表达。从机制上讲，我们发现异常的mtDNA包装会促进mtDNA逃逸到胞质溶胶中，在那里它与DNA传感器cGAS（也称为MB21D1）结合，并促进STING（也称为TMEM173）-IRF3依赖性信号传导，以提高干扰素刺激基因的表达，增强I型干扰素反应并赋予广泛的病毒抗性。此外，我们证明疱疹病毒会诱导mtDNA应激，这在感染期间会增强抗病毒信号和I型干扰素反应。我们的结果进一步证明线粒体是先天免疫的核心参与者，将mtDNA应激确定为抗病毒信号的细胞内触发因素，并表明细胞对mtDNA稳态的监测与经典病毒传感机制协同作用，以充分激活抗病毒先天免疫。
