Mini Review
Proteins that bind to IKKγ (NEMO) and down-regulate the activation of NF-κB

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Abstract

Inhibitor of κB kinase (IKK) gamma (IKKγ), also referred to as nuclear factor κB (NF-κB) essential modulator (NEMO), is an important component of the IKK complex. Following the exposure of cells to NF-κB-inducing stimuli, the IKK complex catalyzes the phosphorylation of inhibitor of κB (IκB) proteins, which is a critical step that leads to the activation of NF-κB via the canonical pathway. The exact functions of IKKγ as part of the IKK complex have not been fully elucidated. A number of proteins have been identified as directly interacting with IKKγ and modulating the activity of the IKK complex. This mini review covers eight proteins that have been reported to bind to IKKγ and lead to the suppression of the activities of the IKK complex and hence result in the down-regulation of the activation of NF-κB. The reported mechanisms by which these interactions suppress the activation of the IKK complex include the deubiquitination of IKKγ and competition with upstream activators for binding to IKKγ.

Introduction

Inhibitor of κB kinase (IKK) gamma (IKKγ), also commonly referred to as nuclear factor κB (NF-κB) essential modulator (NEMO), is an important regulatory component of a high-molecular-weight complex (the IKK complex) that also contains two catalytic proteins known as IKKα and IKKβ[1], [2]. The IKK complex catalyzes the phosphorylation of the inhibitor of κB (IκB) proteins during the activation of NF-κB through the canonical pathway [1], [2]. IKKγ is needed in the activation of NF-κB by a number of stimuli, such as tumor necrosis factor α (TNFα), IL-1, human T-lymphotropic virus type 1 (HTLV1) Tax protein, lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA) [1], [2]. The exact functions of IKKγ are not known but it is believed that the protein regulates the functions of the IKK complex by playing a key role in the assembly of the complex and by linking the complex to upstream activators or inhibitors of the NF-κB pathway [1]. In addition, the induced ubiquitination of IKKγ has been identified as playing an important role in the activation of the IKK complex [3], [4], [5].

IKKγ exists both in the nucleus and cytoplasm and shuttles between the two compartments [6], [7]. The human IKKγ protein has a predicted molecular weight of 48 kDa and contains two coiled-coil regions, a leucine zipper domain and a zinc finger domain (Fig. 1) [7], [8]. There are 419 amino acid residues in the human IKKγ. The first coiled coil is located in the region extending between amino acid residues 63 and 193 and the second coiled coil is situated in the region encompassing amino acid residues 258–298; the leucine zipper spans amino acid residues 319–346, with the zinc finger encompassing the region between residues 397 and 419 at the C-terminus [9].

A number of proteins that directly interact with IKKγ and modulate its function have been reported. A recent review has summarized 16 proteins that bind to IKKγ and promote the activation of NF-κB [10]. The present mini review covers the proteins that have been reported to directly interact with IKKγ and cause the down-regulation of the activity of the IKK complex, thus resulting in the suppression of the activation of NF-κB. Some of these proteins down-regulate the activity of the IKK complex by causing the deubiquitination of IKKγ. At least one protein that suppresses the activity of the IKK complex is believed to exert its effects by interfering with the interaction of IKKγ with upstream activators, while the mechanisms of the other interactions have not been established.

Section snippets

Interactions that lead to the deubiquitination of IKKγ

K63-linked ubiquitination of IKKγ has been identified as playing an essential role in the activation of the IKK complex following stimulation of cells by NF-κB-inducing stimuli such as TNFα, PMA and DNA damage [3], [4], [5]. The proteins that catalyze the attachment of ubiquitin chains to IKKγ include cellular inhibitor of apoptosis protein 1 (cIAP-1) and the CARMA1/Bcl10/MALT1 (CARD-MAGUK Protein 1, B-cell CLL/lymphoma 10 and mucosa-associated lymphoid tissue lymphoma translocation protein 1)

A20 binding inhibitor of NF-κB 2 (ABIN-2)

IKKγ directly interacts with the upstream signaling intermediate RIP following stimulation of cells by TNFα[12], [25], [26]. Liu et al. showed that ABIN-2 binds to IKKγ and prevents the association of IKKγ with RIP [27]. ABIN-2 was identified as a protein that interacts with A20. Overexpression of ABIN-2 inhibits the RIP-induced activation of NF-κB and this is associated with inhibition of the interaction between RIP and IKKγ. In addition, overexpressed ABIN-2 promotes the induction of

COP9 signalosome (CSN)

The COP9 signalosome (CSN) is a multi-protein complex that is involved in the ubiquitin–proteasomal pathway [29]. Using a yeast two-hybrid screen with a bait containing the amino acid residues 297–419 of IKKγ, Hong et al. identified CSN3, a subunit of the COP9 signalosome, as a protein that interacts with IKKγ[30]. According to their findings, the overexpression of CSN3 results in the inhibition of the activation of NF-κB by TNFα treatment and by downstream mediators such as TNFR1, RIP and

Conclusions and perspectives

An extensive search of the Medline database has revealed eight proteins that have been identified as directly binding to IKKγ and suppressing the activation of NF-κB. The sites on IKKγ to which some of these proteins bind are indicated in Fig. 1. The inhibitory effects of these interactions appear to take place at the level of the IKK complex. A diagrammatic depiction of these interactions is presented in Fig. 2. One mechanism that is involved in this process is the deubiquitination of IKKγ.

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