As the name suggests, cGAMP is cyclic molecule composed of one Adenine monophosphate (AMP) and one Guanine monophosphate (GMP) connected by two phosphodiester bonds. Other CDNs (c-di-GMP and c-di-AMP) are commonly found in bacteria, archaea, and protozoa. Main article: Cyclic GMP-AMP synthase Structure Ĭyclic GMP-AMP (cGAMP) is a cyclic dinucleotide (CDN) and the first to be found in metazoans. Here they are stabilized through base stacking, hydrogen bonds, and divalent cations in order to catalyze phosphodiester bond formation to produce the cyclic dinucleotide cGAMP. Upon binding dsDNA, cGAS dimerizes and undergoes conformational changes that open up a catalytic nucleotide binding pocket, allowing GTP and ATP to enter. Mutations in the positively charged residues completely abrogate DNA binding and subsequent interferon production through STING. cGAS directly binds dsDNA via positively charged amino acid residues interacting with the negatively charged DNA phosphate backbone. This activity is dependent on cytosolic DNA.ĬGAS catalyzes formation of cGAMP in the presence of dsDNA. identified cGAS as the DNA-sensing protein able to trigger interferon beta by synthesizing the second messenger, 2’3’-cGAMP. Through biochemical fractionation of cell extracts and quantitative mass spectrometry, Sun, et al. Prior to the discovery of cGAS, it was known that interferon beta was produced in the presence of cytosolic dsDNA and that STING-deficient cells were unable to produce interferon in the presence of dsDNA. cGAS is unable to produce 2’3’-cGAMP in the presence of RNA. IRF3 leads to transcription of type-1 IFN-β. cGAMP then acts a second messenger, binding to STING, to trigger activation of the transcription factor IRF3. Upon directly binding cytosolic DNA, cGAS forms dimers to catalyze production of 2’3’-cGAMP from ATP and GTP. cGAS is also found in the nucleus where tight tethering to chromatin prevents its activation by self-DNA. Function ĬGAS is found at the plasma membrane and is responsible for detecting cytosolic double stranded DNA, normally found in the cell nucleus, in order to stimulate production of IFN-β.
These regions are necessary to form the catalytic pocket for the cGAS substrates: GTP and ATP, and to perform the necessary cyclization reaction. 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.
This region may contain two different DNA binding domains. N-terminal residues 1-212 are necessary to bind dsDNA. IRF3 is able to enter the nucleus to promote transcription of inflammatory genes, such as IFN-β.Ĭyclic GMP-AMP synthase (cGAS) Structure ĬGAS is a 522 amino acid protein and a member of the nucleotidyltransferase family. cGAMP then binds directly to stimulator of interferon genes (STING) which triggers phosphorylation/activation of the transcription factor IRF3 via TBK1. Upon DNA recognition, cGAS dimerizes and stimulates the formation of cyclic-GMP-AMP (cGAMP). One way cytosolic DNA is sensed is via the cGAS/STING pathway, specifically by the cyclic-GMP-AMP synthase (cGAS). 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. In normal cells, DNA is confined to the nucleus or mitochondria. Because all pathogens utilize nucleic acid to propagate, DNA and RNA can be recognized by PRRs to trigger immune activation. Upon recognition of a PAMP, PRRs generate signal cascades leading to transcription of genes associated with the immune response. The innate immune system relies on germline encoded pattern recognition receptors (PRRs) to recognize distinct pathogen-associated molecular patterns (PAMPs). This pathway plays a critical role in mediating immune defense against double-stranded DNA viruses. IRF3 can then go to the nucleus to trigger transcription of inflammatory genes. cGAMP binds to Stimulator of Interferon Genes ( STING) which triggers phosphorylation of IRF3 via TBK1. Upon binding DNA, the protein cyclic GMP-AMP Synthase ( cGAS) triggers reaction of GTP and ATP to form cyclic GMP-AMP (cGAMP). The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria.
DNA is normally found in the nucleus of the cell. 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 or to the activation of defense mechanisms.
0 kommentar(er)
