Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

作者：Tatsuya Saitoh, Naonobu Fujita, Takuya Hayashi, Keigo Takahara, Takashi Satoh, Hanna Lee, Kohichi Matsunaga, Shun Kageyama, Hiroko Omori, Takeshi Noda, Naoki Yamamoto, Taro Kawai, Ken J. Ishii, Osamu Takeuchi, Tamotsu Yoshimori, Shizuo Akira · 发表于：Proceedings of the National Academy of Sciences · 年份：2009 · DOI：10.1073/pnas.0911267106 · 被引用次数：863 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Viral Infections and Outbreaks Research

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 an...