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Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP

Author

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  • Guijun Shang

    (University of Texas Southwestern Medical Center)

  • Conggang Zhang

    (University of Texas Southwestern Medical Center)

  • Zhijian J. Chen

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Xiao-chen Bai

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Xuewu Zhang

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP–AMP synthase, which produces 2′3′-cyclic GMP–AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)1–8. STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain9–13. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP9,14. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.

Suggested Citation

  • Guijun Shang & Conggang Zhang & Zhijian J. Chen & Xiao-chen Bai & Xuewu Zhang, 2019. "Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP," Nature, Nature, vol. 567(7748), pages 389-393, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7748:d:10.1038_s41586-019-0998-5
    DOI: 10.1038/s41586-019-0998-5
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    Citations

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    Cited by:

    1. Matteo Gentili & Bingxu Liu & Malvina Papanastasiou & Deborah Dele-Oni & Marc A. Schwartz & Rebecca J. Carlson & Aziz M. Al’Khafaji & Karsten Krug & Adam Brown & John G. Doench & Steven A. Carr & Nir , 2023. "ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Haruka Kemmoku & Kanoko Takahashi & Kojiro Mukai & Toshiki Mori & Koichiro M. Hirosawa & Fumika Kiku & Yasunori Uchida & Yoshihiko Kuchitsu & Yu Nishioka & Masaaki Sawa & Takuma Kishimoto & Kazuma Tan, 2024. "Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Alex J. Pollock & Shivam A. Zaver & Joshua J. Woodward, 2020. "A STING-based biosensor affords broad cyclic dinucleotide detection within single living eukaryotic cells," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Yongfang Lin & Jing Yang & Qili Yang & Sha Zeng & Jiayu Zhang & Yuanxiang Zhu & Yuxin Tong & Lin Li & Weiqi Tan & Dahua Chen & Qinmiao Sun, 2023. "PTK2B promotes TBK1 and STING oligomerization and enhances the STING-TBK1 signaling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Shirin Fatma & Arpita Chakravarti & Xuankun Zeng & Raven H. Huang, 2021. "Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    6. Martha Triantafilou & Joshi Ramanjulu & Lee M. Booty & Gisela Jimenez-Duran & Hakan Keles & Ken Saunders & Neysa Nevins & Emma Koppe & Louise K. Modis & G. Scott Pesiridis & John Bertin & Kathy Triant, 2022. "Human rhinovirus promotes STING trafficking to replication organelles to promote viral replication," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Wei-Wei Luo & Zhen Tong & Pan Cao & Fu-Bing Wang & Ying Liu & Zhou-Qin Zheng & Su-Yun Wang & Shu Li & Yan-Yi Wang, 2022. "Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Bao-cun Zhang & Marlene F. Laursen & Lili Hu & Hossein Hazrati & Ryo Narita & Lea S. Jensen & Aida S. Hansen & Jinrong Huang & Yan Zhang & Xiangning Ding & Maimaitili Muyesier & Emil Nilsson & Agniesz, 2024. "Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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