Structural mechanism of cGAS inhibition by the nucleosome

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, Nicolas H. Thomä () and Andrea Ablasser ()
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Ganesh R. Pathare: Friedrich Miescher Institute for Biomedical Research
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
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
Joscha Weiss: Friedrich Miescher Institute for Biomedical Research
Zuzanna Kozicka: Friedrich Miescher Institute for Biomedical Research
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
Andrea Ablasser: Swiss Federal Institute of Technology Lausanne (EPFL)

Nature, 2020, vol. 587, issue 7835, 668-672

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2750-6

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