Fig. 4: Phase separation is associated with cGAS-related inflammation.

Following the recognition of dsDNA, cGAS forms liquid-like condensates to catalyse the synthesis of cGAMP, which in turn interacts with and activates the adaptor protein STING to trigger type I interferon production and inflammatory responses through TBK1 and IRF3 signalling. The LLPS of cGAS–DNA droplets not only inhibits TREX1 exonuclease activity but also restricts TREX1 to the droplet periphery. Specifically, the LLPS of cGAS–DNA prevents the TREX1-induced degradation of DNA to allow efficient sensing of pathogenic DNA, thus maintaining appropriate innate immune activation. Multiple cellular and viral proteins modulate the condensation of cGAS. For example, PCBP2 negatively regulates the cGAS-associated innate immune response to dsDNA virus infection by reducing the enzyme activity of cGAS. In contrast to PCBP2, G3BP1 promotes the phase separation of cGAS and cGAS-STING signalling by binding to cGAS. In addition, streptavidin, a pathogenic protein secreted from Streptomyces avidinii, promotes the phase separation of the cGAS‒DNA complex by interacting with cGAS. dsRNA drives the co-condensation of TRIM25 and G3BP1 to form stress granules, which are critical in activating the RNA sensor retinoic acid-inducible gene I protein (RIG-I) signalling pathway, thus restraining RNA virus infection. TRIM25 regulates RIG-I ubiquitination, promotes the phosphorylation of IRF7 and IRF3, and subsequently activates IFN-related immune responses.