IKBKG

Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma
Rendering based on PDB 2JVX.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2JVX, 2JVY, 3BRT, 3BRV, 3CL3, 3FX0, 4BWN
Identifiers
Symbols	IKBKG ; AMCBX1; FIP-3; FIP3; Fip3p; IKK-gamma; IMD33; IP; IP1; IP2; IPD2; NEMO; ZC2HC9
External IDs	OMIM: 300248 MGI: 1338074 HomoloGene: 2698 ChEMBL: 4967 GeneCards: IKBKG Gene
Gene ontology Molecular function • signal transducer activity • protein binding • protein domain specific binding • ubiquitin protein ligase binding • protein homodimerization activity • peroxisome proliferator activated receptor binding • metal ion binding • protein heterodimerization activity • K63-linked polyubiquitin binding • linear polyubiquitin binding Cellular component • ubiquitin ligase complex • spindle pole • intracellular • nucleus • cytoplasm • cytosol • IkappaB kinase complex • mitotic spindle Biological process • activation of MAPK activity • B cell homeostasis • stimulatory C-type lectin receptor signaling pathway • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • transcription, DNA-templated • apoptotic process • inflammatory response • immune response • cellular response to DNA damage stimulus • I-kappaB kinase/NF-kappaB signaling • activation of NF-kappaB-inducing kinase activity • JNK cascade • response to virus • viral process • positive regulation of type I interferon production • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • TRIF-dependent toll-like receptor signaling pathway • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • positive regulation of I-kappaB kinase/NF-kappaB signaling • innate immune response • positive regulation of transcription from RNA polymerase II promoter • T cell receptor signaling pathway • positive regulation of NF-kappaB transcription factor activity • stress-activated MAPK cascade • establishment of vesicle localization • nucleotide-binding oligomerization domain containing signaling pathway • negative regulation of neuron death Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8517	16151
Ensembl	ENSG00000269335	ENSMUSG00000004221
UniProt	Q9Y6K9	O88522
RefSeq (mRNA)	NM_001099856	NM_001136067
RefSeq (protein)	NP_001093326	NP_001129539
Location (UCSC)	Chr X: 154.54 – 154.57 Mb	Chr X: 74.39 – 74.45 Mb
PubMed search	[1]	[2]

NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the IKBKG gene. NEMO is a subunit of the IκB kinase complex that activates NF-κB. The human gene for IKBKG is located on chromosome Xq28. Multiple transcript variants encoding different isoforms have been found for this gene.

Function

Main article: IκB kinase

NEMO (IKK-γ) is the regulatory subunit of the inhibitor of IκB kinase (IKK) complex, which activates NF-κB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways.

Clinical significance

Mutations in the IKBKG gene results in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies.

Incontinentia Pigmenti (IP) is an X-linked dominant disease caused by a mutation in the IKBKG gene. Since IKBKG helps activate NF-κB, which protects cells against TNF-alpha induced apoptosis, a lack of IKBKG (and hence a lack of active NF-κB) makes cells more prone to apoptosis.

As a Drug Target

A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of NF-κB. NBD is a peptide that acts by binding to regulatory subunit NEMO (IKK-γ) thereby preventing it from binding subunits IKK-α and IKK-β and activating the IKK complex. In the absence of regulatory subunit IKK-γ the IKK complex is inactive, preventing the downstream signal transduction cascade leading to NF-κB activation. Binding of IKK-γ to IKK-α and IKK-β subunits activates the IKK complex leading to phosphorylation of IκB kinase, IκBα, and release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive genes. In the presence of the NBD peptide, the IKK complex remains inactive and IκBα sequesters NF-κB dimers in the cytoplasm inhibiting transcription of NF-κB responsive genes. While NF-kB inhibitory drugs have previously been attractive to disease such as chronic inflammation and diabetes, specific cancers have been shown to have constitutive NF-kB activity. Advanced B-cell lymphoma (ABC), a subtype of Diffuse large B-cell lymphoma (DLBCL) has been shown to have fundamental and upregulated NF-κB activity. ABC lymphoma also has the lowest survival rate compared to DLBCL subtypes, Germinal Center B-cell-like and Undefined Type 3 lymphoma, highlighting the great clinical need to define targets for cancer therapy. Notably, the NBD peptide targets the inflammation induced NF-κB activation pathway sparing the protective functions of basal NF-κB activity allowing for greater therapeutic value and fewer undesired side effects.

The NBD peptide was designed by identifying the amino acid binding sequence on IKK-α and IKK-β to which NEMO binds. Studies reveal that a small region on the carboxyl terminus of IKK-α (L738-L743) and IKK-β (L737-L742) is essential for a stable interaction with NEMO and for the assembly of the active IKK complex. Henceforth this region is called the NEMO binding domain (NBD). The NBD peptide consists of the region from T735 to E745 of the IKK-β subunit fused with a sequence derived from the Antennapedia homeodomain that mediates membrane translocation. Furthermore, in vitro studies with the wild type NBD peptide has been shown to does-dependently inhibit interaction of IKKB with NEMO compared to mutant controls. Additionally, NF-κB activation was suppressed in HeLa cells after incubation with NBD wild type peptides. Moreover, to better understand the potential efficacy of the NBD peptide in suppressing inflammation, NBD peptide was tested on collagen induced rheumatoid arthritis mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the pathology of rheumatoid arthritis. Mice injected with wild-type NBD peptide showed only slightly visual signs of paw and joint swelling whereas mice injected with PBS or mutant NBD control peptides developed severe joint inflammation. Additionally, analysis of the number of osteoclasts present in the joints of rheumatoid arthritic showed to be more prevalent in mice treated with PBS or the mutant NBD peptide compared to the NBD wild type peptide. Markedly, throughout the mouse model studies neither toxicity or lethality nor damage to kidneys or livers, was observed.

Despite the potential for NBD peptide as a viable NF- κB inhibitory drug, disadvantages arise because of its peptide form. Peptides as drugs lack membrane permeability, are poorly orally viable, and generally have lower metabolic stability than small molecule drugs. Therefore, the NBD peptide is unable to be an orally available compound and must be administered either intravenously or via intraperitoneal injection.

Interactions

IKBKG has been shown to interact with:

• BCL10,
• CDC37,
• CHUK and
• IKK2,
• IRAK1,
• NCOA3,
• PPM1B,
• TANK,
• TNFAIP3,
• TRAF3IP2, and
• TRAF6.

External links

• IKBKG protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NIH/NCBI/UW entry on Incontinentia Pigmenti
• OMIM IKBKG
• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview