NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''IKBKG''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. NEMO is a subunit of the IκB kinase complex that activates

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

. The human gene for IKBKG is located on the chromosome band 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 IκB kinase (IKK) complex, which activates

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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, a lack of IKBKG (and hence a lack of active NF-κB) makes cells more prone to apoptosis. Moreover, NEMO has been shown to play a role in preeclampsia and may offer insights into the genetic etiology of this condition. An increased level of NEMO gene expression was found in the blood of pregnant women with preeclampsia and their children. However, a decrease of the mRNA levels of total NEMO and the transcripts 1A, 1B, and 1C in placentas derived from preeclamptic women may be the main reason for intensified apoptosis. Sanger sequencing has indicated two distinct variations in the 3’ UTR region of the NEMO gene in preeclamptic women (IKBKG:c.*368C>A and IKBKG:c.*402C>T).http://content.ebscohost.com/ContentServer.asp?T=P&P=AN&K=28654673&S=R&D=mdc&EbscoContent=dGJyMNHX8kSep7I4v%2BbwOLCmr1Cep7VSsq%2B4TLWWxWXS&ContentCustomer=dGJyMPGus0m0q7JQuePfgeyx43zx#page14 The occurrence of a maternal TT genotype and either a TT genotype in the daughter or T allele in the son increases the risk of preeclampsia by 2.59 fold. The configuration of those maternal and fetal genotypes (TT mother/TT daughter or TT mother/T son) is also associated with the level of NEMO gene expression. NEMO deficiency syndrome is a rare genetic condition relating to a fault in IKBKG. It mostly affects males and has a highly variable set of symptoms and prognoses.NEMO deficiency syndrome information
, Great Ormond Street Hospital for Children

As a drug target

A drug called NEMO Binding Domain (NBD) has been designed to inhibit activation of

. 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 In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of IκB kinase,

IκBα IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; NFKBIA) is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuc ...

, and release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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-κB inhibitory drugs have previously been attractive to disease such as chronic inflammation and

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

, specific

cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

have been shown to have constitutive NF-κB activity. Advanced B-cell lymphoma (ABC), a subtype of

Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 ...

(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 Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

was designed by identifying the amino acid binding sequence on IKK-α and IKK-β to which NEMO binds. 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,

wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...

NBD peptide has been shown to dose-dependently inhibit interaction of IKKB with NEMO compared to

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...

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 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

mouse models. Notably, aberrant NF-κB activity is strongly associated with many aspects of the

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

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 An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

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 In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; ...

drugs. Therefore, the NBD peptide is unable to be an orally available compound and must be administered either

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

or via intraperitoneal injection.

Interactions

IKBKG has been shown to interact with: * BCL10, * CDC37, * CHUK and *

IKK2 IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the ''IKBKB'' (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene. Function IKK-β is an enzy ...

, * IRAK1, * NCOA3, * PPM1B, *

TANK A tank is an armoured fighting vehicle intended as a primary offensive weapon in front-line ground combat. Tank designs are a balance of heavy firepower, strong armour, and battlefield mobility provided by tracks and a powerful engine; ...

, * TNFAIP3, * TRAF3IP2, and *

TRAF6 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF rece ...

References

External links