The molecular mechanism of dsDNA sensing through the cGAS-STING pathway

Double stranded DNA (dsDNA) in the cytoplasm triggers the cGAS-STING innate immune pathway to defend against pathogenic infections, tissue damage and malignant cells. Extensive structural and functional studies over the last couple of years have enabled the molecular understanding of dsDNA induced activation of the cGAS-STING signaling pathway. This review highlights recent advances in the structural characterization of key molecules in the cGAS-STING signaling axis by focusing on the mechanism of cGAS activation by dsDNA, the regulation of cGAS activity, the mechanism of STING activation by cGAMP, the molecular basis of TBK1 recruitment and activation by STING, the structural basis of IRF3 recruitment by STING, and the mechanism of IRF3 activation upon phosphorylation by TBK1. These comprehensive structural studies provide a detailed picture of the mechanism of the cGAS-STING signaling pathway, establishing a molecular framework for the development of novel therapeutic strategies targeting this pathway.