CGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING.
Open accessAbstract
Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2'-5' and a 3'-5' phosphodiester linkage >Gp(2'-5')Ap(3'-5')>. We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2'-5'-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2'-5'-linked antiviral biomolecules.
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STING recruits TBK1 and IKK.
“STING recruits TANK-binding kinase 1 (TBK1) and IK-B kinase (IKK) (Ablasser et al., 2013; Diner et al., 2013; Gao et al., 2013; Sun et al., 2013, 2018; Wu et al., 2013; Zhang et al., 2013; Ablasser and Gulen, 2016; Chen et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Ablasser et al., 2013
In presence of ATP and GTP, cGAS catalyzes production of 2′3′ cGAMP which stimulates STING.
“In the presence of ATP and GTP, cGAS catalyzes the production of 2′3′ cyclic GMP-AMP (cGAMP) which stimulates the adaptor protein, STING.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Ablasser et al., 2013
cGAS is a 522 amino acid protein, cytosolic DNA sensor that activates innate immunity upon sensing aberrant dsDNA irrespective of source.
“cGAS a 522 amino acid protein, is a cytosolic DNA sensor that activates innate immunity upon sensing aberrant double stranded (ds) DNA molecules irrespective of the source.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Ablasser et al., 2013
Stimulated by cGAMP, STING changes from monomer to dimer and translocates from the ER to the perinuclear microsome.
“Stimulated by cGAMP, STING changes from monomer to dimer and translocates from ER to perinuclear microsome.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [258]
The cGAS-STING pathway is a cytosolic DNA sensing signaling pathway.
“cGAS-STING pathway is a cytosolic DNA sensing signaling.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [258]
Cytosolic dsDNA binds to cGAS, catalyzing the generation of cGAMP.
“Cytosolic dsDNA binds to cGAS, catalyzing the generation of cyclic GMP-AMP (cGAMP).”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [258]
STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I.
“Then, STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I [257–259].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [258]
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Self-citationEfficacy and mechanism of cGAMP to suppress Alzheimer’s disease by elevating TREM2
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IFI16: At the Interphase between Innate DNA Sensing and Genome Regulation
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STING SNP R293Q Is Associated with a Decreased Risk of Aging-Related Diseases
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- Authors
- Ablasser, A., Goldeck, M., Cavlar, T., Deimling, T., Witte, G., Röhl, I., Hopfner, K.-P., Ludwig, J., & Hornung, V.
- Affiliations
- University of Bonn (DE)
- Ludwig-Maximilians-Universität München (DE)
- Center for Integrated Protein Science Munich (DE)
- Corresponding author
- Ablasser, Andrea
- Hornung, Veit
- Venue
- Nature
- Published
- 2013-05-30
- Volume
- 498
- Issue
- 7454
- Pages
- 380-384
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4143541
- OpenAlex
- W1559117436
- Cited by
- 1,695
- References
- 24
- Citations by year
- 2026: 171 · 2025: 175 · 2024: 196 · 2023: 162 · 2022: 181 · 2021: 168 · 2020: 152 · 2019: 97 · 2018: 82 · 2017: 84 · 2016: 59 · 2015: 74 · 2014: 63 · 2013: 31
- FWCI
- 41.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (U19AI083025)
- 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 › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- cGAS, STING, cyclic dinucleotides, 2'-5' linkage, type I interferon, cytosolic DNA sensing, innate immunity, crystal structure, second messengers, sterile inflammation, autoimmune disease, cGAS inhibitors
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Adenosine Monophosphate, Animals, Cell Line, Cyclization, Cyclic GMP, Humans, Membrane Proteins, Models, Molecular, Magnetic Resonance Spectroscopy, Nucleotidyltransferases, Oligoribonucleotides, Second Messenger Systems, Molecular Structure, Mice, Biocatalysis, HEK293 Cells
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