CGAS gene

The CGAS gene (CGAS stands for: Cyclic GMP-AMP Synthase) is a protein coding gene located on chromsome 6q13. The gene encodes cyclic GMP-AMP synthase, a nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate immunity (Sun L et al. 2013; Yang N et al. 2023).

The 2',3'-cyclic GMP-AMP synthase activity includes chromatin binding activity and phosphatidylinositol-4,5-bisphosphate binding activity. The enzyme is involved in several processes, including cellular response to exogenous dsRNA, positive regulation of intracellular signal transduction and regulation of defense response. Found in several cellular components, including the cytosol, the nucleus and the site of double-strand breaks. Acts as an important DNA sensor: Binds directly to double-stranded DNA (dsDNA) and induces the formation of liquid-like droplets in which CGAS is activated, leading to the synthesis of 2',3'-cGAMP, a second messenger that binds to and activates STING1, triggering the production of type I interferon (Yang X et al. (2022). Acts as an important sensor for foreign DNA, with the presence of double-stranded DNA (dsDNA) in the cytoplasm representing a danger signal that triggers the immune response (Tao J et al. (2017). Has antiviral activity by recognizing the presence of dsDNA from DNA viruses in the cytoplasm. Also acts as an innate immune system sensor for infections by retroviruses such as HIV-2. Also recognizes the presence of neutrophil extracellular traps (NETs), which are translocated to the cytosol after phagocytosis, leading to the synthesis of 2',3'-cGAMP (Apel F et al. )

In addition to foreign DNA, they can also be activated by the body's own nuclear or mitochondrial DNA. When cellular stress (e.g. mitochondrial stress, SARS-CoV-2 infection causing severe COVID-19 disease, DNA damage, mitotic arrest or senescence) causes self-DNA to enter the cytosol or is present in the form of cytosolic micronuclei, CGAS is activated, leading to a state of sterile inflammation. In contrast to other mammals, human CGAS exhibits species-specific mechanisms of DNA recognition and produces less 2',3'-cGAMP, allowing for a more tuned response to pathogens.

Diseases associated with CGAS include Covid-19 infections.

1. Apel F, Andreeva L, Knackstedt LS et al. (2021) The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps. Sci Signal14:eaax7942).
2. Sun L et al. (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science339:786-791.
3. Tao J et al. (2017) Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation. J Immunol 198:3627-3636.
4. Yang N et al. (2023) Vaccinia E5 is a major inhibitor of the DNA sensor cGAS. Nat Commun 14:2898.
5. Yang X et al. (2022) MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation. Sci Signal 15(732):eabk3067.