NFKBIA variant binds NFkB complex

Stable Identifier
R-HSA-9630921
Type
Reaction [binding]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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NFKBIA variant binds NFkB complex
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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

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

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

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

J. Clin. Immunol. 2013
Participants
Input
Output
Participates
as an event of
Normal reaction
NF-kappa-B inhibitor binds NF-kappa-B complex (Homo sapiens)
Functional status

Gain of function of NFKBIA variants [cytosol]

Normal Entity
Disease Entity
Status
Disease
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
Cross References
Mondo
Authored
Shamovsky, V  (2018-11-30)
Reviewed
D'Eustachio, P  (2018-12-04)
Created
Shamovsky, V  (2018-12-04)
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