title: IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP.
abstract: Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: K L
authors.initials: KL
authors.lastname: Jønsson
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Laustsen
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Ulm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Krapp
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: K A
authors.initials: KA
authors.lastname: Skipper
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Thavachelvam
authors.affiliation: Ulm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hotter
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: J H
authors.initials: JH
authors.lastname: Egedal
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|The Danish Diabetes Academy supported by the Novo Nordisk Foundation, Aarhus University, Nordre Ringgade 1, Aarhus C 8000, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Kjolby
authors.affiliation: New York Genome Center, 101 Avenue of the Americas, New York City, New York 10013, USA.|Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York City, New York 10032, USA.
authors.forename: P
authors.identifier: 0000-0003-4457-8552
authors.initials: P
authors.lastname: Mohammadi
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Prabakaran
authors.affiliation: Department of Forensic Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Entrance 1, Aarhus N 8200, Denmark.
authors.forename: L K
authors.initials: LK
authors.lastname: Sørensen
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: S B
authors.initials: SB
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: C K
authors.initials: CK
authors.lastname: Holm
authors.affiliation: University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lebbink
authors.affiliation: Department of Forensic Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Entrance 1, Aarhus N 8200, Denmark.
authors.forename: M
authors.identifier: 0000-0002-2548-7025
authors.initials: M
authors.lastname: Johannsen
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: M
authors.identifier: 0000-0002-2967-6624
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: J G
authors.initials: JG
authors.lastname: Mikkelsen
authors.affiliation: Ulm University Medical Center, Institute of Molecular Virology, Meyerhofstr. 1, Ulm 89081, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: S R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.|Aarhus Research Centre of Innate Immunology, Aarhus University, Wilhelm Meyers Alle 4, Aarhus C 8000, Denmark.
authors.forename: M R
authors.initials: MR
authors.lastname: Jakobsen
mesh_terms: D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007372:Interferons / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D000074084:THP-1 Cells; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D007372:Interferons; D008565:Membrane Proteins; D009687:Nuclear Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C076700:IFI16 protein, human; C403191:TBK1 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase