Structural basis for the inhibition of cGAS by nucleosomes
Open accessAbstract
Saving a host cell from itself: A fundamental mammalian defense mechanism against pathogens and damaged cellular DNA is to recognize DNA fragments in the cytosol and trigger an inflammatory response. The cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) that recognizes cytosolic DNA is also found in the nucleus, but here its activity is suppressed by tethering to chromatin. Two papers now report cryo–electron microscopy structures of cGAS bound to the nucleosome core particle (NCP). Kujirai et al. observed a structure with two cGAS molecules bridging two NCPs, whereas Boyer et al. observed cGAS bound to a single nucleosome. Together, these structures show how cGAS is prevented from autoreactivity toward host DNA. Science , this issue p. 455 , p. 450
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cGAS is suppressed by binding to nucleosomes and disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS.
“Previously, we and others showed that cGAS is suppressed by binding to nucleosomes and that disruption of nucleosome regulation enables robust DNA-dependent activation of cGAS32–37 (Fig. 4a).”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [35]
cGAS is inhibited by nucleosome binding.
“inhibition by nucleosome binding (Boyer et al., 2020; Kujirai et al., 2020; Michalski et al., 2020; Pathare et al., 2020; Zhao et al., 2020b)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Kujirai et al., 2020
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- Authors
- Kujirai, T., Zierhut, C., Takizawa, Y., Kim, R., Negishi, L., Uruma, N., Hirai, S., Funabiki, H., & Kurumizaka, H.
- Affiliations
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Rockefeller University (US)
- Waseda University (JP)
- Corresponding author
- Kujirai, Tomoya
- Zierhut, Christian
- Funabiki, Hironori
- Kurumizaka, Hitoshi
- ORCID
- Venue
- Science
- Published
- 2020-10-23
- Volume
- 370
- Issue
- 6515
- Pages
- 455-458
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7584773
- OpenAlex
- W3086844613
- Cited by
- 243
- References
- 48
- Citations by year
- 2026: 32 · 2025: 30 · 2024: 46 · 2023: 26 · 2022: 39 · 2021: 60 · 2020: 9 · 2013: 1
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R35GM132111)
- Japan Agency for Medical Research and Development (JP20am0101076)
- Japan Society for the Promotion of Science (JP17H01408, JP18H05534, JP19K06522, JP20K15711)
- Japan Science and Technology Agency (JPMJCR16G1, JPMJER1901)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- cGAS, nucleosome, nucleosome core particle, DNA sensing, innate immune signaling, cryo-EM structure
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, DNA, Humans, Nuclear Proteins, Nucleosomes, Nucleotidyltransferases, Protein Conformation, Xenopus, Catalytic Domain, Cryoelectron Microscopy
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