Trends in Biochemical Sciences
IκB kinases: key regulators of the NF-κB pathway
Section snippets
NF-κB and IκB proteins
The NF-κB proteins are a family of ubiquitously expressed transcription factors that, in mammals, consist of five members: p65 (RelA), RelB, c-Rel, NF-κB1 (p50 and its precursor 105) and NF-κB2 (p52 and its precursor p100) 1, 3, 4 (Table 1). All five family members share an N-terminal domain of ∼300 amino acids, designated the Rel-homology-domain (RHD), which mediates their DNA binding, dimerization and nuclear translocation. Three members of the NF-κB family – p65, RelB and c-Rel – contain
IκB kinases: key regulators of NF-κB activation
An essential step in the stimulus-induced activation of the canonical NF-κB pathway is the phosphorylaton of IκB proteins by the IKKs (Figure 1). IKK activity resides in a high-molecular-weight complex comprising at least two catalytic subunits, IKKα and IKKβ, and the associated regulatory subunit IKKγ/NEMO. IKKα and IKKβ share 52% amino acid homology and have similar functional domains including an N-terminal catalytic domain, a centrally positioned leucine-zipper motif that is involved in
Mechanisms that lead to IKK activation
The mechanism by which cytokines lead to the activation of the IKK complex is still unclear, but there are at least two proposed models. One model suggests that the activation of the mitogen-activated protein kinase kinase kinase (MAP3K) family stimulates IKK activity, whereas the other model suggests that IKK recruitment to receptor complexes at the cell membrane results in its autophosphorylation and subsequent activation. MAP3 kinases, such as NF-κB-inducing kinase (NIK) [32],
IKKα regulates an alternative NF-κB activation pathway
IKKα also plays a key part in activating a non-canonical pathway that is involved in NF-κB activation. This pathway, which regulates the processing of p100, is crucial for modulating the levels and activity of the RelB–p52 heterodimer complex (Figure 2). In contrast to p65 and/or p50, the RelB–p52 heterodimer only weakly associates with IκB proteins, but is retained in cytoplasm as a RelB–p100 precursor complex [49]. The C-terminal domain of p100 contains ankyrin repeats, which are homologous
A nuclear role for IKKα in regulating the canonical NF-κB pathway
Previous results indicate that IKKβ activates the canonical NF-κB pathway by phosphorylating IκB to result in its degradation, whereas IKKα activates the non-canonical pathway by phosphorylating p100 to result in p52 processing. However, a recently discovered novel function of IKKα is also important in activating the canonical pathway 62, 63. Surprisingly, IKKα was demonstrated to function in the nucleus to regulate histone function (Figure 3). Histone proteins H1, H2, H3 and H4, which form
Concluding remarks
Since the discovery of NF-κB in 1986 [71], NF-κB has attracted a great deal of interest because of its unique mechanism of regulation and the various functional consequences of its activity. Although IKKβ initially appeared to be the key regulator of the NF-κB pathway in response to cytokines, new information has increased the prominence of the role that IKKα has in regulating the NF-κB pathway. IKKα has several unique roles including the activation of the noncanonical NF-κB pathway, the
Acknowledgements
We thank Alex Herrera for preparation of the figures.
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