IKBKG

IKBKG Background

Inhibitory kappa-B kinase gamma (IKKγ) is a 48 kDa non-catalytic protein in humans that is encoded by the IKBKG gene. IKKγ, also known as nuclear factor kappa B (NF-κB) essential modulator (NEMO), is a subunit of the inhibitory kappa-B (IκB) kinase complex that activates NF-κB leading to activation of genes involved in inflammation, immunity, cell survival, and other pathways against apoptosis. Molecular cloning and sequencing indicate that IKKγ is composed of several potential coiled-coil motifs. It plays a scaffolding/regulatory role and is required for kinase function ^[1][2]. IKKγ interacts preferentially with IKKβ and is indispensable for the activation of the IKK complex ^[3]. Binding of IKKγ to IKKα and IKKβ subunits activate the IKK complex leading to phosphorylation of IκB kinase IκBα and the release of NF-κB dimers p105 and RELA to translocate to the nucleus and activate transcription of NF-κB responsive genes. An IKKγ C-terminal truncation mutant that still binds IKKβ blocks the activation of IKK and NF-κB ^[3]. An N-terminal α-helical region of IKKγ associated with a C-terminal segment of IKKα and IKKβ is termed the NEMO-binding domain (NBD). A cell-permeable NBD peptide blocked association of NEMO with the IKK complex and inhibited cytokine-induced NF-κB activation and NF-κB–dependent gene expression ^[4]. Lack of IKKγ, therefore, makes cells more prone to apoptosis. Hypomorphic mutations in IKBKG lead to X-linked anhidrotic ectodermal dysplasia with immunodeficiency or to isolated immunodeficiency. IKBKG mutations also result in incontinentia pigmenti ^[5], hypohidrotic ectodermal dysplasia ^[6], and several other types of immunodeficiencies.

[1] Rothwarf DM, Zandi E, et al. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex [J]. Nature. 1998 Sep 17; 395(6699):297-300.
[2] Yamaoka S, Courtois G, et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation [J]. Cell. 1998 Jun 26; 93(7):1231-40.
[3] David M. Rothwarf, Ebrahim Zandi, et al. IKK-γ is an essential regulatory subunit of the IκB kinase complex [J]. Nature volume 395, pages297-300(1998).
[4] Michael J. May, Fulvio D'Acquisto, et al. Selective Inhibition of NF-κB Activation by a Peptide That Blocks the Interaction of NEMO with the IκB Kinase Complex [J]. Science. 2000:Vol. 289, Issue 5484, pp. 1550-1554.
[5] Aradhya S, Woffendin H, et al. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations [J]. Human Molecular Genetics. 2001, 10 (19): 2171-9.
[6] Zonana J, Elder ME, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO) [J]. American Journal of Human Genetics. 2000, 67 (6): 1555-62.