Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity.
IKKepsilon is an IKK (inhibitor of nuclear factor kappaBkinase)-related kinase implicated in virus induction of interferon-beta (IFNbeta). We report that, although mice lacking IKKepsilon produce normal amounts of IFNbeta, they are hypersusceptible to viral infection because of a defect in the IFN signaling pathway. Specifically, a subset of type I IFN-stimulated genes are not activated in the absence of IKKepsilon because the interferon-stimulated gene factor 3 complex (ISGF3) does not bind to promoter elements of the affected genes. We demonstrate that IKKepsilon is activated by IFNbeta and that IKKepsilon directly phosphorylates signal transducer and activator of transcription 1 (STAT1), a component of ISGF3. We conclude that IKKepsilon plays a critical role in the IFN-inducible antiviral transcriptional response.
Tenoever
Benjamin R
BR
Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Ng
Sze-Ling
SL
Chua
Mark A
MA
McWhirter
Sarah M
SM
García-Sastre
Adolfo
A
Maniatis
Tom
T
D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000502:physiology; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D019562:Viral Load; D014779:Virus Replication
D050832:Interferon-Stimulated Gene Factor 3; D016601:RNA-Binding Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D016899:Interferon-beta; D051550:I-kappa B Kinase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase