The mechanism of STING autoinhibition and activation

Sheng Liu¹, Bo Yang², Yingxiang Hou³, Kaige Cui⁴, Xiaozhu Yang⁴, Xiaoxiong Li⁴, Lianwan Chen⁵, Shichao Liu⁴, Zhichao Zhang⁴, Yuanyuan Jia⁴, Yufeng Xie⁶, Ying Xue⁴, Xiaomei Li⁷, Bingxue Yan⁷, Changxin Wu⁸, Wen Deng⁹, Jianxun Qi¹⁰, Defen Lu¹¹, George F Gao¹², Peiyi Wang¹³, Guijun Shang¹⁴

Affiliations

¹ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Cryo-EM Center, Southern University of Science and Technology, Shenzhen 518055, China.
² Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China.
³ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
⁴ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China.
⁵ National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
⁷ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China.
⁸ The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
⁹ College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.
¹⁰ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Life Science Academy, Beijing 102209, China.
¹¹ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China. Electronic address: ludefen1@sxau.edu.cn.
¹² Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: gaof@im.ac.cn.
¹³ Cryo-EM Center, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: wangpy@sustech.edu.cn.
¹⁴ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China. Electronic address: gjshang@gmail.com.

PMID: 37086726
DOI: 10.1016/j.molcel.2023.03.029

The mechanism of STING autoinhibition and activation

Sheng Liu et al. Mol Cell. 2023.

. 2023 May 4;83(9):1502-1518.e10.

doi: 10.1016/j.molcel.2023.03.029. Epub 2023 Apr 21.

Authors

Affiliations

¹ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Cryo-EM Center, Southern University of Science and Technology, Shenzhen 518055, China.
² Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China.
³ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
⁴ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China.
⁵ National Key Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
⁷ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China.
⁸ The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
⁹ College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.
¹⁰ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Life Science Academy, Beijing 102209, China.
¹¹ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China. Electronic address: ludefen1@sxau.edu.cn.
¹² Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: gaof@im.ac.cn.
¹³ Cryo-EM Center, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: wangpy@sustech.edu.cn.
¹⁴ Shanxi Provincial Key Laboratory of Protein Structure Determination, Shanxi Academy of Advanced Research and Innovation, Taiyuan 030012, China; College of Life Sciences, Shanxi Agricultural University, Taiyuan 030031, China; Shanxi Provincial Key Laboratory for Major Infectious Disease Response, Taiyuan 030012, China. Electronic address: gjshang@gmail.com.

PMID: 37086726
DOI: 10.1016/j.molcel.2023.03.029

Abstract

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.

Keywords: STING; activation; autoinhibition; cGAMP; cGAS.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

Bilayer STING goes head to head to stay put.
Yang K, Yan N. Yang K, et al. Mol Cell. 2023 May 4;83(9):1372-1374. doi: 10.1016/j.molcel.2023.04.004. Mol Cell. 2023. PMID: 37146568

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The mechanism of STING autoinhibition and activation

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The mechanism of STING autoinhibition and activation

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Abstract

Conflict of interest statement

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