The binding of TBK1 to STING requires exocytic membrane traffic from the ER
The binding of TBK1 to STING requires exocytic membrane traffic from the ER
复制标题
DOI：
10.1016/j.bbrc.2018.05.199
复制
发表时间：
2018-09-03
影响因子：
3.1
通讯作者：
Taguchi, Tomohiko
中科院分区：
文献类型：
--
作者：
Ogawa, Emari;Mukai, Kojiro;Taguchi, Tomohiko
干扰素基因刺激因子（STING）是I型干扰素和抗DNA病原体的促炎反应所必需的。响应于胞质DNA的存在，STING从内质网（ER）易位到高尔基体，并激活TANK结合激酶1（TBK 1），这是一种对于STING依赖性下游信号传导的激活至关重要的胞质激酶。TBK 1与STING结合的细胞器仍然未知。在这里，我们表明TBK 1在高尔基体而不是ER与STING结合。用布雷菲德菌素A（一种阻断内质网-高尔基体交通的药物）或敲低Sar 1（一种调节外壳蛋白复合物II（COP-II）介导的内质网-高尔基体交通的小GT酶）治疗，抑制TBK 1与STING的结合。如免疫荧光显微镜所示，当STING被运送到高尔基体时，内源性TBK 1被募集到高尔基体。在自身炎性疾病患者中发现了组成型诱导I型干扰素应答的STING变体。当STING变体被困在ER中时，即使这些致病性STING变体也不能与TBK 1结合。这些结果表明，高尔基体是STING招募并激活TBK 1以触发STING依赖性I型干扰素反应的细胞器。(C)2018爱思唯尔公司All rights reserved.
Stimulator of interferon genes (STING) is essential for the type I interferon and pro-inflammatory responses against DNA pathogens. In response to the presence of cytosolic DNA, STING translocates from the endoplasmic reticulum (ER) to the Golgi, and activates TANK-binding kinase 1 (TBK1), a cytosolic kinase that is essential for the activation of STING-dependent downstream signalling. The organelles where TBK1 binds to STING remain unknown. Here we show that TBK1 binds to STING at the Golgi, not at the ER. Treatment with brefeldin A, an agent to block ER-to-Golgi traffic, or knockdown of Sar1, a small GTPase that regulates coat protein complex II (COP-II)-mediated ER-to-Golgi traffic, inhibited the binding of TBK1 to STING. Endogenous TBK1 was recruited to the Golgi when STING was transported to the Golgi, as shown by immunofluorescence microscopy. STING variants that constitutively induce the type I interferon response were found in patients with autoinflammatory diseases. Even these disease-causative STING variants could not bind to TBK1 when the STING variants were trapped in the ER. These results demonstrate that the Golgi is an organelle at which STING recruits and activates TBK1 for triggering the STING-dependent type I interferon response. (C) 2018 Elsevier Inc. All rights reserved.