title: Interferon γ-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses.
abstract: The interferon γ-inducible protein 16 (IFI16) has recently been linked to the detection of nuclear and cytosolic DNA during infection with herpes simplex virus-1 and HIV. IFI16 binds dsDNA via HIN200 domains and activates stimulator of interferon genes (STING), leading to TANK (TRAF family member-associated NF-κB activator)-binding kinase-1 (TBK1)-dependent phosphorylation of interferon regulatory factor (IRF) 3 and transcription of type I interferons (IFNs) and related genes. To better understand the role of IFI16 in coordinating type I IFN gene regulation, we generated cell lines with stable knockdown of IFI16 and examined responses to DNA and RNA viruses as well as cyclic dinucleotides. As expected, stable knockdown of IFI16 led to a severely attenuated type I IFN response to DNA ligands and viruses. In contrast, expression of the NF-κB-regulated cytokines IL-6 and IL-1β was unaffected in IFI16 knockdown cells, suggesting that the role of IFI16 in sensing these triggers was unique to the type I IFN pathway. Surprisingly, we also found that knockdown of IFI16 led to a severe attenuation of IFN-α and the IFN-stimulated gene retinoic acid-inducible gene I (RIG-I) in response to cyclic GMP-AMP, a second messenger produced by cyclic GMP-AMP synthase (cGAS) as well as RNA ligands and viruses. Analysis of IFI16 knockdown cells revealed compromised occupancy of RNA polymerase II on the IFN-α promoter in these cells, suggesting that transcription of IFN-stimulated genes is dependent on IFI16. These results indicate a broader role for IFI16 in the regulation of the type I IFN response to RNA and DNA viruses in antiviral immunity.
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Mikayla R
authors.initials: MR
authors.lastname: Thompson
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Maninjay
authors.initials: M
authors.lastname: Atianand
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark, and.
authors.forename: Søren B
authors.initials: SB
authors.lastname: Jensen
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Susan
authors.initials: S
authors.lastname: Carpenter
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, evelyn.kurt-jones@umassmed.edu.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004267:DNA Viruses / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012328:RNA Viruses / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D007370:Interferon Type I; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human
keywords: DNA; Host-Pathogen Interaction; Innate Immunity; Interferon; Pattern Recognition Receptor (PRR); RIG-I-like Receptor (RLR); RNA; Toll-like Receptor (TLR); Transcription Regulation; Virus