Recent advances in the activation and regulation of the cGAS-STING pathway

Abstract

The cGAS-STING pathway is responsible for cytoplasmic double-stranded DNA (dsDNA) -triggered innate immunity and involved in the pathology of various diseases including infection, autoimmune diseases, neurodegeneration and cancer. Understanding the activation and regulatory mechanisms of this pathway is critical to develop therapeutic strategies toward these diseases. Here, we review the signal transduction, cellular functions and regulations of cGAS and STING, particularly highlighting the latest understandings on the activation of cGAS by dsDNA and/or Manganese (Mn²⁺), STING trafficking, sulfated glycosaminoglycans (sGAGs)-induced STING polymerization and activation, and also regulation of the cGAS-STING pathway by different biocondensates formed via phase separation of proteins from host cells and viruses.

Keywords: Apoptosis; Biomolecular condensate; Cancer immunotherapy; Caspase; Cyclic-dinucleotides (CDNs); DAMPs; Double-stranded DNA (dsDNA); Infection; Inflammasome; Innate immunity; Manganese (Mn(2+)); PAMPs; Phase separation; STING; STING phase-separator; STING trafficking; Sulfated glycosaminoglycans (sGAGs); TBK1; Type I-IFNs; cGAMP; cGAS.