The mechanism of STING autoinhibition and activation

Liu，Sheng1,2,3; Yang，Bo1,4,5; Hou，Yingxiang1,6; Cui，Kaige1,5; Yang，Xiaozhu1,5; Li，Xiaoxiong1,5; Chen，Lianwan7; Liu，Shichao1,5; Zhang，Zhichao1,5; Jia，Yuanyuan1,5; Xie，Yufeng1,2,8; Xue，Ying1,5; Li，Xiaomei1; Yan，Bingxue1; Wu，Changxin6; Deng，Wen9; Qi，Jianxun2,10; Lu，Defen1,4; Gao，George F.1,2; Wang，Peiyi3; Shang，Guijun1,4,5

2023-05-04

10.1016/j.molcel.2023.03.029

Molecular Cell   影响因子和分区

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.

activation autoinhibition cGAMP cGAS STING

SCI

英语

NI论文

通讯

China Postdoctoral Science Foundation[2021M691434];National Natural Science Foundation of China[32070876];

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000999370900001

CELL PRESS

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85153527484

Scopus

1.Shanxi Provincial Key Laboratory of Protein Structure Determination,Shanxi Academy of Advanced Research and Innovation,Taiyuan,030012,China
2.CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing,100101,China
3.Cryo-EM Center,Southern University of Science and Technology,Shenzhen,518055,China
4.College of Life Sciences,Shanxi Agricultural University,Taiyuan,030031,China
5.Shanxi Provincial Key Laboratory for Major Infectious Disease Response,Taiyuan,030012,China
6.The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province,Institutes of Biomedical Sciences,Shanxi University,Taiyuan,030006,China
7.National Key Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China
8.Department of Basic Medical Sciences,School of Medicine,Tsinghua University,Beijing,100084,China
9.College of Veterinary Medicine,Northwest A&F University,Yangling,712100,China
10.Beijing Life Science Academy,Beijing,102209,China

Liu，Sheng,Yang，Bo,Hou，Yingxiang,et al. The mechanism of STING autoinhibition and activation[J]. Molecular Cell,2023,83(9):1502-1518.e10.

Liu，Sheng.,Yang，Bo.,Hou，Yingxiang.,Cui，Kaige.,Yang，Xiaozhu.,...&Shang，Guijun.(2023).The mechanism of STING autoinhibition and activation.Molecular Cell,83(9),1502-1518.e10.

Liu，Sheng,et al."The mechanism of STING autoinhibition and activation".Molecular Cell 83.9(2023):1502-1518.e10.