Structure-based mechanisms of 2′3′-cGAMP intercellular transport in the cGAS–STING immune pathway

Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2′3′-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2′3′-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2′3′-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2′3′-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation.