Abstract
Inhibitor of κB kinase ε (IKKε) and TANK binding kinase 1 (TBK1), so-called non-canonical IKKs or IKK-related kinases, are involved in the cellular innate immunity by inducing type I IFNs. Two kinases commonly phosphorylate transcription factors IRF3 and IRF7 in type I IFN production pathway. In contrast to TBK1, underlying mechanisms of IKKε activation and regions required for activation of downstream molecules are poorly understood. In this study, we investigated regions of IKKε required for the activation of type I IFN promoter specially, by focusing on the C-terminal region. To show the functional significance of the IKKε C-terminal region on type I IFN production, we employed various mutant forms of IKKε and compared to corresponding region of TBK1. We identified the specific regions and residues of IKKε involved in the activation of downstream signaling. Interestingly, corresponding region and residues are not required for activation of downstream signaling by TBK1. The results highlight the importance of the C-terminal region in the functional activity of IKKε in innate immune response and also the difference in activation mechanisms between IKKε and the closely related TBK1.
Highlights
Viral infection induces the cellular immune responses, which prevent viral propagation and pathogenic activities
In contrast to TANK-binding kinase 1 (TBK1), the C-terminal deletion mutants of Inhibitor of kB kinase e (IKKe) failed to activate the IFNb promoter, even with a deletion of only 31 amino acids (1-685), indicating that the C-terminal region of TBK1 and IKKe plays a different role in the activation of downstream signaling, and this region in IKKe is indispensable for the activation of the IFNb promoter in contrast to TBK1
Given that deletion of the C-terminal region in TBK1 and IKKe yielded a different effect on downstream signaling, we continued the investigation with a detailed domain analysis of IKKe
Summary
Viral infection induces the cellular immune responses, which prevent viral propagation and pathogenic activities. Activated TBK1 and IKKe phosphorylate IRF3 and IRF7, leading to the nuclear translocation of these transcription factors and subsequent induction of type I IFN promoter activity [3,4,10,11].TBK1 is constitutively expressed in a broad range of cells, while the expression of IKKe is inducible and predominantly takes place in immune cells [12,13,14] Despite these differences, TBK1 and IKKe are found together in a complex and are targeted to the phosphorylation of the C-terminal Ser/Thr rich region of IRF3 and IRF7 [3,15]. We focused on the C-terminal region of IKKe and investigated its functional significance upon the dimerization of IKKe, phosphorylation of IRF3 and activation of the IFNb promoter, respectively
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