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Article: An alternative splice product of IκB kinase (IKKγ), IKKγ-Δ, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-κB activation

TitleAn alternative splice product of IκB kinase (IKKγ), IKKγ-Δ, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-κB activation
Authors
Issue Date2006
PublisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/
Citation
Journal Of Virology, 2006, v. 80 n. 9, p. 4227-4241 How to Cite?
AbstractNF-κB is an inducible transcription factor mediating innate immune responses whose activity is controlled by the multiprotein Ikappa;B kinase (IKK) "signalsome". The core IKK consists of two catalytic serine kinases, IKKα and IKKβ and a noncatalytic subunit, IKKγ. IKKγ is required for IKK activity by mediating kinase oligomerization and serving to couple the core catalytic subunits to upstream mitogen-activated protein 3-kinase cascades. We have discovered an alternatively spliced IKKγ mRNA isoform, encoding an in-frame deletion of exon 5, termed IKKγ-Δ. Using a specific reverse transcription-PCR assay, we find that IKKγ-Δ is widely expressed in cultured human cells and normal human tissues. Because IKKγ-Δ protein is lacking a critical coiled-coil domain important in protein-protein interactions, we sought to determine its signaling properties by examining its ability to self associate, couple to activators of the canonical pathway, and mediate human T-cell leukemia virus type 1 (HTLV-1) Tax-induced NF-κB activity. Coimmunoprecipitation and confocal colocalization assays indicate IKKγ-Δ has strong homo- and heterotypic association with wild-type (WT) IKKγ and, like IKKγ WT, associates with the IKKβ kinase. Similarly, IKKγ-Δ mediates IKK kinase activity and downstream NFκB-dependent transcription in response to tumor necrosis factor (TNF) and the NF-κB-inducing kinase-IKKα signaling pathway. Surprisingly, however, in contrast IKKγ WT, IKKγ-Δ is not able to mediate HTLV-1 Tax-induced NFκB-dependent transcription, even though IKKγ-Δ binds and colocalizes with Tax. These observations suggest that IKKγ-Δ is a functionally distinct alternatively spliced mRNA product differentially mediating TNF-induced, but not Tax-induced, signals converging on the IKK signalsome. Differing levels of IKKγ-Δ expression, therefore, may affect signal transduction cascades coupling to IKK. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/157442
ISSN
2015 Impact Factor: 4.606
2015 SCImago Journal Rankings: 3.347
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHai, Ten_US
dc.contributor.authorYeung, MLen_US
dc.contributor.authorWood, TGen_US
dc.contributor.authorWei, Yen_US
dc.contributor.authorYamaoka, Sen_US
dc.contributor.authorGatalica, Zen_US
dc.contributor.authorJeang, KTen_US
dc.contributor.authorBrasier, ARen_US
dc.date.accessioned2012-08-08T08:50:00Z-
dc.date.available2012-08-08T08:50:00Z-
dc.date.issued2006en_US
dc.identifier.citationJournal Of Virology, 2006, v. 80 n. 9, p. 4227-4241en_US
dc.identifier.issn0022-538Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/157442-
dc.description.abstractNF-κB is an inducible transcription factor mediating innate immune responses whose activity is controlled by the multiprotein Ikappa;B kinase (IKK) "signalsome". The core IKK consists of two catalytic serine kinases, IKKα and IKKβ and a noncatalytic subunit, IKKγ. IKKγ is required for IKK activity by mediating kinase oligomerization and serving to couple the core catalytic subunits to upstream mitogen-activated protein 3-kinase cascades. We have discovered an alternatively spliced IKKγ mRNA isoform, encoding an in-frame deletion of exon 5, termed IKKγ-Δ. Using a specific reverse transcription-PCR assay, we find that IKKγ-Δ is widely expressed in cultured human cells and normal human tissues. Because IKKγ-Δ protein is lacking a critical coiled-coil domain important in protein-protein interactions, we sought to determine its signaling properties by examining its ability to self associate, couple to activators of the canonical pathway, and mediate human T-cell leukemia virus type 1 (HTLV-1) Tax-induced NF-κB activity. Coimmunoprecipitation and confocal colocalization assays indicate IKKγ-Δ has strong homo- and heterotypic association with wild-type (WT) IKKγ and, like IKKγ WT, associates with the IKKβ kinase. Similarly, IKKγ-Δ mediates IKK kinase activity and downstream NFκB-dependent transcription in response to tumor necrosis factor (TNF) and the NF-κB-inducing kinase-IKKα signaling pathway. Surprisingly, however, in contrast IKKγ WT, IKKγ-Δ is not able to mediate HTLV-1 Tax-induced NFκB-dependent transcription, even though IKKγ-Δ binds and colocalizes with Tax. These observations suggest that IKKγ-Δ is a functionally distinct alternatively spliced mRNA product differentially mediating TNF-induced, but not Tax-induced, signals converging on the IKK signalsome. Differing levels of IKKγ-Δ expression, therefore, may affect signal transduction cascades coupling to IKK. Copyright © 2006, American Society for Microbiology. All Rights Reserved.en_US
dc.languageengen_US
dc.publisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/en_US
dc.relation.ispartofJournal of Virologyen_US
dc.subject.meshAlternative Splicing - Geneticsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Membrane - Metabolismen_US
dc.subject.meshCell Nucleus - Metabolismen_US
dc.subject.meshCytoplasm - Metabolismen_US
dc.subject.meshEnzyme Activation - Drug Effectsen_US
dc.subject.meshExons - Geneticsen_US
dc.subject.meshGene Deletionen_US
dc.subject.meshGene Expressionen_US
dc.subject.meshGene Products, Tax - Genetics - Metabolismen_US
dc.subject.meshHuman T-Lymphotropic Virus 1 - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshI-Kappa B Kinase - Genetics - Metabolismen_US
dc.subject.meshNf-Kappa B - Genetics - Metabolismen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProtein-Serine-Threonine Kinases - Metabolismen_US
dc.subject.meshRna, Messenger - Geneticsen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshTumor Necrosis Factor-Alpha - Pharmacologyen_US
dc.titleAn alternative splice product of IκB kinase (IKKγ), IKKγ-Δ, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-κB activationen_US
dc.typeArticleen_US
dc.identifier.emailYeung, ML:pmlyeung@hku.hken_US
dc.identifier.authorityYeung, ML=rp01402en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1128/JVI.80.9.4227-4241.2006en_US
dc.identifier.pmid16611882-
dc.identifier.scopuseid_2-s2.0-33646165544en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33646165544&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume80en_US
dc.identifier.issue9en_US
dc.identifier.spage4227en_US
dc.identifier.epage4241en_US
dc.identifier.isiWOS:000236980000003-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHai, T=7006724710en_US
dc.identifier.scopusauthoridYeung, ML=8350940900en_US
dc.identifier.scopusauthoridWood, TG=7402253202en_US
dc.identifier.scopusauthoridWei, Y=7404094580en_US
dc.identifier.scopusauthoridYamaoka, S=7103289817en_US
dc.identifier.scopusauthoridGatalica, Z=7003793463en_US
dc.identifier.scopusauthoridJeang, KT=7004824803en_US
dc.identifier.scopusauthoridBrasier, AR=7007058345en_US

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