title: Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach.
abstract: The innate immune system senses viral DNA that enters mammalian cells, or in aberrant situations self-DNA, and triggers type I interferon production. Here we present an integrative approach that combines quantitative proteomics, genomics and small molecule perturbations to identify genes involved in this pathway. We silenced 809 candidate genes, measured the response to dsDNA and connected resulting hits with the known signaling network. We identified ABCF1 as a critical protein that associates with dsDNA and the DNA-sensing components HMGB2 and IFI204. We also found that CDC37 regulates the stability of the signaling molecule TBK1 and that chemical inhibition of the CDC37-HSP90 interaction and several other pathway regulators potently modulates the innate immune response to DNA and retroviral infection.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Lee
authors.forename: Matthew
authors.initials: M
authors.lastname: Roy
authors.forename: Shao-En
authors.initials: SE
authors.lastname: Ong
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.forename: Alexandra-Chloé
authors.initials: AC
authors.lastname: Villani
authors.forename: Weibo
authors.initials: W
authors.lastname: Li
authors.forename: Farokh
authors.initials: F
authors.lastname: Dotiwala
authors.forename: Jayita
authors.initials: J
authors.lastname: Sen
authors.forename: John G
authors.initials: JG
authors.lastname: Doench
authors.forename: Megan H
authors.initials: MH
authors.lastname: Orzalli
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.forename: David M
authors.initials: DM
authors.lastname: Knipe
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D018833:Chaperonins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D020868:Gene Silencing; D015497:HIV-1 / Q000502:physiology; D024261:HMGB2 Protein / Q000235:genetics / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D054852:Small Molecule Libraries / Q000494:pharmacology; D018116:Vesiculovirus / Q000502:physiology
chemical_list: C115776:ABCF1 protein, human; D018528:ATP-Binding Cassette Transporters; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D024261:HMGB2 Protein; D018841:HSP90 Heat-Shock Proteins; C489664:Ifi16 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D018833:Chaperonins