CGAS

CGAS (Cyclic GMP-AMP Synthase) is a Protein Coding gene. Diseases associated with CGAS include Aicardi-Goutieres Syndrome and Renpenning Syndrome 1. Among its related pathways are Innate Immune System and Cytosolic sensors of pathogen-associated DNA.

Cyclic GMP-AMP Synthase

Nucleotidyltransferase that catalyzes the formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and plays a key role in innate immunity (PubMed:23258413, PubMed:23707061, PubMed:23722159, PubMed:24077100, PubMed:25131990, PubMed:29976794, PubMed:30799039).
Catalysis involves both the formation of a 2',5' phosphodiester linkage at the GpA step and the formation of a 3',5' phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p] (PubMed:28363908, PubMed:28214358).
Acts as a key cytosolic DNA sensor, the presence of double-stranded DNA (dsDNA) in the cytoplasm being a danger signal that triggers the immune responses (PubMed:28363908).
Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production (PubMed:28363908, PubMed:28314590).
Preferentially recognizes and binds curved long DNAs (PubMed:30007416).
In contrast to other mammals, human CGAS displays species-specific mechanisms of DNA recognition and produces less cyclic GMP-AMP (cGAMP), allowing a more fine-tuned response to pathogens (PubMed:30007416).
Has antiviral activity by sensing the presence of dsDNA from DNA viruses in the cytoplasm (PubMed:28363908).
Also acts as an innate immune sensor of infection by retroviruses, such as HIV-1, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:23929945).
Detection of retroviral reverse-transcribed DNA in the cytosol may be indirect and be mediated via interaction with PQBP1, which directly binds reverse-transcribed retroviral DNA (PubMed:26046437).
Also detects the presence of DNA from bacteria, such as M.tuberculosis (PubMed:26048138).
cGAMP can be transferred from producing cells to neighboring cells through gap junctions, leading to promote TMEM173/STING activation and convey immune response to connecting cells (PubMed:24077100).
cGAMP can also be transferred between cells by virtue of packaging within viral particles contributing to IFN-induction in newly infected cells in a cGAS-independent but TMEM173/STING-dependent manner (PubMed:26229115).
In addition to antiviral activity, also involved in the response to cellular stresses, such as senescence, DNA damage or genome instability (PubMed:28738408, PubMed:28759889).
Acts as a regulator of cellular senescence by binding to cytosolic chromatin fragments that are present in senescent cells, leading to trigger type-I interferon production via TMEM173/STING and promote cellular senescence (By similarity).
Also involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability (PubMed:28738408, PubMed:28759889).
Micronuclei, which as frequently found in cancer cells, consist of chromatin surrounded by its own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, CGAS binds self-DNA exposed to the cytosol, leading to cGAMP synthesis and subsequent activation of TMEM173/STING and type-I interferon production (PubMed:28738408, PubMed:28759889).
Acts as a suppressor of DNA repair in response to DNA damage: translocates to the nucleus following dephosphorylation at Tyr-215 and inhibits homologous recombination repair by interacting with PARP1, the CGAS-PARP1 interaction leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214).

Activation of innate immune response Source: UniProtKB
Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to exogenous dsRNA Source: UniProtKB
Defense response to virus Source: UniProtKB
Determination of adult lifespan Source: Ensembl
DNA repair Source: UniProtKB-KW
Innate immune response Source: UniProtKB-KW
Negative regulation of double-strand break repair via homologous recombination Source: UniProtKB
Paracrine signaling Source: UniProtKB
Positive regulation of cAMP-mediated signaling Source: UniProtKB
Positive regulation of cellular senescence Source: UniProtKB
Positive regulation of cGMP-mediated signaling Source: UniProtKB
Positive regulation of defense response to virus by host Source: UniProtKB
Positive regulation of type I interferon production Source: UniProtKB
Regulation of immunoglobulin production Source: Ensembl
Regulation of T cell activation Source: Ensembl
Viral process Source: UniProtKB-KW

Nucleus; Cytosol; Cell membrane. In resting conditions, localizes at the cell membrane as a peripheral membrane protein by binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:30827685). Localization at the cell membrane is required to limit the recognition of self-DNA (PubMed:30827685). Following detection of double-stranded DNA (dsDNA), released from the cell membrane into the cytosol in order to signal (PubMed:30827685). Upon transfection with dsDNA forms punctate structures that co-localize with DNA and Beclin-1 (BECN1) (PubMed:26048138). Phosphorylation at Tyr-215 promotes cytosolic retention; translocates into the nucleus following dephosphorylation (PubMed:30356214).
(Microbial infection) Upon infection with virulent M.tuberculosis forms aggregates with dsDNA, non-virulent bacteria (without the ESX-1 locus) do not form these aggregates (PubMed:26048138).

Phosphorylation at Tyr-215 by BLK promotes cytosolic retention (PubMed:30356214). Translocates into the nucleus following dephosphorylation at Tyr-215 (PubMed:30356214).
(Microbial infection) Deamidated on 'Asn-210' by herpes simplex virus 1 protein UL37. This modification significantly reduces CGAS-dependent cGAMP production and innate immune signaling induced by dsDNA.
Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to impair the nucleotidyltransferase activity. Deglutamylated by AGBL5/CCP5 and AGBL6/CCP6.
Cleaved by CASP1 at Asp-140 and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 and CASP5 during non-canonical inflammasome activation; they don't cut at the same sites than CASP1 (PubMed:28314590).
Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic GMP-AMP synthase activity (PubMed:30799039). Deacetylated upon cytosolic DNA challenge such as viral infections (PubMed:30799039). Acetylation can be mediated by aspirin (acetylsalicylate) drug, which directly acetylates CGAS (PubMed:30799039). Acetylation by aspirin efficiently inhibits CGAS-mediated immune responses and is able to suppress self-DNA-induced autoimmunity (PubMed:30799039).