2′,3′-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2′,3′-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.

2',3'-cGAMP 由 DNA 传感器 cGAS 产生，可激活干扰素基因刺激物(STING) 并在感染期间触发免疫反应。人们已经付出了巨大的努力来阐明 STING 激活的机制。然而，人们对 STING 抑制知之甚少。在这里，我们发现 apo-STING 表现出一个双层结构，具有头对头和并排堆积，由其配体结合域 (LBD) 介导。这种类型的组件将两个内质网 (ER) 膜结合在一起，不仅可以防止 STING ER 退出，还可以消除 TBK1 的募集, 代表 STING 的自动抑制状态。此外，我们获得了 STING/2',3'-cGAMP 复合物的细丝结构，它采用由 LBD 和跨膜结构域 (TMD) 介导的弯曲单层组装。活性、弯曲的 STING 聚合物可以使 ER 膜变形以支持其 ER 出口和顺行运输。我们的数据共同提供了关于 STING 自身抑制和激活的全景视图，这大大增加了当前对 cGAS-STING 通路的理解。