Inhibitor of nuclear factor kappa-B kinase subunit beta

Definition:

Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation. Phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation. Phosphorylates RIPK1 at 'Ser-25' which represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (By similarity). Phosphorylates the C-terminus of IRF5, stimulating IRF5 homodimerization and translocation into the nucleus.

References:

[1]. Kristopher Clark, et al. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. [Content Brief]

[2]. Jun Cui, et al. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010 Apr 30;141(3):483-96. [Content Brief]

[3]. Mickey C-T Hu, et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004 Apr 16;117(2):225-37. [Content Brief]

[4]. Chelisa Cardinez, et al. Gain-of-function IKBKB mutation causes human combined immune deficiency. J Exp Med. 2018 Nov 5;215(11):2715-2724. [Content Brief]

[5]. Hsu-Ping Kuo, et al. Phosphorylation of ARD1 by IKKbeta contributes to its destabilization and degradation. Biochem Biophys Res Commun. 2009 Nov 6;389(1):156-61. [Content Brief]

[6]. Fabrice Yoboua, et al. Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta. J Virol. 2010 Jul;84(14):7267-77. [Content Brief]

[7]. Yoshihiro Tsuchiya, et al. Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation. Mol Cell. 2010 Aug 27;39(4):570-82. [Content Brief]

[8]. Camille Lobry, et al. Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):908-13. [Content Brief]

[9]. A Salmerón, et al. Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem. 2001 Jun 22;276(25):22215-22. [Content Brief]

[10]. Marta Lopez-Pelaez, et al. Protein kinase IKKβ-catalyzed phosphorylation of IRF5 at Ser462 induces its dimerization and nuclear translocation in myeloid cells. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17432-7. [Content Brief]

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