Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway

By Lijun Sun, Jiaxi Wu, Fenghe Du, Xiang Chen, Zhijian J. Chen. Science, 2012

4,534 citations recorded by the source corpus.

DNA Sensing Is a (c)GAS DNA is normally localized to the nucleus, and so its cytoplasmic localization sends off alarm bells to the immune system because it indicates that a virus may have entered. But how does the immune system actually detect the DNA (see the Perspective by O'Neill)? Sun et al. (p. 786, published online 20 December) identify cyclic GMP-AMP (cGAMP) cyclase (cGAS), which can bind to cytoplasmic DNA directly and catalyze the production of cGAMP. cGAMP then acts as a second messenger to activate downstream signaling events that trigger antiviral immunity. Wu et al. (p. 826, published online 20 December) show that cGAMP, produced in response to cytoplasmic DNA, binds to and activates the signaling adaptor protein STING. Cyclic guanosine monophosphate–adenosine monophosphate synthase is identified and shown to be activated by DNA, but not RNA, in mammalian cells. [Also see Perspective by O'Neill] The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/81f5847f62848b948808bd76febd45da1a128cea

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Citations in the corpus

Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, neutral): “131 The combination of cGAS and mtDNA can catalyze cGAMP.”
Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics (2022, background): “Nucleic acid sensor cGAS is pivotal for eliciting immune reaction cGAS is a recently discovered nucleic acid sensor that is initially identified to recognize viruses.(306) Typically, activation of cGAS contributes to the induction of inflammasome as a means against viral or intracellular bacterial i”
Coronavirus infections and immune responses (2020, background): “In addition to TLR9 in the TLR family, Cytoplasmic DNA receptor (CDR) can recognizes DNA CpG islands.32 More than 10 CDRs distributed in the cytoplasm have been identified, including AIM2‐like receptors (ALRs), DNA‐dependent activator of IFN‐regulatory factor (DAI), interference stimulator of interf”
Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins (2014, background): “introduced into cells triggers cyclic GMP-AMP synthase activation (Sun et al. 2013).”
The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, background): “It is also possible that cGAS forms larger oligomers in cells upon binding to longer DNA, as cGAS was shown to form punctate structures together with DNA in cells (Sun et al., 2013).”
Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses (2015, neutral): “We considered increases in dsRNA, viral single-strandedRNA (ssRNA), and unmethylatedCpGDNA thatmight trigger cytosolic sensors (Sun et al., 2013).”
Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1 (2014, background): “STING may directly associate with stimulatory ligands, which include dsDNA, as well as with cyclic dinucleotides (CDNs) (9), produced directly by pathogens or metabolized from dsDNA by cyclic-GMP-AMP (cGAMP) synthase (cGAS) (10, 11).”
Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “Although CDN synthesis has been considered a unique feature of bacterial species, the recently identified mammalian enzyme cGAS can synthesize the CDN cyclic di-GMP/AMP (cGAMP) (239, 240).”
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors (2014, background): “Recent data have indicated that the ultimate direct ligand of STING is cyclic dinucleotides, generated in response to cyto- I solic DNA binding the enzyme cGAS (Sun et al., 2013; Wu et al., 2013).”