Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University.
Cell Struct Funct. 2022 Mar 8;47(1):19-30. doi: 10.1247/csf.21080. Epub 2022 Feb 5.
Stimulator of interferon genes (STING) is essential for the type I interferon response induced by microbial DNA or self-DNA leaked from mitochondria/nuclei. In response to the emergence of such DNAs in the cytosol, STING relocates from the endoplasmic reticulum (ER) to the Golgi, and activates TANK-binding kinase 1 (TBK1), a cytosolic kinase essential for the activation of STING-dependent downstream signalling. To understand at which subcellular compartments TBK1 becomes associated with STING, we generated cells stably expressing fluorescent protein-tagged STING (mNeonGreen-STING) and TBK1 (TBK1-mScarletI). We found that after STING stimulation, TBK1 became associated with the trans-Golgi network (TGN), not the other parts of the Golgi. STING variants that constitutively induce the type I interferon response have been identified in patients with autoinflammatory diseases named "STING-associated vasculopathy with onset in infancy (SAVI)". Even in cells expressing these constitutively active STING variants, TBK1 was found to be associated with TGN, not the other parts of the Golgi. These results suggest that TGN acts as a specific platform where STING associates with and activates TBK1.Key words: the Golgi, membrane traffic, innate immunity, STING.
干扰素基因刺激物 (STING) 对于微生物 DNA 或从线粒体/核泄漏的自身 DNA 诱导的 I 型干扰素反应是必不可少的。为了响应细胞质中出现这种 DNA，STING 从内质网 (ER) 重新定位到高尔基体，并激活 TANK 结合激酶 1 (TBK1)，TBK1 是激活 STING 依赖性下游信号所必需的细胞质激酶。为了了解 TBK1 在哪个亚细胞区室与 STING 相关联，我们生成了稳定表达荧光蛋白标记的 STING（mNeonGreen-STING）和 TBK1（TBK1-mScarletI）的细胞。我们发现，在 STING 刺激后，TBK1 与高尔基体的反式结构域 (TGN) 相关联，而不是高尔基体的其他部分。在自身炎症性疾病命名为“婴儿期起病的 STING 相关血管病（SAVI）”的患者中已经鉴定出了组成性诱导 I 型干扰素反应的 STING 变体。即使在表达这些组成性激活的 STING 变体的细胞中，也发现 TBK1 与 TGN 相关联，而不是高尔基体的其他部分。这些结果表明 TGN 充当 STING 与之关联并激活 TBK1 的特定平台。关键词：高尔基体、膜运输、先天免疫、STING。
