title: Ancient Origin of cGAS-STING Reveals Mechanism of Universal 2',3' cGAMP Signaling.
abstract: 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.
authors: Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute (HHMI), University of California, Berkeley, CA 94720, USA.
authors: Philip J
authors: PJ
authors: Kranzusch
authors: Department of Chemistry, University of California, Berkeley, CA 94720, USA.
authors: Stephen C
authors: SC
authors: Wilson
authors: Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Center for RNA Systems Biology, University of California, Berkeley, CA 94720, USA.
authors: Amy S Y
authors: AS
authors: Lee
authors: Department of Biophysics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: James M
authors: JM
authors: Berger
authors: Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, CA 94720, USA; Center for RNA Systems Biology, University of California, Berkeley, CA 94720, USA; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute (HHMI), University of California, Berkeley, CA 94720, USA. Electronic address: doudna@berkeley.edu.
authors: Jennifer A
authors: JA
authors: Doudna
authors: Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA; Cancer Research Laboratory, University of California, Berkeley, CA 94720, USA; Howard Hughes Medical Institute (HHMI), University of California, Berkeley, CA 94720, USA. Electronic address: rvance@berkeley.edu.
authors: Russell E
authors: RE
authors: Vance
mesh_terms: D000595:Amino Acid Sequence; D031883:Anemone / Q000235:genetics*; D001059:Apoproteins / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006150:Guanine Nucleotides / Q000737:chemistry*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015290:Second Messenger Systems; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D001059:Apoproteins; D006150:Guanine Nucleotides; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C078170:2',3'-cyclic GMP; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase