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Structural mechanism of cGAS inhibition by the nucleosome

Author

Listed:
  • Ganesh R. Pathare

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Alexiane Decout

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Selene Glück

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Simone Cavadini

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Kristina Makasheva

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Ruud Hovius

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Georg Kempf

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Joscha Weiss

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Zuzanna Kozicka

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Baptiste Guey

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Pauline Melenec

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Beat Fierz

    (Swiss Federal Institute of Technology Lausanne (EPFL))

  • Nicolas H. Thomä

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Andrea Ablasser

    (Swiss Federal Institute of Technology Lausanne (EPFL))

Abstract

The DNA sensor cyclic GMP–AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2′3′ cGMP–AMP, which triggers the induction of inflammatory cytokines and type I interferons 2–7. cGAS is also present inside the cell nucleus, which is replete with genomic DNA8, where chromatin has been implicated in restricting its enzymatic activity9. However, the structural basis for inhibition of cGAS by chromatin remains unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes. cGAS makes extensive contacts with both the acidic patch of the histone H2A–H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also find cGAS engaged to a second nucleosome in trans. Mechanistically, binding of the nucleosome locks cGAS into a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS–acidic patch interface are sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash the activity of cGAS on genomic DNA in living cells. Our work uncovers the structural basis of the interaction between cGAS and chromatin and details a mechanism that permits self–non-self discrimination of genomic DNA by cGAS.

Suggested Citation

  • Ganesh R. Pathare & Alexiane Decout & Selene Glück & Simone Cavadini & Kristina Makasheva & Ruud Hovius & Georg Kempf & Joscha Weiss & Zuzanna Kozicka & Baptiste Guey & Pauline Melenec & Beat Fierz & , 2020. "Structural mechanism of cGAS inhibition by the nucleosome," Nature, Nature, vol. 587(7835), pages 668-672, November.
    • Handle: RePEc:nat:nature:v:587:y:2020:i:7835:d:10.1038_s41586-020-2750-6
    DOI: 10.1038/s41586-020-2750-6
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    Citations

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    Cited by:

    1. Lina Wang & Siru Li & Kai Wang & Na Wang & Qiaoling Liu & Zhen Sun & Li Wang & Lulu Wang & Quentin Liu & Chengli Song & Caigang Liu & Qingkai Yang, 2022. "DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Zhengyi Zhen & Yu Chen & Haiyan Wang & Huanyin Tang & Haiping Zhang & Haipeng Liu & Ying Jiang & Zhiyong Mao, 2023. "Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Hervé Técher & Diyavarshini Gopaul & Jonathan Heuzé & Nail Bouzalmad & Baptiste Leray & Audrey Vernet & Clément Mettling & Jérôme Moreaux & Philippe Pasero & Yea-Lih Lin, 2024. "MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    5. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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