NFKBIA variant binds NFkB complex

Stable Identifier
Reaction [binding]
Homo sapiens
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Under normal conditions, stimuli-induced nuclear factor kappa B (NFkB) signaling induces IkB kinase (IKK)-mediated phosphorylation of the inhibitor of NFkB alpha (IKBA or NFKBIA) protein at two critical residues, Ser32 and Ser36 (Karin M & Ben-Neriah 2000). This triggers polyubiquitination of NFKBIA at Lys21 and Lys22 and subsequent proteasomal degradation thus allowing nuclear translocation of NFkB dimers (Karin M & Ben-Neriah Y 2000; Kanarek N & Ben-Neriah Y 2012). Several patients with ectodermal dysplasia with immunodeficiency (EDA-ID) were found to carry mutations in NFKBIA gene (Courtois G et al. 2003; MacDonald DR et al. 2007; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnidi H et al. 2012). All human NFKBIA mutations are heterozygous gain-of-function (GoF) mutations that augment NF-kB inhibition, causing autosomal dominant disease (Courtois G et al. 2003; Schimke LF et al. 2013; Zhang Q et al. 2016). NFKBIA mutations are either substitutions (S32I or M37K) affecting the phosphorylation of residues Ser32 and Ser36 or nonsense mutations (W11TER or E14TER) (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Zhang Q et al. 2016). The nonsense mutations in NFKBIA gene causing premature termination codons at positions 9 (Q9TER), 11 (W11TER), or 14 (E14TER) lead to translation reinitiation at an in-frame M37 downstream of the nonsense mutations resulting in the N-terminally truncated variant (NFKBIA F2_M37del) that lacks the critical phosphorylation sites at Ser32 or Ser36 (Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnishi H et al. 2012).The NFKBIA (IkBa) protein variants are expressed but cannot undergo phosphorylation-driven degradation. Disregarding induction signals, they remain constitutively bound to NFkB dimer and freeze the pathway sequestering NFkB dimers in the cytoplasm (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013). This has been verified by overexpressing mutant NFKBIA proteins encoded by patient alleles and showing that they override the wild-type protein and block NFkB-induced gene expression (Courtois G et al., 2003). NFkB signaling can be variably impaired in patients with IKBA-deficiency ranging from severe dominant-negative effect of NFKBIA S32I variant comparing to NFKBIA W11TER which results in functional NFkB haploinsufficiency (Lopes-Granados E et al. 2008; McDonald DR et al, 2007).

Literature References
PubMed ID Title Journal Year
18412279 A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency

Kinney, MC, Leo, H, Keenan, JE, Jain, A, Lopez-Granados, E, Jain, N, Gelfand, EW, Ma, CA, Quinones, R

Hum. Mutat. 2008
23708964 A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy

Hubbard, N, Notheis, G, Rylaarsdam, S, Repp, R, Hökfelt, T, Schwarz, HP, Albert, MH, Belohradsky, BH, Rieber, N, Torgerson, TR, Puel, A, Picard, C, Cabral-Marques, O, Sombke, SA, Schimke, LF, Renner, ED, Kallmann, L, Kammer, B, Ochs, HD, Casanova, JL

J. Clin. Immunol. 2013
Normal reaction
Functional status

Gain of function of NFKBIA variants [cytosol]

Name Identifier Synonyms
severe combined immunodeficiency DOID:627 Severe combined immunodeficiency, combined T and B cell inborn immunodeficiency, SCID, Severe combined immunodeficiency disease (disorder), SCID
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