title: The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection.
abstract: Viral infection and stimulation with lipopolysaccharide (LPS) or double stranded RNA (dsRNA) induce phosphorylation of interferon (IFN) regulatory factor (IRF)-3 and its translocation to the nucleus, thereby leading to the IFN-beta gene induction. Recently, two IkappaB kinase (IKK)-related kinases, inducible IkappaB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-beta production in Toll-like receptor (TLR) signaling and viral infection. In this work, we investigated the physiological roles of these kinases by gene targeting. TBK1-deficient embryonic fibroblasts (EFs) showed dramatic decrease in induction of IFN-beta and IFN-inducible genes in response to LPS or dsRNA as well as after viral infection. However, dsRNA-induced expression of these genes was residually detected in TBK1-deficient cells and intact in IKK-i-deficient cells, but completely abolished in IKK-i/TBK1 doubly deficient cells. IRF-3 activation, in response not only to dsRNA but also to viral infection, was impaired in TBK1-deficient cells. Together, these results demonstrate that TBK1 as well as, albeit to a lesser extent, IKK-i play a crucial role in the induction of IFN-beta and IFN-inducible genes in both TLR-stimulated and virus-infected EFs.
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hemmi
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Hideki
authors.initials: H
authors.lastname: Sanjo
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000502:physiology; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D012330:RNA, Double-Stranded / Q000235:genetics*; D012475:Salmonella / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014777:Virus Diseases / Q000503:physiopathology*
chemical_list: D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D012330:RNA, Double-Stranded; D014157:Transcription Factors; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse