Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling

Mol Cell. 2015 Sep 17;59(6):891-903. doi: 10.1016/j.molcel.2015.07.022. Epub 2015 Aug 20.


In humans, the cGAS-STING immunity pathway signals in response to cytosolic DNA via 2',3' cGAMP, a cyclic dinucleotide (CDN) second messenger containing mixed 2'-5' and 3'-5' phosphodiester bonds. Prokaryotes also produce CDNs, but these are exclusively 3' linked, and thus the evolutionary origins of human 2',3' cGAMP signaling are unknown. Here we illuminate the ancient origins of human cGAMP signaling by discovery of a functional cGAS-STING pathway in Nematostella vectensis, an anemone species >500 million years diverged from humans. Anemone cGAS appears to produce a 3',3' CDN that anemone STING recognizes through nucleobase-specific contacts not observed in human STING. Nevertheless, anemone STING binds mixed-linkage 2',3' cGAMP indistinguishably from human STING, trapping a unique structural conformation not induced by 3',3' CDNs. These results reveal that human mixed-linkage cGAMP achieves universal signaling by exploiting a deeply conserved STING conformational intermediate, providing critical insight for therapeutic targeting of the STING pathway.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Anemone / genetics*
  • Apoproteins / chemistry
  • Apoproteins / genetics
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • Guanine Nucleotides / chemistry*
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleotidyltransferases / chemistry*
  • Nucleotidyltransferases / genetics
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Second Messenger Systems


  • Apoproteins
  • Guanine Nucleotides
  • Membrane Proteins
  • STING1 protein, human
  • 2',3'-cyclic GMP
  • Nucleotidyltransferases
  • cGAS protein, human