title: Novel splice variants of human IKKε negatively regulate IKKε-induced IRF3 and NF-kB activation.
abstract: The inhibitor of κB kinase ε (IKKε) is pivotal for an efficient innate immune response to viral infections and has been recognized as breast cancer oncogene. The antiviral function of IKKε involves activation of the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB, thus inducing the expression of type I IFN. Here, we have identified two novel splice variants of human IKKε, designated IKKε-sv1 and IKKε-sv2, respectively. Interestingly, RT-PCR revealed quantitatively different isoform expression in PBMC from different individuals. Moreover, we found cell type- and stimulus-specific protein expression of the various splice variants. Overexpression of full-length wt IKKε (IKKε-wt) leads to the activation of NF-κB- as well as IRF3-driven luciferase reporter genes. Although none of the splice variants activates IRF3, IKKε-sv1 still activates NF-κB, whereas IKKε-sv2 is also defective in NF-κB activation. Both splice variants form dimers with IKKε-wt and inhibit IKKε-wt-induced IRF3 signaling including the antiviral activity in a dominant-negative manner. The lack of IRF3 activation is likely caused by the failure of the splice variants to interact with the adapter proteins TANK, NAP1, and/or SINTBAD. Taken together, our data suggest alternative splicing as a novel regulatory mechanism suitable to shift the balance between different functions of IKKε.
authors.affiliation: Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Koop
authors.forename: Inga
authors.initials: I
authors.lastname: Lepenies
authors.forename: Oliver
authors.initials: O
authors.lastname: Braum
authors.forename: Parvin
authors.initials: P
authors.lastname: Davarnia
authors.forename: Gudrun
authors.initials: G
authors.lastname: Scherer
authors.forename: Helmut
authors.initials: H
authors.lastname: Fickenscher
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Sabine
authors.initials: S
authors.lastname: Adam-Klages
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016899:Interferon-beta / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*; D012359:tRNA Methyltransferases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D011506:Proteins; C484406:TANK protein, human; C524349:TBKBP1 protein, human; D016899:Interferon-beta; C498548:TRMO protein, human; D012359:tRNA Methyltransferases; D051550:I-kappa B Kinase