Recent progress on the activation of the cGAS–STING pathway and its regulation by biomolecular condensation

The cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthetase (cGAS)–stimulator of interferon genes(STING) pathway, comprising the DNA sensor cGAS, the second messenger cyclic GMP–AMP (cGAMP), and the endoplasmicreticulum (ER) adaptor protein STING, detects cytoplasmic double-stranded DNA (dsDNA) to trigger type I-interferon responses forhost defense against pathogens. Previous studies defined a model for the allosteric activation of cGAS by DNA-binding, but recentwork reveals other layers of mechanisms to regulate cGAS activation such as the phase condensation and metal ions, especially thediscovery of Mn^(2+) as a cGAS activator. Activation of the 23-cGAMP sensor STING requires translocating from the ER to the Golgiapparatus. The sulfated glycosaminoglycans at the Golgi are found to be the second STING ligand promoting STING oligomerizationand activation in addition to 23-cGAMP, while surpassed levels of 23-cGAMP induce ER-located STING to form a highly organizedER membranous condensate named STING phase-separator to restrain STING activation. Here, we summarize recent advances in theregulation of cGAS–STING activation and their implications in physiological or pathological conditions, particularly focusing on theemerging complexity of the regulation.