CGAS

Cyclic GMP-AMP synthase (cGAS) is a nucleotidyltransferase of the mab-21 / cGAS-DncV-like nucleotidyltransferase family that serves as the principal cytosolic sensor of double-stranded DNA in innate immunity. Upon binding dsDNA in a sequence-independent, length-dependent manner, cGAS forms a 2:2 enzyme-DNA complex and undergoes DNA-driven liquid-liquid phase separation into condensates in which it becomes catalytically active. Activated cGAS synthesizes the cyclic dinucleotide second messenger 2',3'-cGAMP from ATP and GTP (EC 2.7.7.86), forming a product with mixed 2'-5'/3'-5' phosphodiester linkages. 2',3'-cGAMP binds and activates the adaptor STING1, triggering TBK1/IRF3 activation and type I interferon production, and can spread immunity to neighboring cells through gap junctions. cGAS thereby drives antiviral defense against DNA viruses and retroviruses and mediates sterile inflammatory responses to self-DNA that reaches the cytosol during genome instability, micronucleus formation, mitochondrial stress and cellular senescence. Although often described as cytosolic, cGAS is predominantly nuclear at steady state, where it is tethered to chromatin and held inactive through direct binding to the nucleosome H2A-H2B acidic patch, which blocks DNA engagement. In the nucleus cGAS also has an enzyme-independent role, interacting with PARP1 to suppress homologous-recombination-mediated DNA double-strand break repair. Its activity is extensively controlled by phosphorylation, ubiquitination, sumoylation, acetylation, glutamylation and other modifications, and by numerous protein cofactors and viral antagonists.

Disorders

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