Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20842-6. doi: 10.1073/pnas.0911267106. Epub 2009 Nov 19.
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.
微生物核酸对于先天免疫反应的诱导至关重要，先天免疫反应是宿主防御微生物感染的机制。最近的研究表明，双链 DNA（dsDNA）通过诱导 I 型干扰素（IFN）和 IFN 诱导基因来引发强烈的先天免疫反应。然而，dsDNA 触发信号的调节机制尚未完全阐明。在这里，我们表明必需信号转导物刺激干扰素基因（STING）和 TANK 结合激酶 1（TBK1）的易位和组装对于 dsDNA 触发的先天免疫反应是必需的。在感知 dsDNA 后，STING 从内质网（ER）转移到高尔基氏体，最终到达细胞质点状结构与 TBK1 组装。在 STING 的 C 末端添加一个 ER 保留信号会降低其诱导抗病毒反应的能力。我们还表明，在 dsDNA 刺激后，STING 与自噬蛋白微管相关蛋白 1 轻链 3（LC3）和自噬相关基因 9a（Atg9a）共定位。Atg9a 的缺失，但不是另一个自噬相关基因（Atg7）的缺失，大大增强了 dsDNA 诱导的 STING 和 TBK1 的组装，导致先天免疫反应的异常激活。因此，Atg9a 作为 dsDNA 刺激后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，动态膜运输介导了 STING 的顺序易位和组装，这两者都是 dsDNA 触发的先天免疫反应最大激活所必需的过程。
