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STING cyclic dinucleotide sensing originated in bacteria

Author

Listed:
  • Benjamin R. Morehouse

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Apurva A. Govande

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Adi Millman

    (Weizmann Institute of Science)

  • Alexander F. A. Keszei

    (Harvard Medical School)

  • Brianna Lowey

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Gal Ofir

    (Weizmann Institute of Science)

  • Sichen Shao

    (Harvard Medical School)

  • Rotem Sorek

    (Weizmann Institute of Science)

  • Philip J. Kranzusch

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute)

Abstract

Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides that are released during bacterial infection and in endogenous cyclic GMP–AMP signalling during viral infection and anti-tumour immunity1–5. STING shares no structural homology with other known signalling proteins6–9, which has limited attempts at functional analysis and prevented explanation of the origin of cyclic dinucleotide signalling in mammalian innate immunity. Here we reveal functional STING homologues encoded within prokaryotic defence islands, as well as a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to cyclic di-GMP synthesized by a neighbouring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple the recognition of cyclic dinucleotides with the formation of protein filaments to drive oligomerization of TIR effector domains and rapid NAD+ cleavage. We reconstruct the evolutionary events that followed the acquisition of STING into metazoan innate immunity, and determine the structure of a full-length TIR–STING fusion from the Pacific oyster Crassostrea gigas. Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signalling and reveal the conservation of a functional cGAS–STING pathway in prokaryotic defence against bacteriophages.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:586:y:2020:i:7829:d:10.1038_s41586-020-2719-5
    DOI: 10.1038/s41586-020-2719-5
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    Cited by:

    1. Elin Movert & Jaume Salgado Bolarin & Christine Valfridsson & Jorge Velarde & Steinar Skrede & Michael Nekludov & Ole Hyldegaard & Per Arnell & Mattias Svensson & Anna Norrby-Teglund & Kyu Hong Cho & , 2023. "Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. 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.
    3. Shuangshuang Wang & Sirong Kuang & Haiguang Song & Erchao Sun & Mengling Li & Yuepeng Liu & Ziwei Xia & Xueqi Zhang & Xialin Wang & Jiumin Han & Venigalla B. Rao & Tingting Zou & Chen Tan & Pan Tao, 2024. "The role of TIR domain-containing proteins in bacterial defense against phages," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Jiafeng Huang & Keli Zhu & Yina Gao & Feng Ye & Zhaolong Li & Yao Ge & Songqing Liu & Jing Yang & Ang Gao, 2024. "Molecular basis of bacterial DSR2 anti-phage defense and viral immune evasion," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Chia-Shin Yang & Tzu-Ping Ko & Chao-Jung Chen & Mei-Hui Hou & Yu-Chuan Wang & Yeh Chen, 2023. "Crystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. 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.
    7. 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.

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