title: cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection.
abstract: Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Megan H
authors.initials: MH
authors.lastname: Orzalli
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Broekema
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 05844; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Diner
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112.
authors.forename: Dustin C
authors.initials: DC
authors.lastname: Hancks
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112.
authors.forename: Nels C
authors.initials: NC
authors.lastname: Elde
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 05844; and.
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Cristea
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; david_knipe@hms.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000378:metabolism* / Q000821:virology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D018139:Simplexvirus / Q000378:metabolism*; D014158:Transcription, Genetic; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C489664:Ifi16 protein, mouse; C076700:IFI16 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse
keywords: DNA sensing; innate immunity; protein–protein interactions; virus–host interactions
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