Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects

By Xiao-Dong Li, Jiaxi Wu, Daxing Gao, Hua Wang, Lijun Sun, Zhijian J. Chen. Science, 2013

1,059 citations recorded by the source corpus.

Alarm Bells The presence of DNA in the cytosol of mammalian cells is a danger signal, indicating, for example, that a DNA-containing virus has infected the cell. This signal triggers an innate immune response, which involves the expression of type I interferons, and is critical for antiviral immunity and responses to DNA vaccines. Cyclic GMP-AMP synthase (cGAS) was recently identified as a sensor of cytosolic DNA. Li et al. (p. 1390, published online 29 August) now use knockout mice to provide genetic evidence that, in multiple cell types, cGAS is the primary DNA sensor required for the type I interferon response in vivo. The cytosolic DNA sensor cyclic guanosine monophosphate–adenosine monophosphate synthase is essential for antiviral immunity in vivo. Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochemical approaches led to the identification of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas−/−) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas−/− mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody production in mice.

Subfields: Immunology, Molecular Biology, Parasitology

View Paper: https://www.semanticscholar.org/paper/78a3eb5b1b7523d19e7e0162b74d43380b6d3a18

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. G. Barber
3. Tuo Li
4. G. Shadel
5. A. West
6. Xiang Chen
7. T. Gajewski
8. V. Deretic

In Molecular Biology

1. Zhijian J. Chen
2. Tuo Li
3. G. Barber
4. T. Gajewski
5. G. Shadel
6. A. West
7. Xiang Chen
8. V. Deretic

In Parasitology

1. G. Barber
2. Tuo Li
3. Zhijian J. Chen
4. V. Deretic
5. Beth Levine
6. G. Hotamışlıgil

Citations in the corpus

• Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases (2015, methodology): “However, so far, only cGAS has been demonstrated by genetic experiments to function as a nonredundant and essential cytosolic DNA sensor that activates the type-I IFN pathway in vivo (13, 41).”
• Cyclic GMP-AMP Synthase is Activated by Double-stranded DNA-Induced Oligomerization (2013, background): “The critical role of cGAS in antiviral immunity and cytosolic DNA sensing has been confirmed by recent studies of cGASdeficient mice (Li et al., 2013).”
• STING: infection, inflammation and cancer (2015, positive): “For example, ablation of this enzyme rendered RNA virus-infected cells sensitive to viral replication, even though RNA species do not trigger cGAS activity or the generation of CDNs 44, 45 .”
• Autophagy in inflammation, infection, and immunometabolism (2021, background): “cGAS recognizes dsDNA, generates a second messenger cyclic-AMP-GMP (cGAMP) which in turn activates STING and TBK1 to induce phosphorylation of IRF3 and activate type I IFN expression (Li et al., 2013; Liu et al., 2015; Zhang et al., 2019).”