How does cGAMP activate STING?

The cGAS–cGAMP–STING pathway is activated by DNA damage to mediate antitumor immunity, senescence, and inflammatory responses. In addition to inducing cytokines, DNA damage also enhances the expression of ligands of natural killer (NK) cells such as NKG2D ligands (Gasser et al., 2005; Lam et al., 2014).

What does cGAS STING stand for?

Upon binding DNA, the protein cyclic GMP-AMP Synthase (cGAS) triggers reaction of GTP and ATP to form cyclic GMP-AMP (cGAMP). cGAMP binds to Stimulator of Interferon Genes (STING) which triggers phosphorylation of IRF3 via TBK1.

What is cGAS in biology?

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major responder to the pathogenic DNA of viruses and bacteria. Upon DNA binding, cGAS becomes enzymatically active to generate the second messenger cGAMP, leading to activation of inflammatory genes, type I interferon production, autophagy, and cell death.

Is cGAS a pattern recognition receptor?

Cyclic GMP-AMP synthase (cGAS), a pattern recognition receptor of the innate immune system, induces the expression of type-I interferon (IFN-I) genes upon detecting cytosolic double-stranded (ds)DNA and synthesizing the unique second messenger, cyclic GMP-AMP (cGAMP), from ATP and GTP (Sun, Wu, Du, Chen, & Chen, 2013).

Is cGAS a PRR?

Cyclic GMP-AMP synthase (cGAS) is one such PRR that detects cytosolic double-stranded DNA (dsDNA), whether foreign or self. Upon detection of dsDNA, cGAS binds it and synthesizes the second messenger cyclic GMP-AMP (cGAMP)2,3.

Who discovered cGAS?

One of the world’s leading investigators in deciphering cell signaling, Dr. Chen was awarded the 2019 Breakthrough Prize in Life Sciences for his discovery of the DNA-sensing enzyme cGAS, which launches the body’s immune defense against infections.

Is STING a PRR?

As a signaling hub in innate immunity, STING is a pattern recognition receptor (PRR) of paramount importance in orchestrating the body’s response to pathogenic, tumor, or self DNA in the cytoplasm.

What is cGAS enzyme?

Cyclic GMP–AMP synthase (cGAS) is a signaling enzyme in human cells that controls immune-sensing of cytosolic DNA. The recent discoveries of diverse structural homologs of cGAS in animals and bacteria reveal that cGAS-like signaling is surprisingly ancient and widespread in biology.

Is cGAS an ISG?

Further experiments indicated that cGAS is an IFN-stimulated gene (ISG), and two adjacent IFN-sensitive response elements (ISREs) in the promoter region of cGAS mediate the induction of cGAS by IFN-I.

When was STING discovered?

The stimulator of interferon genes (STING) is a novel player with pleiotropic effects in the field of the immune system. The discovery of STING as a 42-kDa “dimeric adaptor protein” in 2008 quickly expanded the fields of immunology research as well as cancer immunotherapy [4].

Who discovered STING?

The innate immune sensor STING and STING controlled cytosolic DNA innate immune signaling pathway was discovered by the laboratory of Glen N Barber (Nature, 2008). STING senses cyclic dinucleotides (CDN’s) generated by intracellular bacteria or produced by cytosolic DNA species via a cellular CDN synthase, cGAS.

What is cGAS inhibitor?

G140 is a small-molecule inhibitor of the double-stranded DNA (dsDNA) sensor, cGAS (cyclic GMP-AMP synthase; cGAMP synthase). cGAS is the primary sensor of cytosolic dsDNA, a danger signal indicating possible disturbances in homeostasis caused by infection, sterile tissue damage, and/or cancer.

What is the function of CGAS?

cGAS is a sensor of cytosolic DNA and responds equally to exogenous and endogenous DNA. After recognition of cytosolic dsDNA or ssDNA, cGAS synthesizes the second messenger 2’3′-cGAMP, which then binds to and activates stimulator of interferon genes (STING). STING plays an essential role in respondi …

Is the cytosolic DNA sensor cGAS an oligomeric complex?

Zhang, X. et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 6, 421–430 (2014).

How does cytosolic CGAS activate inflammatory cytokines?

Upon activation by double-stranded DNA, cytosolic cGAS produces 2′3′ cGMP–AMP, which triggers the induction of inflammatory cytokines and type I interferons 2, 3, 4, 5, 6, 7. cGAS is also present inside the cell nucleus, which is replete with genomic DNA 8, where chromatin has been implicated in restricting its enzymatic activity 9.

What is the difference between cgas1 and ncp1?

The two individual nucleosomes are held together by two cGAS protomers. While the first cGAS protomer and its corresponding NCP (designated cGAS1 and NCP1) are well resolved, the second nucleosome–cGAS pair (NCP2 and cGAS2) is less ordered (Extended Data Fig. 3e ).