| Structural highlights
Disease
[IKKA_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[IKKA_HUMAN] 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 and phosphorylates inhibitors of NF-kappa-B on 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. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Distinct signaling pathways activate the NF-kappaB family of transcription factors. The canonical NF-kappaB-signaling pathway is mediated by IkappaB kinase 2/beta (IKK2/beta), while the non-canonical pathway depends on IKK1/alpha. The structural and biochemical bases for distinct signaling by these otherwise highly similar IKKs are unclear. We report single-particle cryoelectron microscopy (cryo-EM) and X-ray crystal structures of human IKK1 in dimeric ( approximately 150 kDa) and hexameric ( approximately 450 kDa) forms. The hexamer, which is the representative form in the crystal but comprises only approximately 2% of the particles in solution by cryo-EM, is a trimer of IKK1 dimers. While IKK1 hexamers are not detectable in cells, the surface that supports hexamer formation is critical for IKK1-dependent cellular processing of p100 to p52, the hallmark of non-canonical NF-kappaB signaling. Comparison of this surface to that in IKK2 indicates significant divergence, and it suggests a fundamental role for this surface in signaling by these kinases through distinct pathways.
Structural Basis for the Activation of IKK1/alpha.,Polley S, Passos DO, Huang DB, Mulero MC, Mazumder A, Biswas T, Verma IM, Lyumkis D, Ghosh G Cell Rep. 2016 Nov 15;17(8):1907-1914. doi: 10.1016/j.celrep.2016.10.067. PMID:27851956[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yamamoto Y, Verma UN, Prajapati S, Kwak YT, Gaynor RB. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003 Jun 5;423(6940):655-9. PMID:12789342 doi:http://dx.doi.org/10.1038/nature01576
- ↑ Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004 Apr 16;117(2):225-37. PMID:15084260
- ↑ Huang WC, Ju TK, Hung MC, Chen CC. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Mol Cell. 2007 Apr 13;26(1):75-87. PMID:17434128 doi:http://dx.doi.org/10.1016/j.molcel.2007.02.019
- ↑ Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010 Apr 30;141(3):483-96. doi: 10.1016/j.cell.2010.03.040. PMID:20434986 doi:10.1016/j.cell.2010.03.040
- ↑ Razani B, Zarnegar B, Ytterberg AJ, Shiba T, Dempsey PW, Ware CF, Loo JA, Cheng G. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal. 2010 May 25;3(123):ra41. doi: 10.1126/scisignal.2000778. PMID:20501937 doi:http://dx.doi.org/10.1126/scisignal.2000778
- ↑ Shembade N, Pujari R, Harhaj NS, Abbott DW, Harhaj EW. The kinase IKKalpha inhibits activation of the transcription factor NF-kappaB by phosphorylating the regulatory molecule TAX1BP1. Nat Immunol. 2011 Jul 17;12(9):834-43. doi: 10.1038/ni.2066. PMID:21765415 doi:http://dx.doi.org/10.1038/ni.2066
- ↑ Polley S, Passos DO, Huang DB, Mulero MC, Mazumder A, Biswas T, Verma IM, Lyumkis D, Ghosh G. Structural Basis for the Activation of IKK1/alpha. Cell Rep. 2016 Nov 15;17(8):1907-1914. doi: 10.1016/j.celrep.2016.10.067. PMID:27851956 doi:http://dx.doi.org/10.1016/j.celrep.2016.10.067
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