The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation

Abstract

Rel homology domain nuclear localization sequence tumor necrosis factor interleukin IκB kinase leucine zipper helix-loop-helix IKK complex-associated protein IKK kinase NF-κB/Rel proteins are dimeric, sequence-specific transcription factors that control a variety of important biological decisions from formation of dorsal-ventral polarity in insects to activation of inflammatory and innate immune responses (reviewed in Ref. 1Baeuerle P.A. Baltimore D. Cell. 1996; 87: 13-20Abstract Full Text Full Text PDF PubMed Scopus (2954) Google Scholar). NF-κB proteins are related through the Rel homology domain (RHD),1 which subjects them to a particular type of regulation, centered around nuclear-cytoplasmic shuttling (reviewed in Ref. 2Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5649) Google Scholar). The RHD serves several functions. It is the dimerization and DNA binding domain, and we have learned in atomic detail how RHDs dimerize and interact with DNA (3Chen F.E. Huang D-B. Chen Y.-Q. Ghosh G. Nature. 1998; 391: 410-413Crossref PubMed Scopus (342) Google Scholar). In addition, the RHD contains a nuclear localization sequence (NLS), and most importantly it is the site for binding of inhibitors of NF-κB, the IκBs (reviewed in Ref. 2Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5649) Google Scholar). The IκBs also form a small family with a core composed of six or more ankyrin repeats, an N-terminal regulatory domain, and a C-terminal domain that contains a PEST motif (reviewed in Ref. 2Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5649) Google Scholar). By binding to NF-κB dimers, the IκBs mask their NLS and cause their cytoplasmic retention. Some IκBs, such as IκBα, contain a nuclear export sequence and when combining with NF-κB dimers in the nucleus (which the IκBs can presumably enter by diffusion) cause their exportin-mediated transport to the cytoplasm (4Arenzana-Seisdedos F. Turpin P. Rodriguez M. Thomas D. Hay R.T. Virelizier J.L. Dargemont C. J. Cell Sci. 1997; 110: 369-378Crossref PubMed Google Scholar). Recently the three-dimensional structures of NF-κB·IκB ternary complexes (composed of the RHDs of p50 and p65 and the ankyrin repeat core of IκBα) were solved (5Huxford T. Huang D.B. Malek S. Ghosh G. Cell. 1998; 95: 759-770Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar, 6Jacobs M.D. Harrison S.C. Cell. 1998; 95: 749-758Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar). These fascinating structures indicate that the ankyrin repeats of IκBα form a slightly bent cylinder through a stacked arrangement of α-helices that compose their ankyrin repeats. The peptide loops that connect these helices make specific contacts with the two RHDs, whose N-terminal Ig-like repeats flank the IκB core; the C-terminal Ig-like repeats (responsible for dimerization) contact each other with the IκB cylinder lying on top of them. Although the structures solved by two independent groups differ on the way by which IκB masks the NLS located next to the C-terminal Ig-like repeats of the RHDs (5Huxford T. Huang D.B. Malek S. Ghosh G. Cell. 1998; 95: 759-770Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar, 6Jacobs M.D. Harrison S.C. Cell. 1998; 95: 749-758Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar) it is likely that the first two ankyrin repeats sterically hinder the binding of importins to the NLS of NF-κB. Initially, NF-κB was thought to be a B cell-specific transcription factor (1Baeuerle P.A. Baltimore D. Cell. 1996; 87: 13-20Abstract Full Text Full Text PDF PubMed Scopus (2954) Google Scholar). However, it was quickly recognized that NF-κB activity can be induced in most cell types upon treatment with phorbol esters, the proinflammatory cytokines, tumor necrosis factor (TNF), and interleukin 1 (IL-1) and bacterial endotoxin. Subsequently, the list of NF-κB inducers has grown to contain double-stranded (ds) RNA, viruses, and the Tax protein of HTLV-1. It was also recognized that upon cell stimulation with these inducers, NF-κB dimers translocate from the cytoplasm to the nucleus where they bind target genes and regulate their transcription. Subsequently, the nuclear translocation of NF-κB was found to parallel and depend on induced degradation of IκBs (reviewed in Refs. 2Baldwin A.S. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5649) Google Scholar and 7Verma I.M. Stevenson J.K. Schwarz E.M. Van Antwerp D. Miyamoto S. Genes Dev. 1995; 9: 2723-2735Crossref PubMed Scopus (1669) Google Scholar). Potent NF-κB activators can induce almost complete degradation of IκBs (especially IκBα) within minutes. This process, which is mediated by the 26 S proteasome (8Alkalay I. Yaron A. Hatzubai A. Jung S. Avraham A. Gerlitz O. Pashut-Lavon I. Ben-Neriah Y. Mol. Cell. Biol. 1995; 15: 1294-1301Crossref PubMed Google Scholar, 9DiDonato J.A. Mercurio F. Karin M. Mol.