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

Trends Immunol. 2023 Jun;44(6):450-467. doi: 10.1016/j.it.2023.04.006. Epub 2023 May 4.

Abstract

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.

Keywords: 2’3’-cGAMP intercellular transport; CDN importers and exporters; folate and antifolate transport; gap junctions; immunotransmitter; transport cycle.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Humans
  • Inflammation
  • Membrane Proteins* / metabolism
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases* / metabolism

Substances

  • cyclic guanosine monophosphate-adenosine monophosphate
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Nucleotidyltransferases
  • STING1 protein, human
  • cGAS protein, human