Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response
Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response
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DOI：
10.1073/pnas.0911267106
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发表时间：
2009-12-08
影响因子：
11.1
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Saitoh, Tatsuya;Fujita, Naonobu;Akira, Shizuo
微生物核酸对于诱导先天免疫应答是至关重要的，先天免疫应答是宿主抵抗微生物感染的防御机制。最近的研究表明，双链DNA（dsDNA）通过诱导I型IFN（IFN）和IFN诱导基因诱导强有力的先天免疫应答。然而，dsDNA触发的信号转导的调控机制尚未完全理解。在这里，我们表明，必要的信号转导，刺激因子IFN基因（STING）和TANK结合激酶1（TBK 1）的易位和组装，需要双链DNA触发的先天免疫反应。在感应dsDNA后，STING从内质网（ER）移动到高尔基体，最终到达细胞质点状结构与TBK1组装。向STING的C末端添加ER保留信号抑制其诱导抗病毒应答的能力。我们还表明，STING共定位与自噬蛋白，微管相关蛋白1轻链3（LC 3）和自噬相关基因9a（Atg9a），dsDNA刺激后。Atg9a的丢失，而不是另一个自噬相关基因（Atg7）的丢失，极大地增强了dsDNA对STING和TBK1的组装，导致先天免疫应答的异常激活。因此，Atg9a作为dsDNA刺激后的先天免疫的调节剂以及必需的自噬蛋白发挥作用。这些结果表明，动态膜运输介导STING的顺序易位和组装，这两者都是由dsDNA触发的先天免疫应答的最大激活所需的基本过程。
Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.