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Tight nuclear tethering of cGAS is essential for preventing autoreactivity
Open accessAbstract
cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that endogenous cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We identify the evolutionarily conserved tethering surface on cGAS and we show that mutation of single amino acids within this surface renders cGAS massively and constitutively active against self-DNA. Thus, tight nuclear tethering maintains the resting state of cGAS and prevents autoreactivity.
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“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 [37]
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Metadata
- Authors
- Volkman, H. E., Cambier, S., Gray, E. E., & Stetson, D. B.
- Affiliations
- University of Washington (US)
- Corresponding author
- Stetson, Daniel B
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-12-06
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6927687
- OpenAlex
- W2994585472
- Cited by
- 303
- References
- 42
- Citations by year
- 2026: 38 · 2025: 42 · 2024: 55 · 2023: 36 · 2022: 37 · 2021: 59 · 2020: 36
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (AI084914)
- Jane Coffin Childs Memorial Fund for Medical Research
- Burroughs Wellcome Fund (1013540)
- Howard Hughes Medical Institute (55108572)
- Bill and Melinda Gates Foundation (OPP1156262)
- Cancer Research Institute (A84161)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- cGAS, innate immunity, double-stranded DNA sensing, self-DNA, autoreactivity, chromatin, cytosolic DNA sensing, constitutive activation, nucleic acid sensors
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cell Nucleus, Cells, Cultured, Cytosol, DNA, DNA Damage, HeLa Cells, Humans, Mice, Inbred C57BL, Nuclear Proteins, Nucleotidyltransferases, Protein Binding, Cell Line, Tumor, DNA Cleavage
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