Defective IKBKG (NEMO) destabilizes the association of IKBKA:IKBKB:IKBKG (via TLR)

Stable Identifier
Reaction [transition]
Homo sapiens
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A group of hypomorphic IKBKG (NEMO) mutations has been associated with X-linked ectodermal dysplasia with immunodeficiency disorder (EDA-ID) (Döffinger R et al. 2001; Fusco F et al. 2004; Hanson EP et al. 2008).

The IKBKG molecule consists of several structural domains. The N-terminal containing a large coiled-coil motif (CC1) is responsible for the interaction with IKK kinases (Marienfeld RB et al. 2006; Rushe M et al. 2008). The C-terminal domain is composed of a coiled-coil motif (CC2, aa 251-285)3, a leucine zipper (LZ; aa 301-337), and a zinc finger motif (ZF; aa 390-410). The C-terminal domain accounts for the oligomerization and binding to Lys-63-linked polyubiquitin chains (Agou F et al. 2004; Laplantine E et al. 2009; Ngadjeua F et al. 2013). This module shows a set of selected EDA-ID associated IKBKG mutations found across the coding gene range, that have been functionally tested in response to known toll like receptors (TLR) agonists. A mutation in the N-terminal domain, required for IKK assembly, reduced but did not abolish NF-kappaB activation following lipopolysaccharide stimulation (Fusco F et al. 2004). Mutations that disrupt the C-terminal domain, required for the recruitment of upstream factors, showed lower or no NF-kappaB activation (Fusco F et al. 2004; Cordier F et al. 2008)

NEMO-deficient human 3T8 Jurkat T cell line reconstituted with a construct of missense IKBKG variant L153R or C417R showed reduced NBkB activation in response to flagellin (TLR5 agonist) (Hanson EP et al. 2008). In addition, a C417R mutation located in ZF of IKBKG abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKBKB (Yang F et al. 2004). The other EDA-ID associated missense mutation in ZF, IKBKG D406V, was also found to reduce NFkB activation upon stimulation of Jurkat T cell with IL-1beta, but did not alter the ZF structure as judged by fluorescence spectroscopy and metal binding colorimetric assay (Ngadjeua F et al. 2013). Moreover, dendritic cells from patients with EDA-ID caused by a C-terminal E391* deletion of the zinc finger of NEMO and by missense mutation C417R exhibit impaired MAPK activation in response to lipopolysaccharide (TLR4 agonist)(Ma CA et al. 2011). LPS-stimulated whole blood cells derived from patient with IKBKG R173G showed reduced NFkB activation (Ku CL et al. 2007). Furthermore, TLR-mediated TNF production was validated first in peripheral blood mononuclear cells (PBMC) from healthy donors and then evaluated in PBMC from 3 IKBKG-deficient patients bearing two missense (L153A and C417Y) and one nonsense (c.1056-1118del) mutations (Deering RP and Orange JS 2006). Mean TNF responses were significantly impaired across almost all TLR ligands tested, with the exception of c.1056-1118del variant in response to TLR9 agonist, which produced means within the control donor normative range (Deering RP and Orange JS 2006). Several experimental studies on the molecular basis for the observed functional defects suggest that IKBKG deficiency causes alteration in the assembly of IKK complex due to IKBKG oligomer instability (Fusco et al. 2004; Doffinger et al. 2001; Vinolo et al. 2006). A pathogenic mutation in the ZF domain of IKBKG was also reported to affect the interaction with Lys-63 and Met-1-linked di-ubiquitin, which correlates with its ubiquitin binding defect in vivo (Ngadjeua F et al. 2013).

Literature References
PubMed ID Title Journal Year
24100029 Two-sided ubiquitin binding of NF-?B essential modulator (NEMO) zinc finger unveiled by a mutation associated with anhidrotic ectodermal dysplasia with immunodeficiency syndrome

Chiaravalli, J, Traincard, F, Ngadjeua, F, Agou, F, Fontan, E, Raynal, B

J. Biol. Chem. 2013
15229184 Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation

Courtois, G, Miano, MG, Fusco, F, D'Urso, M, Israel, A, Mercadante, V, Ursini, MV, Fimiani, G, Bardaro, T, Falco, G

Hum. Mol. Genet. 2004
11242109 X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling

Belani, K, Wood, P, Kalhoff, H, Blanche, S, Conley, ME, Courtois, G, Headon, DJ, Abinun, M, Durandy, A, Bodemer, C, Rabia, SH, Israël, A, Geissmann, F, Döffinger, R, Kenwrick, S, Casanova, JL, Kumararatne, DS, Le Deist, F, Smahi, A, Dupuis-Girod, S, Reimund, E, Holland, SM, Bessia, C, Fischer, A, Overbeek, PA, Munnich, A, Shapiro, R, Feinberg, J

Nat. Genet. 2001
Normal reaction
Functional status

Loss of function of TLR associated IKBKG variants [cytosol]

Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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