Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes.
TANK-binding kinase 1 (TBK1/NAK/T2K) and I-kappaB Kinase (IKK-i/IKK-epsilon) play important roles in the regulation of interferon (IFN)-inducible genes during the immune response to bacterial and viral infections. Cell stimulation with ssRNA virus, dsDNA virus or gram-negative bacteria leads to activation of TBK1 or IKK-i, which in turn phosphorylates the transcription factors, IFN-regulatory factor (IRF) 3 and IRF7, promoting their translocation in the nucleus. To understand the molecular basis of activation of TBK1, we analyzed the sequence of TBK1 and IKK-i and identified a ubiquitin-like domain (ULD) adjacent to their kinase domains. Deletion or mutations of the ULD in TBK1 or IKK-i impaired activation of respective kinases, failed to induce IRF3 phosphorylation and nuclear localization and to activate IFN-beta or RANTES promoters. The importance of the ULD of TBK1 in LPS- or poly(I:C)-stimulated IFN-beta production was demonstrated by reconstitution experiments in TBK1-IKK-i-deficient cells. We propose that the ULD is a regulatory component of the TBK1/IKK-i kinases involved in the control of the kinase activation, substrate presentation and downstream signaling pathways.
Ikeda
Fumiyo
F
Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
Hecker
Christina Maria
CM
Rozenknop
Alexis
A
Nordmeier
Rolf Dietrich
RD
Rogov
Vladimir
V
Hofmann
Kay
K
Akira
Shizuo
S
Dötsch
Volker
V
Dikic
Ivan
I
D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051550:I-kappa B Kinase; D007372:Interferons / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects
D008070:Lipopolysaccharides; D007372:Interferons; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D011070:Poly I-C