title: Species-specific detection of the antiviral small-molecule compound CMA by STING.
abstract: Extensive research on antiviral small molecules starting in the early 1970s has led to the identification of 10-carboxymethyl-9-acridanone (CMA) as a potent type I interferon (IFN) inducer. Up to date, the mode of action of this antiviral molecule has remained elusive. Here we demonstrate that CMA mediates a cell-intrinsic type I IFN response, depending on the ER-resident protein STING. CMA directly binds to STING and triggers a strong antiviral response through the TBK1/IRF3 route. Interestingly, while CMA displays extraordinary activity in phosphorylating IRF3 in the murine system, CMA fails to activate human cells that are otherwise responsive to STING ligands. This failure to activate human STING can be ascribed to its inability to bind to the C-terminal ligand-binding domain of human STING. Crystallographic studies show that two CMA molecules bind to the central Cyclic diguanylate (c-diGMP)-binding pocket of the STING dimer and fold the lid region in a fashion similar, but partially distinct, to c-diGMP. Altogether, these results provide novel insight into ligand-sensing properties of STING and, furthermore, unravel unexpected species-specific differences of this innate sensor.
authors.affiliation: Unit for Clinical Biochemistry, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Taner
authors.initials: T
authors.lastname: Cavlar
authors.forename: Tobias
authors.initials: T
authors.lastname: Deimling
authors.forename: Andrea
authors.initials: A
authors.lastname: Ablasser
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007369:Interferon Inducers / Q000378:metabolism / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000099197:STING Protein
chemical_list: D000166:Acridines; D006152:Cyclic GMP; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D011994:Recombinant Proteins; C494233:Irf3 protein, mouse; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C062025:bis(3',5')-cyclic diguanylic acid; C026430:10-carboxymethyl-9-acridanone