Cyclic-GMP-AMP Is An Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA

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

1,747 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 acts as a second messenger that turns on antiviral immunity in response to cytoplasmic DNA. [Also see Perspective by O'Neill] Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e4197f5ec280c1cc6641c7e12b1a138ddd1c87af

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Zhijian J. Chen
2. S. Tait
3. Tuo Li
4. Joel S. Riley
5. A. Ablasser
6. Jiaxi Wu
7. Lijun Sun
8. Xiang Chen

In Molecular Biology

1. Zhijian J. Chen
2. Tuo Li
3. A. Ablasser
4. S. Tait
5. Joel S. Riley
6. Jiaxi Wu
7. Lijun Sun
8. Xiang Chen

Citations in the corpus

• The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases.”
• Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High Affinity Ligand for STING (2013, positive): “We have recently identified cyclic GMP-AMP synthase (cGAS) as a DNA sensor that activates STING (Sun et al., 2013; Wu et al., 2013).”
• Cyclic GMP-AMP Synthase is a Cytosolic DNA Sensor that Activates the Type-I Interferon Pathway (2012, positive): “Mass spectrometry and SRM quantification of cGAMP was described in Wu et al (4).”
• Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase (2013, neutral): “Nevertheless, the mass spectroscopic approach utilized (Wu et al., 2013) cannot distinguish between 30,50 and 20,50 linkages for one or both phosphodiester bonds of cyclic GAMP.”