Mini ReviewProteins that bind to IKKγ (NEMO) and down-regulate the activation of NF-κB
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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Cited by (19)
NEMO Links Nuclear Factor-κB to Human Diseases
2017, Trends in Molecular MedicineSMN1 functions as a novel inhibitor for TRAF6-mediated NF-κB signaling
2017, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :To prevent the sustained and chronic activation of NF-κB, inhibitory proteins should function properly to turn off inflammatory NF-κB signaling [3]. To date, several inhibitory proteins including A20 and cylindromatosis protein (CYLD) have been identified [4]. NF-κB in a basal state remains inactive with forming a complex with an inhibitor of NF-κB (IκB) in the cytoplasm.
NEMO differentially regulates TCR and TNF-α induced NF-κB pathways and has an inhibitory role in TCR-induced NF-κB activation
2012, Cellular SignallingCitation Excerpt :Meanwhile, a number of NEMO-binding proteins including positive and negative regulators of NF-κB have been reported. By far, the exact functions of NEMO in NF-κB pathway are not clear [3]. In T cells, upon aggregation of T cell receptor (TCR) and CD28 coreceptors, protein kinase C-θ (PKCθ) is recruited to the immunological synapse (IS) and activated, and in turn phosphorylates CARMA1 and facilitates its association with Bcl10-MALT complex, leading to the assembly of CARMA1-Bcl10-MALT1 (CBM) complex [4–8].
Celastrol regulates innate immunity response via NF-B and Hsp70 in human retinal pigment epithelial cells
2011, Pharmacological ResearchCitation Excerpt :Lipopolysaccharides (LPS) can induce TLR 4 activation, resulting in TGF-beta activated kinase 1 (TAK-1)-mediated canonical pathway IKK complex activation [12]. In response to signal transmission, a variety of proteins can form temporary connections with IKK complex, including NEMO (NF-κB essential modulator), a regulatory subunit of the IKK complex, thereby affecting NF-κB activation and subsequently gene regulation, e.g. pro-inflammatory cytokine expression [26,27]. The pro-inflammatory mediators themselves have been associated with NF-κB related inflammatory and age-related diseases [28,29].
FKBP51 and the NF-κB regulatory pathway in cancer
2011, Current Opinion in PharmacologyCitation Excerpt :The NF-κB activation signal can be classified into ‘canonical’ and ‘noncanonical’ pathways. The IKK signalsome of the canonical pathway contains two regulated IκB kinases with catalytical activity, IKKα (or IKK1) and IKKβ (or IKK2), and the regulatory scaffold subunit IKKγ, also called NEMO for NF-κB essential modulator [5,6]. Upon the stimulation of cells by specific stimuli, IκBα is phosphorylated at Ser32 and Ser36 and degraded via the ubiquitin–proteasome pathway [4,5].
Peptidylarginine deiminase 2 suppresses inhibitory κB kinase activity in lipopolysaccharide-stimulated RAW 264.7 macrophages
2010, Journal of Biological ChemistryCitation Excerpt :The above finding suggests that PAD2 suppresses NF-κB activity by affecting the IKK complex. Given the fact that IKKγ interacts with many different proteins (29, 30), we then hypothesized that PAD2 might also interact with IKKγ to achieve suppression. To test this hypothesis, we performed coimmunoprecipitation of HEK 293 cells expressing PAD2 and IKKγ.