NF-κB activation through IKK-i-dependent I-TRAF/TANK phosphorylation
Article first published online: 25 DEC 2001
Genes to Cells
Volume 5, Issue 3, pages 191–202, March 2000
How to Cite
Nomura, Kawai, Nakanishi, K. and Akira, S. (2000), NF-κB activation through IKK-i-dependent I-TRAF/TANK phosphorylation . Genes to Cells, 5: 191–202. doi: 10.1046/j.1365-2443.2000.00315.x
- Issue published online: 25 DEC 2001
- Article first published online: 25 DEC 2001
- Cited By
NF-κB is an ubiquitously expressed transcription factor that plays an important role in the immune, anti-apoptotic and inflammatory responses. NF-κB is normally sequestered in the cytoplasm by interacting with inhibitory IκB molecules. Upon stimulation, IκB is phosphorylated and subsequently degraded by the proteasome, allowing NF-κB to translocate into the nucleus where they regulate target gene expression. Two kinases, IKK-α and IKK-β, which are responsible for IκB phosphorylation were recently identified. We have recently identified a cytokine inducible IKK-i, a kinase related to IKK-α and -β. IKK-i significantly induced NF-κB activation upon over-expression, as did IKK-α and IKK-β. Unlike IKK-α and IKK-β, IKK-i phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF-κB by distinct mechanisms from the conventional IKKs.
I-TRAF/TANK was isolated as a molecule that interacts specifically with inducible IκB kinase (IKK-i) by the yeast two-hybrid screening procedure. The association of IKK-i and I-TRAF is mediated via the interaction between the N-terminal domain of I-TRAF and the C-terminal portion of IKK-i. In vitro kinase assays demonstrate that IKK-i phosphorylates I-TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I-TRAF/TRAF2 complex after I-TRAF phosphorylation. NF-κB activation by IKK-i is significantly blocked by coexpression of the N-terminal domain of I-TRAF, dominant negative TRAF2, and dominant negative NIK and IKK-β. IKK-i over-expression also induced c-Jun N-terminal kinase. These results show that I-TRAF is a substrate of IKK-i. NF-κB activation by IKK-i may be mediated through phosphorylation of I-TRAF by IKK-i and subsequent liberation of TRAF2.
These results indicate that NF-κB activation by IKK-i is mediated through phosphorylation of I-TRAF/TANK by IKK-i and subsequent liberation of TRAF2.