title: Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection.
abstract: TANK-binding kinase-1 (TBK1) and the inducible IkappaB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1(-/-) macrophages, but defective in TBK1(-/-) embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1(-/-) embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor-mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 8-240 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095, USA.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Perry
authors.forename: Edward K
authors.initials: EK
authors.lastname: Chow
authors.forename: Julia B
authors.initials: JB
authors.lastname: Goodnough
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D051193:Toll-Like Receptors; D014157:Transcription Factors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases