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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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Cites
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
Sun, L., Wu, J., Du, F., Chen, X., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1232458 · Cited by 4,996
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Ishikawa, H., & Barber, G. N. (2008) · Nature · doi:10.1038/nature07317 · Cited by 3,576
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Ishikawa, H., Ma, Z., & Barber, G. N. (2009) · Nature · doi:10.1038/nature08476 · Cited by 2,759 · cited 7×
“The cGAS-STING DNA sensing pathway has emerged as a key innate immune response that is important for antiviral immunity (Goubau et al., 2013), contributes to specific autoimmune diseases (Crowl et al., 2017), and mediates important aspects of antitumor immunity (Li and Chen, 2018). cGAS binds to double-stranded DNA an…”
BackgroundInfluentialCyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., & Chen, Z. J. (2012) · Science · doi:10.1126/science.1229963 · Cited by 2,628
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation
Liu, S., Cai, X., Wu, J., Cong, Q., Chen, X., Li, T., Du, F., Ren, J., Wu, Y.-T., Grishin, N. V., et al. (2015) · Science · doi:10.1126/science.aaa2630 · Cited by 1,927
cGAS surveillance of micronuclei links genome instability to innate immunity
Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., et al. (2017) · Nature · doi:10.1038/nature23449 · Cited by 1,752
Mitotic progression following DNA damage enables pattern recognition within micronuclei
Harding, S. M., Benci, J. L., Irianto, J., Discher, D. E., Minn, A. J., & Greenberg, R. A. (2017) · Nature · doi:10.1038/nature23470 · Cited by 1,508
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer
Li, T., & Chen, Z. J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180139 · Cited by 1,293
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3586 · Cited by 1,196
DNA-induced liquid phase condensation of cGAS activates innate immune signaling
Du, M., & Chen, Z. J. (2018) · Science · doi:10.1126/science.aat1022 · Cited by 1,089
Extraction, purification and analysis of histones
Shechter, D., Dormann, H. L., Allis, C. D., & Hake, S. B. (2007) · Nature Protocols · doi:10.1038/nprot.2007.202 · Cited by 1,054
Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses
Gao, D., Wu, J., Wu, Y.-T., Du, F., Aroh, C., Yan, N., Sun, L., & Chen, Z. J. (2013) · Science · doi:10.1126/science.1240933 · Cited by 1,032
cGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009
Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response
Stetson, D. B., & Medzhitov, R. M. (2006) · Immunity · doi:10.1016/j.immuni.2005.12.003 · Cited by 1,003
Self-citationStructural mechanism of cytosolic DNA sensing by cGAS
Çivril, F., Deimling, T., Mann, C. C. D. O., Ablasser, A., Moldt, M., Witte, G., Hornung, V., & Hopfner, K. (2013) · Nature · doi:10.1038/nature12305 · Cited by 916
Goubau, D., Deddouche, S., & Sousa, C. R. E. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.007 · Cited by 875
Cyclic GMP-AMP Synthase Is Activated by Double-Stranded DNA-Induced Oligomerization
Li, X., Shu, C., Yi, G., Chaton, C. T., Shelton, C. L., Diao, J., Zuo, X., Kao, C. C., Herr, A. B., & Li, P. (2013) · Immunity · doi:10.1016/j.immuni.2013.10.019 · Cited by 681
Chromothripsis and Kataegis Induced by Telomere Crisis
Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J., & de Lange, T. (2015) · Cell · doi:10.1016/j.cell.2015.11.054 · Cited by 675
Nuclear cGAS suppresses DNA repair and promotes tumorigenesis
Liu, H., Zhang, H., Wu, X., Ma, D., Wu, J., Wang, L., Jiang, Y., Fei, Y., Zhu, C., Tan, R., et al. (2018) · Nature · doi:10.1038/s41586-018-0629-6 · Cited by 672
Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6
Toogood, P. L., Harvey, P. J., Repine, J. T., Sheehan, D. J., VanderWel, S. N., Zhou, H., Keller, P. R., McNamara, D. J., Sherry, D., Zhu, T., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049354h · Cited by 513
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders
Andreeva, L., Hiller, B., Kostrewa, D., Lässig, C., de Oliveira Mann, C. C., Jan Drexler, D., Maiser, A., Gaidt, M., Leonhardt, H., Hornung, V., et al. (2017) · Nature · doi:10.1038/nature23890 · Cited by 511
HIV-1 evades innate immune recognition through specific cofactor recruitment
Rasaiyaah, J., Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., Selwood, D. L., James, L. C., Noursadeghi, M., et al. (2013) · Nature · doi:10.1038/nature12769 · Cited by 474
DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
Lau, L., Gray, E. E., Brunette, R. L., & Stetson, D. B. (2015) · Science · doi:10.1126/science.aab3291 · Cited by 466
Self-citationThe Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death
Zierhut, C., Yamaguchi, N., Paredes, M. C. G., Luo, J., Carroll, T., & Funabiki, H. (2019) · Cell · doi:10.1016/j.cell.2019.05.035 · Cited by 411
Lahaye, X., Satoh, T., Gentili, M., Cerboni, S., Conrad, C., Hurbain, I., El Marjou, A., Lacabaratz, C., Lelièvre, J.-D., & Manel, N. (2013) · Immunity · doi:10.1016/j.immuni.2013.11.002 · Cited by 390
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
Zhou, W., Whiteley, A. T., Mann, C. C. D. O., Morehouse, B. R., Nowak, R. P., Fischer, E. S., Gray, N. S., Mekalanos, J. J., & Kranzusch, P. J. (2018) · Cell · doi:10.1016/j.cell.2018.06.026 · Cited by 387
Gray, E. E., Treuting, P. M., Woodward, J. J., & Stetson, D. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500969 · Cited by 384
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Bootsma, D., Budke, L., & Vos, O. (1964) · Experimental Cell Research · doi:10.1016/s0014-4827(64)81035-1 · Cited by 342
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
Ma, Z., Jacobs, S. R., West, J. A., Stopford, C. M., Zhang, Z., Davis, Z. H., Barber, G. N., Glaunsinger, B. A., Dittmer, D. P., & Damania, B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503831112 · Cited by 318
A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS-Mediated Exhaustion
Xia, P., Wang, S., Ye, B., Du, Y., Li, C., Xiong, Z., Qu, Y., & Fan, Z. (2018) · Immunity · doi:10.1016/j.immuni.2018.03.016 · Cited by 285
Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein
Wu, J., Li, W., Shao, Y., Avey, D. R., Fu, B., Gillen, J., Hand, T. H., Ma, S., Liu, X., Miley, W., et al. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.07.015 · Cited by 278
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Orzalli, M. H., Broekema, N. M., Diner, B. A., Hancks, D. C., Elde, N. C., Cristea, I. M., & Knipe, D. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424637112 · Cited by 275
Barnett, K. C., Coronas-Serna, J. M., Zhou, W., Ernandes, M. J., Cao, A., Kranzusch, P. J., & Kagan, J. C. (2019) · Cell · doi:10.1016/j.cell.2019.01.049 · Cited by 275
Jiang, H., Xue, X., Panda, S., Kawale, A. S., Hooy, R. M., Liang, F., Sohn, J., Sung, P., & Gekara, N. O. (2019) · The EMBO Journal · doi:10.15252/embj.2019102718 · Cited by 270
Gentili, M., Lahaye, X., Nadalin, F., Nader, G. P. F., Lombardi, E. P., Hervé, S., Silva, N. S. D., Rookhuizen, D. C., Zueva, E., Goudot, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.105 · Cited by 256
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Gray, E. E., Winship, D., Snyder, J. M., Child, S. J., Geballe, A. P., & Stetson, D. B. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.015 · Cited by 197
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Ibsen, M. S., Gad, H. H., Andersen, L. L., Hornung, V., Julkunen, I., Sarkar, S. N., & Hartmann, R. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv389 · Cited by 76
Gentili, M., Lahaye, X., Nadalin, F., Nader, G. P. F., Lombardi, E. P., Hervé, S., Silva, N. S. D., Rookhuizen, D. C., Zueva, E., Goudot, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.049 · Cited by 64
Luo, Y., Tucker, S. C., & Casadevall, A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.7226 · Cited by 46
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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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