title: Cytosolic RNA:DNA hybrids activate the cGAS-STING axis.
abstract: Intracellular recognition of non-self and also self-nucleic acids can result in the initiation of potent pro-inflammatory and antiviral cytokine responses. Most recently, cGAS was shown to be critical for the recognition of cytoplasmic dsDNA. Binding of dsDNA to cGAS results in the synthesis of cGAMP(2'-5'), which then binds to the endoplasmic reticulum resident protein STING. This initiates a signaling cascade that triggers the induction of an antiviral immune response. While most studies on intracellular nucleic acids have focused on dsRNA or dsDNA, it has remained unexplored whether cytosolic RNA:DNA hybrids are also sensed by the innate immune system. Studying synthetic RNA:DNA hybrids, we indeed observed a strong type I interferon response upon cytosolic delivery of this class of molecule. Studies in THP-1 knockout cells revealed that the recognition of RNA:DNA hybrids is completely attributable to the cGAS-STING pathway. Moreover, in vitro studies showed that recombinant cGAS produced cGAMP upon RNA:DNA hybrid recognition. Altogether, our results introduce RNA:DNA hybrids as a novel class of intracellular PAMP molecules and describe an alternative cGAS ligand next to dsDNA.
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Mankan
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Goldeck
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Klara
authors.initials: K
authors.lastname: Höning
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gaidt
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kubarenko
authors.affiliation: Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Andreeva
authors.affiliation: Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.affiliation: Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany veit.hornung@uni-bonn.de.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
mesh_terms: D001733:Bites and Stings; D002460:Cell Line; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology; D009693:Nucleic Acid Hybridization; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D014780:Viruses / Q000276:immunology*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D007370:Interferon Type I; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D012313:RNA; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: RNA:DNA hybrids; STING; cGAS; innate immunity; pattern recognition receptor