Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Nat Commun. 2021 Jan 4;12(1):61. doi: 10.1038/s41467-020-20234-9.
Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome.
外套蛋白复合物 I（COP-I）介导从高尔基体到内质网（ER）的逆行运输。编码 COP-I 亚基（α-COP）之一的 COPA 基因突变会导致一种称为 COPA 综合征的免疫失调疾病。逆行运输受损导致自身炎症的分子机制仍知之甚少。在这里，我们报告 STING，一种先天免疫蛋白，是逆行膜运输的货物。在致病的 α-COP 变体存在下，STING 不能从高尔基体中回收回 ER。STING 的强制高尔基体驻留导致 cGAS 非依赖性和棕榈酰化依赖性 STING 下游信号通路的激活。Surf4，一种在 ER/ER-Golgi 中间隔室/Golgi 之间循环的蛋白质，与 STING 和 α-COP 结合，并介导 STING 向 ER 的逆行运输。在致病的 α-COP 变体存在下，STING/Surf4/α-COP 复合物被破坏。我们还发现 STING 配体 cGAMP 会损害 STING/Surf4/α-COP 复合物的形成。我们的结果表明，逆行膜运输在静止状态下对 STING 进行了动态平衡调节，并为 COPA 综合征的发病机制提供了新的见解。
