Cyclic GMP-AMP synthase (cGAS) (cGAS)

Cyclic GMP-AMP synthase (cGAS) is a critical cytosolic DNA sensor that plays a central role in the innate immune system by detecting the presence of double-stranded DNA (dsDNA) in the cytoplasm (UniProt Q8C6L5). Upon binding to dsDNA, cGAS undergoes a conformational change and catalyzes the synthesis of the second messenger 2'3'-cyclic GMP-AMP (cGAMP) from ATP and GTP (PubMed: 23258413). This cGAMP then binds to and activates the Stimulator of Interferon Genes (STING) protein, leading to the recruitment of TBK1 and the subsequent induction of Type I interferons and pro-inflammatory cytokines (PubMed: 23407006). While this pathway is vital for defense against viral and bacterial pathogens, its chronic activation by self-DNA is a major driver of autoimmune and autoinflammatory diseases such as Aicardi-Goutières syndrome and systemic lupus erythematosus (PubMed: 26229117). Murine cGAS is a primary model for studying these mechanisms and is the target of specific small-molecule inhibitors like RU.521, which are used to validate the therapeutic potential of cGAS inhibition in preclinical models (PubMed: 28284825). Small molecule inhibitors of cGAS are currently being explored to treat interferonopathies and other inflammatory conditions where the cGAS-STING pathway is overactive.

Other names

Mb21d1Mab-21 domain-containing protein 1Cgasm-cGASMurine cGAS

Inhibition of the nucleotidyltransferase activity of cGAS, preventing the synthesis of 2'3'-cGAMP from ATP and GTP, thereby blocking the downstream STING-mediated inflammatory response.