Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
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DOI：
10.1073/pnas.0807694106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Iwasaki, Akiko
中科院分区：
文献类型：
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作者：
Tal, Michal Caspi;Sasai, Miwa;Iwasaki, Akiko
自噬是一个高度保守的过程，通过清除受损的细胞器和长寿命的蛋白质来维持体内平衡。自噬缺陷的后果表现在多种病理状态中，包括神经退行性疾病、炎性病症和癌症。在这里，我们研究了自噬在先天性抗病毒防御的稳态调节中的作用。单链RNA病毒被胞质溶胶中的RIG-I样受体（RLR）成员识别。RLR通过IPS-1发出信号，导致产生关键的抗病毒细胞因子I型IFN。自噬缺陷Atg 5（-/-）细胞表现出增强的RLR信号，增加IFN分泌，并抵抗水泡性口炎病毒感染。在没有自噬的情况下，细胞积累功能障碍的线粒体，以及与细胞相关的IPS-1。与功能失调的线粒体相关的活性氧（ROS）在很大程度上负责Atg 5（-/-）细胞中增强的RLR信号传导，因为抗氧化剂处理阻断了过量的RLR信号传导。此外，通过用鱼藤酮处理细胞，线粒体ROS的自噬非依赖性增加足以放大WT细胞中的RLR信号传导。这些数据表明，自噬通过清除功能障碍的线粒体有助于先天性抗病毒防御的稳态调节，并揭示了与线粒体相关的ROS在增强RLR信号传导中起关键作用。
Autophagy is a highly conserved process that maintains homeostasis by clearing damaged organelles and long-lived proteins. The consequences of deficiency in autophagy manifest in a variety of pathological states including neurodegenerative diseases, inflammatory disorders, and cancer. Here, we studied the role of autophagy in the homeostatic regulation of innate antiviral defense. Single-stranded RNA viruses are recognized by the members of the RIG-I-like receptors (RLRs) in the cytosol. RLRs signal through IPS-1, resulting in the production of the key antiviral cytokines, type I IFNs. Autophagy-defective Atg5(-/-) cells exhibited enhanced RLR signaling, increased IFN secretion, and resistance to infection by vesicular stomatitis virus. In the absence of autophagy, cells accumulated dysfunctional mitochondria, as well as mitochondria-associated IPS-1. Reactive oxygen species (ROS) associated with the dysfunctional mitochondria were largely responsible for the enhanced RLR signaling in Atg5(-/-) cells, as antioxidant treatment blocked the excess RLR signaling. In addition, autophagy-independent increase in mitochondrial ROS by treatment of cells with rotenone was sufficient to amplify RLR signaling in WT cells. These data indicate that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling.