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Review
. 2010:2010:823821.
doi: 10.1155/2010/823821. Epub 2010 Apr 12.

Regulation of IkappaBalpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages

Amin Majdalawieh  1 , Hyo-Sung Ro
Affiliations
Review

Regulation of IkappaBalpha function and NF-kappaB signaling: AEBP1 is a novel proinflammatory mediator in macrophages

Amin Majdalawieh et al. Mediators Inflamm. 2010.

Abstract

NF-kappaB comprises a family of transcription factors that are critically involved in various inflammatory processes. In this paper, the role of NF-kappaB in inflammation and atherosclerosis and the regulation of the NF-kappaB signaling pathway are summarized. The structure, function, and regulation of the NF-kappaB inhibitors, IkappaBalpha and IkappaBbeta, are reviewed. The regulation of NF-kappaB activity by glucocorticoid receptor (GR) signaling and IkappaBalpha sumoylation is also discussed. This paper focuses on the recently reported regulatory function that adipocyte enhancer-binding protein 1 (AEBP1) exerts on NF-kappaB transcriptional activity in macrophages, in which AEBP1 manifests itself as a potent modulator of NF-kappaB via physical interaction with IkappaBalpha and a critical mediator of inflammation. Finally, we summarize the regulatory roles that recently identified IkappaBalpha-interacting proteins play in NF-kappaB signaling. Based on its proinflammatory roles in macrophages, AEBP1 is anticipated to serve as a therapeutic target towards the treatment of various inflammatory conditions and disorders.

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Figures

Figure 1
Figure 1
Structural Organization of NF-κB/Rel and IκB Proteins. (a) A schematic representation of some members of the Rel family of proteins. Members of this family contain a unique, highly conserved Rel homology domain (RHD) towards the N-terminus, and this domain carries a nuclear localization signal (NLS). Most members of the Rel family contain a C-terminally located transactivation domain (TAD) that is important for optimal transcriptional activity. RelB is a structurally unique member of the NF-κB protein family in that it contains a leucine zipper-like (LZ) region at its N-terminus. (b) A schematic representation of some members of the IκB family of proteins, which are uniquely characterized by the presence of 30-33-amino acid ankyrin (ANK) repeats. At least for IκBα and IκBβ the most well-characterized members of the IκB family, there are two conserved serine residues at the N-terminus preceding the first ANK repeat. Phosphorylation of these two serine residues is known to be crucial for signaling IκB proteins for ubiquitination and proteolytic degradation. At the C-terminus of IκB proteins, there is a region rich with proline, glutamate, serine, and threonine residues, and hence, it is named the PEST domain. The number of amino acid residues within the indicated proteins in mouse is shown.
Figure 2
Figure 2
NF-κB Signaling Pathway. A cartoon representing the cascade of biochemical events that are initiated by various stimuli, eventually leading to NF-κB nuclear translocation and transcriptional activation. Recruitment of different adaptor molecules to different receptor complexes coupled with activation of different downstream kinases is shown. There are mainly two signaling pathways leading to NF-κB activation, classical (also known as canonical) and alternative. The formation and activation of the IKK complex, which consists of catalytically active kinases (e.g., IKKα, IKKβ, and IKKγ) and noncatalytic regulatory proteins (e.g., NEMO and ELKS), is a universal event in both signaling pathways. In the classical signaling pathway, ligand binding to a cell surface receptor leads to the recruitment of adaptor proteins (e.g., TRAF6) to the receptor, leading to the recruitment of IKK complex and subsequent phosphorylation and degradation of the IκB proteins. Unlike the classical signaling pathway, the alternative signaling pathway, which is normally triggered by non-proinflammatory cytokines (e.g., LTβ, BAFF, and CD40L) as well as some viruses (e.g., HTLV and EBV), does not allow the recruitment of NEMO. Instead, ligand binding to a cell surface receptor leads to the recruitment of NIK, which in turn phosphorylates and activates IKKα dimers. Typically, the classical signaling pathway leads to the activation of NF-κB dimers consisting of RelA, c-Rel, RelB, and p50, while the alternative signaling pathway leads to the activation of NF-κB dimers consisting primarily of RelB and p52.
Figure 3
Figure 3
Regulation of IκBα and IκBβ. A cartoon representing the most critical intracellular events leading to NF-κB transcriptional activation. Interaction between diverse ligands and their receptors eventually leads to activation of the IKK complex, which allows IκBα and IκBβ phosphorylation in the cytosol. This phosphorylation step is followed by IκBα, but not IκBβ, ubiquitination, and subsequently, IκBα and IκBβ are subjected to proteolytic degradation. Once IκBα and IκBβ molecules are degraded, NF-κB dimers are liberated, and they translocate to the nucleus subsequent to unmasking of their NLS. Once in the nucleus, NF-κB dimers bind to κB sites within the promoter/enhancer regions of their target genes, driving gene transactivation.
Figure 4
Figure 4
Amino Acid Sequence Comparison between  IκBα and IκBβ. (a) Alignment of amino acid sequences of mouse IκBα and IκBβ is shown. The six highly conserved ANK repeats in both proteins are highlighted in grey, yellow, green, red, pink, and blue, respectively. (b) A cartoon illustrating a comparison of the slightly different structural domain organizations of mouse IκBα and IκBβ proteins. The signal-induced kinase domain, six ANK repeats, and PEST domain of each protein are shown.
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