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An alternative splice product of IkappaB kinase (IKKgamma), IKKgamma-delta, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-kappaB activation.

ABSTRACT: NF-kappaB is an inducible transcription factor mediating innate immune responses whose activity is controlled by the multiprotein IkappaB kinase (IKK) "signalsome". The core IKK consists of two catalytic serine kinases, IKKalpha and IKKbeta, and a noncatalytic subunit, IKKgamma. IKKgamma 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 IKKgamma mRNA isoform, encoding an in-frame deletion of exon 5, termed IKKgamma-delta. Using a specific reverse transcription-PCR assay, we find that IKKgamma-delta is widely expressed in cultured human cells and normal human tissues. Because IKKgamma-Delta 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-kappaB activity. Coimmunoprecipitation and confocal colocalization assays indicate IKKgamma-delta has strong homo- and heterotypic association with wild-type (WT) IKKgamma and, like IKKgamma WT, associates with the IKKbeta kinase. Similarly, IKKgamma-delta mediates IKK kinase activity and downstream NF-kappaB-dependent transcription in response to tumor necrosis factor (TNF) and the NF-kappaB-inducing kinase-IKKalpha signaling pathway. Surprisingly, however, in contrast to IKKgamma WT, IKKgamma-delta is not able to mediate HTLV-1 Tax-induced NF-kappaB-dependent transcription, even though IKKgamma-delta binds and colocalizes with Tax. These observations suggest that IKKgamma-delta 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 IKKgamma-delta expression, therefore, may affect signal transduction cascades coupling to IKK.

SUBMITTER: Hai T

PROVIDER: S-EPMC1472011 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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An alternative splice product of IkappaB kinase (IKKgamma), IKKgamma-delta, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-kappaB activation.

Hai Tao T Yeung Man-Lung ML Wood Thomas G TG Wei Yuanfen Y Yamaoka Shoji S Gatalica Zoran Z Jeang Kuan-Teh KT Brasier Allan R AR

Journal of virology 20060501 9

NF-kappaB is an inducible transcription factor mediating innate immune responses whose activity is controlled by the multiprotein IkappaB kinase (IKK) "signalsome". The core IKK consists of two catalytic serine kinases, IKKalpha and IKKbeta, and a noncatalytic subunit, IKKgamma. IKKgamma 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 spl ...[more]

PMID: 16611882

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Project description:Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-kappaB and IRF3 pathways. Recent work has shown that the IkappaB kinase (IKK)gamma scaffolding protein is the final common adapter protein required by RIG-I.MAVS to activate divergent rate-limiting kinases downstream controlling the NF-kappaB and IRF3 pathways. Previously we discovered a ubiquitous IKKgamma splice-variant, IKKgammaDelta, that exhibits distinct signaling properties.We examined the regulation and function of IKKgamma splice forms in response to ssRNA virus infection, a condition that preferentially induces full length IKKgamma-WT mRNA expression. In IKKgammaDelta-expressing cells, we found increased viral translation and cytopathic effect compared to those expressing full length IKKgamma-WT. IKKgammaDelta fails to support viral-induced IRF3 activation in response to ssRNA infections; consequently type I IFN production and the induction of anti-viral interferon stimulated genes (ISGs) are significantly attenuated. By contrast, ectopic RIG-I.MAVS or TNFalpha-induced canonical NF-kappaB activation is preserved in IKKgammaDelta expressing cells. Increasing relative levels of IKKgamma-WT to IKKgammaDelta (while keeping total IKKgamma constant) results in increased type I IFN expression. Conversely, overexpressing IKKgammaDelta (in a background of constant IKKgamma-WT expression) shows IKKgammaDelta functions as a dominant-negative IRF3 signaling inhibitor. IKKgammaDelta binds both IKK-alpha and beta, but not TANK and IKKepsilon, indicating that exon 5 encodes an essential TANK binding domain. Finally, IKKgammaDelta displaces IKKgammaWT from MAVS explaining its domainant negative effect.Relative endogenous IKKgammaDelta expression affects cellular selection of inflammatory/anti-viral pathway responses to ssRNA viral infection.

Dataset Information

An alternative splice product of IkappaB kinase (IKKgamma), IKKgamma-delta, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-kappaB activation.

Publications

An alternative splice product of IkappaB kinase (IKKgamma), IKKgamma-delta, differentially mediates cytokine and human T-cell leukemia virus type 1 tax-induced NF-kappaB activation.

Similar Datasets

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