Functionally distinct effects of the C-terminal regions of IKKε and TBK1 on type I IFN production.
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.
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Yuichiro
Y
Nakatsu
Department of Bacteriology II, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Mayumi
M
Matsuoka
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Tsung-Hsien
TH
Chang
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Noriyuki
N
Otsuki
Infectious Diseases Surveillance Center, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Masahiro
M
Noda
Infectious Diseases Surveillance Center, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Hirokazu
H
Kimura
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Kouji
K
Sakai
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Hiroshi
H
Kato
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Makoto
M
Takeda
Department of Virology III, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, Japan.
Toru
T
Kubota
D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D007739:L Cells; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D007370:Interferon Type I; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase