Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Autophagy. 2010 Apr;6(3):430-2. doi: 10.4161/auto.6.3.11611. Epub 2010 Apr 25.
Microbial nucleic acids are potent inducers of innate immune response--the first line of host defense against microbes. It is known that double-stranded (ds) DNA triggers the expression of type I interferons (IFNs) and IFN-inducible genes resulting in the establishment of an antimicrobial environment. However, the regulatory mechanisms underlying the signaling pathways responsible for the induction of innate immune responses by dsDNA are still not fully understood. Recently, we showed that the translocation and subsequent assembly of the multispanning membrane protein, stimulator of interferon genes (STING), is critical for dsDNA-triggered innate immune responses. Following stimulation by dsDNA, STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus where it associates with TANK-binding kinase 1 (TBK1) on cytoplasmic punctate structures to induce the interferon regulatory factor 3 (IRF3)-dependent transcription of type I IFNs and IFN-inducible genes. We have also shown that dsDNA stimulation induces the colocalization of STING with the autophagy-related proteins Atg9a and microtubule-associated protein 1 light chain 3 (LC3). The targeted disruption of Atg9a, a multispanning membrane protein essential for autophagy, greatly promotes the dsDNA-driven assembly of STING and TBK1 leading to the aberrant activation of the innate immune response. However, the loss of Atg7, another essential component for autophagosome formation, does not affect the dsDNA-stimulated translocation of STING. Hence, Atg9a is a regulator of STING-mediated innate immune response as well as an essential autophagy protein. These findings indicate that dynamic membrane trafficking is triggered by dsDNA stimulation and plays a pivotal role in the signal transduction required for optimal activation of the innate immune response.
微生物核酸是先天免疫反应的有效诱导物，是宿主防御微生物的第一道防线。已知双链 DNA 可触发 I 型干扰素 (IFN) 和 IFN 诱导基因的表达，从而建立抗菌环境。然而，双链 DNA 诱导先天免疫反应的信号通路的调控机制尚不完全清楚。最近，我们发现多跨膜蛋白刺激干扰素基因 (STING) 的易位和随后的组装对于双链 DNA 触发的先天免疫反应至关重要。在双链 DNA 刺激后，STING 从内质网 (ER) 易位到高尔基体，在那里与细胞质点状结构上的 TANK 结合激酶 1 (TBK1) 结合，诱导干扰素调节因子 3 (IRF3) 依赖性 I 型 IFN 和 IFN 诱导基因的转录。我们还表明，双链 DNA 刺激诱导 STING 与自噬相关蛋白 Atg9a 和微管相关蛋白 1 轻链 3 (LC3) 的共定位。Atg9a 是自噬所必需的多跨膜蛋白，其靶向敲除极大地促进了 STING 和 TBK1 的双链 DNA 驱动组装，导致先天免疫反应的异常激活。然而，另一个对于自噬体形成必不可少的 Atg7 的缺失并不影响 STING 的双链 DNA 刺激易位。因此，Atg9a 是 STING 介导的先天免疫反应的调节剂，也是必需的自噬蛋白。这些发现表明，双链 DNA 刺激引发了动态膜转运，并在最佳激活先天免疫反应所需的信号转导中发挥了关键作用。
