IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v587y2020i7835d10.1038_s41586-020-2750-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2750-6
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-020-2750-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:587:y:2020:i:7835:d:10.1038_s41586-020-2750-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.