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Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING

Author

Listed:
  • Mei-Hui Hou

    (Genomics BioSci. & Tech. Co. Ltd.)

  • Yu-Chuan Wang

    (Genomics BioSci. & Tech. Co. Ltd.)

  • Chia-Shin Yang

    (Genomics BioSci. & Tech. Co. Ltd.)

  • Kuei-Fen Liao

    (Hsinchu Science Park)

  • Je-Wei Chang

    (Hsinchu Science Park)

  • Orion Shih

    (Hsinchu Science Park)

  • Yi-Qi Yeh

    (Hsinchu Science Park)

  • Manoj Kumar Sriramoju

    (Academia Sinica)

  • Tzu-Wen Weng

    (Academia Sinica
    National Taiwan University)

  • U-Ser Jeng

    (Hsinchu Science Park
    National Tsing Hua University)

  • Shang-Te Danny Hsu

    (Academia Sinica
    National Taiwan University)

  • Yeh Chen

    (National Chung Hsing University)

Abstract

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) signaling pathway plays a critical protective role against viral infections. Metazoan STING undergoes multilayers of regulation to ensure specific signal transduction. However, the mechanisms underlying the regulation of bacterial STING remain unclear. In this study, we determined the crystal structure of anti-parallel dimeric form of bacterial STING, which keeps itself in an inactive state by preventing cyclic dinucleotides access. Conformational transition between inactive and active states of bacterial STINGs provides an on-off switch for downstream signaling. Some bacterial STINGs living in extreme environment contain an insertion sequence, which we show codes for an additional long lid that covers the ligand-binding pocket. This lid helps regulate anti-phage activities. Furthermore, bacterial STING can bind cyclic di-AMP in a triangle-shaped conformation via a more compact ligand-binding pocket, forming spiral-shaped protofibrils and higher-order fibril filaments. Based on the differences between cyclic-dinucleotide recognition, oligomerization, and downstream activation of different bacterial STINGs, we proposed a model to explain structure-function evolution of bacterial STINGs.

Suggested Citation

  • Mei-Hui Hou & Yu-Chuan Wang & Chia-Shin Yang & Kuei-Fen Liao & Je-Wei Chang & Orion Shih & Yi-Qi Yeh & Manoj Kumar Sriramoju & Tzu-Wen Weng & U-Ser Jeng & Shang-Te Danny Hsu & Yeh Chen, 2023. "Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44052-x
    DOI: 10.1038/s41467-023-44052-x
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    References listed on IDEAS

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    1. Gaëlle Hogrel & Abbie Guild & Shirley Graham & Hannah Rickman & Sabine Grüschow & Quentin Bertrand & Laura Spagnolo & Malcolm F. White, 2022. "Cyclic nucleotide-induced helical structure activates a TIR immune effector," Nature, Nature, vol. 608(7924), pages 808-812, August.
    2. Tzu-Ping Ko & Yu-Chuan Wang & Chia-Shin Yang & Mei-Hui Hou & Chao-Jung Chen & Yi-Fang Chiu & Yeh Chen, 2022. "Crystal structure and functional implication of bacterial STING," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Cheng-Yu Huang & Piotr Draczkowski & Yong-Sheng Wang & Chia-Yu Chang & Yu-Chun Chien & Yun-Han Cheng & Yi-Min Wu & Chun-Hsiung Wang & Yuan-Chih Chang & Yen-Chen Chang & Tzu-Jing Yang & Yu-Xi Tsai & Ka, 2022. "In situ structure and dynamics of an alphacoronavirus spike protein by cryo-ET and cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Benjamin R. Morehouse & Apurva A. Govande & Adi Millman & Alexander F. A. Keszei & Brianna Lowey & Gal Ofir & Sichen Shao & Rotem Sorek & Philip J. Kranzusch, 2020. "STING cyclic dinucleotide sensing originated in bacteria," Nature, Nature, vol. 586(7829), pages 429-433, October.
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