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Structural basis of STING binding with and phosphorylation by TBK1

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  • Conggang Zhang

    (University of Texas Southwestern Medical Center)

  • Guijun Shang

    (University of Texas Southwestern Medical Center)

  • Xiang Gui

    (University of Texas Southwestern Medical Center)

  • Xuewu Zhang

    (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)

  • Zhijian J. Chen

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

Abstract

The invasion of mammalian cytoplasm by microbial DNA from infectious pathogens or by self DNA from the nucleus or mitochondria represents a danger signal that alerts the host immune system1. Cyclic GMP–AMP synthase (cGAS) is a sensor of cytoplasmic DNA that activates the type-I interferon pathway2. On binding to DNA, cGAS is activated to catalyse the synthesis of cyclic GMP–AMP (cGAMP) from GTP and ATP3. cGAMP functions as a second messenger that binds to and activates stimulator of interferon genes (STING)3–9. STING then recruits and activates tank-binding kinase 1 (TBK1), which phosphorylates STING and the transcription factor IRF3 to induce type-I interferons and other cytokines10,11. However, how cGAMP-bound STING activates TBK1 and IRF3 is not understood. Here we present the cryo-electron microscopy structure of human TBK1 in complex with cGAMP-bound, full-length chicken STING. The structure reveals that the C-terminal tail of STING adopts a β-strand-like conformation and inserts into a groove between the kinase domain of one TBK1 subunit and the scaffold and dimerization domain of the second subunit in the TBK1 dimer. In this binding mode, the phosphorylation site Ser366 in the STING tail cannot reach the kinase-domain active site of bound TBK1, which suggests that STING phosphorylation by TBK1 requires the oligomerization of both proteins. Mutational analyses validate the interaction mode between TBK1 and STING and support a model in which high-order oligomerization of STING and TBK1, induced by cGAMP, leads to STING phosphorylation by TBK1.

Suggested Citation

  • Conggang Zhang & Guijun Shang & Xiang Gui & Xuewu Zhang & Xiao-chen Bai & Zhijian J. Chen, 2019. "Structural basis of STING binding with and phosphorylation by TBK1," Nature, Nature, vol. 567(7748), pages 394-398, March.
  • Handle: RePEc:nat:nature:v:567:y:2019:i:7748:d:10.1038_s41586-019-1000-2
    DOI: 10.1038/s41586-019-1000-2
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    Citations

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    Cited by:

    1. Ying Huang & Geng Qin & TingTing Cui & Chuanqi Zhao & Jinsong Ren & Xiaogang Qu, 2023. "A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Xintao Tu & Ting-Ting Chu & Devon Jeltema & Kennady Abbott & Kun Yang & Cong Xing & Jie Han & Nicole Dobbs & Nan Yan, 2022. "Interruption of post-Golgi STING trafficking activates tonic interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Tomalika R. Ullah & Matt D. Johansen & Katherine R. Balka & Rebecca L. Ambrose & Linden J. Gearing & James Roest & Julian P. Vivian & Sunil Sapkota & W. Samantha N. Jayasekara & Daniel S. Wenholz & Vi, 2023. "Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. 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.
    5. 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.
    6. Yaling Dou & Rui Chen & Siyao Liu & Yi-Tsang Lee & Ji Jing & Xiaoxuan Liu & Yuepeng Ke & Rui Wang & Yubin Zhou & Yun Huang, 2023. "Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Xudong Chen & Min Xie & Sensen Zhang & Marta Monguió-Tortajada & Jian Yin & Chang Liu & Youqi Zhang & Maeva Delacrétaz & Mingyue Song & Yixue Wang & Lin Dong & Qiang Ding & Boda Zhou & Xiaolin Tian & , 2023. "Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. Remzi Onur Eren & Göksu Gökberk Kaya & Robin Schwarzer & Manolis Pasparakis, 2024. "IKKε and TBK1 prevent RIPK1 dependent and independent inflammation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. 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.

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