Abstract
The transcription factor NF-κB coordinates the activation of numerous genes in response to pathogens and pro-inflammatory cytokines, and is, therefore, vital in the development of acute and chronic inflammatory diseases1,2,3,4,5,6. NF-κB is activated by phsophorylation of its inhibitory subunit, IκB-α (ref. 7), on serine residues 32 and 36 by cytokine-activated IκB kinases (IKKs); this phosphorylation precedes rapid degradation of IκB8,9,10,11. IKK-α and IKK-β isozymes are found in large complexes of relative molecular mass 700,000–900,000 (Mr 70K–90K), but little is known about other components that organize and regulate these complexes12,13,14,15,16,17. IKK-α was independently discovered as a NF-κB-inducing kinase18 (NIK)-associated protein in a yeast two-hybrid screen19, and IKK-β was also identified by homology screening20. It is, however, unknown whether NIK is part of the IKK complex. Here we isolate large, interleukin-1-inducible IKK complexes that contain NIK, IKK-α, IKK-β, IκB-α, NF-κB/RelA and a protein of Mr 150K. This latter component is a new protein, termed IKK-complex-associated protein (IKAP), which can bind NIK and IKKs and assemble them into an active kinase complex. We show that IKAP is a scaffold protein and a regulator for threedifferent kinases involved in pro-inflammatory cytokine signalling.
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Acknowledgements
We thank J. Woronicz, C. Régnier, M. Ayres, S. Li, C. Lehel and T. Hoey for providing reagents; K. Williamson for DNA sequencing; and C. Béraud, M. Rothe, Z. Cao and D. Goeddel for discussions throughout the project and comments on the manuscript.
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Cohen, L., Henzel, W. & Baeuerle, P. IKAP is a scaffold protein of the IκB kinase complex. Nature 395, 292–296 (1998). https://doi.org/10.1038/26254
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DOI: https://doi.org/10.1038/26254
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