title: The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING.
abstract: The presence of foreign DNA in the cytosol of mammalian cells elicits a potent antiviral interferon response. Recently, cytosolic DNA was proposed to induce the synthesis of cyclic GMP-AMP (cGAMP) upon binding to an enzyme called cGAMP synthase (cGAS). cGAMP activates an interferon response by binding to a downstream receptor called STING. Here, we identify natural variants of human STING (hSTING) that are poorly responsive to cGAMP yet, unexpectedly, are normally responsive to DNA and cGAS signaling. We explain this paradox by demonstrating that the cGAS product is actually a noncanonical cyclic dinucleotide, cyclic [G(2'-5')pA(3'-5')p], which contains a single 2'-5' phosphodiester bond. Cyclic [G(2'-5')pA(3'-5')p] potently activates diverse hSTING receptors and, therefore, may be a useful adjuvant or immunotherapeutic. Our results indicate that hSTING variants have evolved to distinguish conventional (3'-5') cyclic dinucleotides, known to be produced mainly by bacteria, from the noncanonical cyclic dinucleotide produced by mammalian cGAS.
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Elie J
authors.initials: EJ
authors.lastname: Diner
authors.forename: Dara L
authors.initials: DL
authors.lastname: Burdette
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Wilson
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Monroe
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Kellenberger
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Ming C
authors.initials: MC
authors.lastname: Hammond
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009712:Nucleotides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D009841:Oligonucleotides; D034741:RNA, Small Interfering; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C584941:cyclic(G(2'-5')pA(3'-5')p); C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase