The mechanism of STING autoinhibition and activation

• Published in: Molecular cell Vol. 83; no. 9; pp. 1502 - 1518.e10
• Main Authors: Liu, Sheng, Yang, Bo, Hou, Yingxiang, Cui, Kaige, Yang, Xiaozhu, Li, Xiaoxiong, Chen, Lianwan, Liu, Shichao, Zhang, Zhichao, Jia, Yuanyuan, Xie, Yufeng, Xue, Ying, Li, Xiaomei, Yan, Bingxue, Wu, Changxin, Deng, Wen, Qi, Jianxun, Lu, Defen, Gao, George F., Wang, Peiyi, Shang, Guijun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2023
• Subjects: activation; autoinhibition; cGAMP; cGAS; DNA; Immunity, Innate; Membrane Proteins - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Protein Serine-Threonine Kinases - metabolism; Signal Transduction; STING; cGAS; STING; cGAMP; autoinhibition; activation
• DOI: 10.1016/j.molcel.2023.03.029
• ISSN: 1097-2765; 1097-4164

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. [Display omitted] •Apo-STING exists as oligomer in the cell•Apo-STING oligomer adopts a bilayer with head-to-head and side-by-side packing of LBD•Apo-STING bilayer is crucial for STING ER retention and autoinhibition•Activated STING filament displays a bent conformation mediated by LBD and TMD Liu et al. show that apo-STING forms oligomers with bilayer assembly zippering two ER membranes in the resting state whereby STING fulfills its ER retention and autoinhibition. The activated STING filament adopts a bent conformation that deforms the membrane, which is fit for its anterograde transportation.