IKBKG

NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a is_associated_with::protein that in humans is encoded by the IKBKG is_associated_with::gene. NEMO is a subunit of the is_associated_with::IκB kinase complex that activates is_associated_with::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
NEMO (IKK-γ) is the regulatory subunit of the inhibitor of is_associated_with::IκB kinase (IKK) complex, which activates is_associated_with::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 is_associated_with::incontinentia pigmenti, is_associated_with::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 is_associated_with::TNF-alpha induced is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::phosphorylation of is_associated_with::IκB kinase, is_associated_with::IκBα, and release of NF-κB dimers p105 and is_associated_with::RELA to translocate to the nucleus and activate transcription of NF-κB responsive is_associated_with::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 is_associated_with::chronic inflammation and is_associated_with::diabetes, specific is_associated_with::cancers have been shown to have constitutive NF-kB activity. Advanced is_associated_with::B-cell lymphoma (ABC), a subtype of is_associated_with::Diffuse large B-cell lymphoma (DLBCL) has been shown to have fundamental and is_associated_with::upregulated NF-κB activity. ABC lymphoma also has the lowest survival rate compared to DLBCL subtypes, is_associated_with::Germinal Center is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::Antennapedia is_associated_with::homeodomain that mediates membrane translocation. Furthermore, is_associated_with::in vitro studies with the is_associated_with::wild type NBD peptide has been shown to does-dependently inhibit interaction of IKKB with NEMO compared to is_associated_with::mutant controls. Additionally, NF-κB activation was suppressed in is_associated_with::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 is_associated_with::rheumatoid arthritis mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the is_associated_with::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 is_associated_with::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 is_associated_with::small molecule drugs. Therefore, the NBD peptide is unable to be an orally available compound and must be administered either is_associated_with::intravenously or via is_associated_with::intraperitoneal injection.

Interactions
IKBKG has been shown to interact with:


 * is_associated_with::BCL10,
 * is_associated_with::CDC37,
 * is_associated_with::CHUK and
 * is_associated_with::IKK2,
 * is_associated_with::IRAK1,
 * NCOA3,
 * is_associated_with::PPM1B,
 * TANK,
 * is_associated_with::TNFAIP3,
 * is_associated_with::TRAF3IP2,  and
 * is_associated_with::TRAF6.