IκB kinases: key regulators of the NF-κB pathway

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Abstract

The nuclear factor (NF)-κB pathway is important for the expression of a wide variety of genes that are involved in the control of the host immune and inflammatory response, and in the regulation of cellular proliferation and survival. The constitutive activation of this pathway is associated with inflammatory and autoimmune diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease, in addition to atherosclerosis, Alzheimer's disease, cancer and diabetes. One of the key steps in activating the NF-κB pathway is the stimulation of the IκB (inhibitor of κB) kinases. Recent data indicate that these kinases activate the NF-κB pathway through distinct steps that are operative in both the cytoplasm and the nucleus. A better understanding of the mechanisms that activate this pathway provides the potential for defining new therapeutic targets that might prevent the aberrant activation of NF-κB in a variety of human diseases.

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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