Zebrafish IkappaB kinase 1 negatively regulates NF-kappaB activity.
The IkappaB kinase (IKK) activity is critical for processing IkappaB inhibitory proteins and activating the NF-kappaB signaling, which is involved in a series of physiological and developmental steps in vertebrates. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS. IKK2 is the major cytokine-responsive IkappaB kinase because depletion of IKK1 does not interfere with the IKK activity. In fact, IKK1-/- mice display morphological abnormalities that are independent of its kinase activity and NF-kappaB activation. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-kappaB. Ikk1-/- zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-kappaB-responsive genes and increased NF-kappaB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-kappaB blockage in vivo. Zebrafish Ikk1 forms complexes with NEMO that represses NF-kappaB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-kappaB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-kappaB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-kappaB.
Correa
Ricardo G
RG
The Salk Institute for Biological Studies, La Jolla, CA 92037-1099, USA.
Matsui
Takaaki
T
Tergaonkar
Vinay
V
Rodriguez-Esteban
Concepcion
C
Izpisua-Belmonte
Juan Carlos
JC
Verma
Inder M
IM
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D019295:Computational Biology; D017931:DNA Primers; D015536:Down-Regulation; D040461:Gene Components; D006801:Humans; D051550:I-kappa B Kinase; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000378:metabolism*
D017931:DNA Primers; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human