cGAS–STING cytosolic DNA sensing pathway
The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence[1] or to the activation of defense mechanisms.
Upon recognition of a PAMP, PRRs generate signal cascades leading to transcription of genes associated with the immune response.
Because all pathogens utilize nucleic acid to propagate, DNA and RNA can be recognized by PRRs to trigger immune activation.
The presence of DNA in the cytosol is indicative of cellular damage or infection and leads to activation of genes associated with the immune response.
C-terminal residues 213-522 contain part of the nucleotidyltransferase (NTase) motif and a Mab21 domain and are highly conserved in cGAS from zebrafish to humans.
Through biochemical fractionation of cell extracts and quantitative mass spectrometry, Sun, et al.[8] identified cGAS as the DNA-sensing protein able to trigger interferon beta by synthesizing the second messenger, 2’3’-cGAMP.
Mutations in the positively charged residues completely abrogate DNA binding and subsequent interferon production through STING.
cGAMP was discovered by Zhijian "James" Chen and colleagues[11] by collecting cytoplasmic extracts from cells transfected with different types of DNA.
[9] STING is an endoplasmic reticulum–resident protein and has been shown to directly bind to a variety of different cyclic-di-nucleotides, such as cyclic adenosine-inosine monophosphate.
[12] STING was identified in murine embryonic fibroblasts, and is required for the type 1 interferon response in both immune and non-immune cells.
The signaling pathways activated by STING combine to induce an innate immune response to cells with ectopic DNA in the cytosol.
Loss of STING activity inhibits the ability of mouse embryonic fibroblasts to fight against infection by certain viruses, and more generally, is required for the type 1 IFN response to introduced cytosolic DNA.
This has recently led to speculation that 2’-3’ cGAMP could be used as a more efficient and direct adjuvant than DNA to induce immune responses.
It was shown that DNA viruses, such as HSV-1, are able to trigger cGAMP production and subsequent activation of interferon beta via STING .
In these studies, inhibitors of retroviral reverse transcription abrogated IFN production, suggesting that it is the viral cDNA which is activating cGAS.
[20] Moreover, activation of the STING pathway in bone marrow macrophages has been shown to inhibit the growth of acute myeloid leukaemia cells in mice models.
Mutations in the 3’ repair exonuclease, TREX1, cause endogenous retroelements to accumulate in the cytosol, which can lead to cGAS/STING activation, resulting in IFN production.
[9] Studies have shown that vaccines encoded with the chicken antigen, ovalbumin (OVA), in conjunction with cGAMP, were able to activate antigen-specific T and B cells in a STING-dependent manner in vivo.
[23] Furthermore, the enhanced stability of cGAMP, due to the unique 2’-5’ phosphodiester bond, may make it a preferred adjuvant to DNA for in vivo applications.
