title: Regulation of NF-κB by ubiquitination and degradation of the IκBs.
abstract: The nuclear factor-κB (NF-κB) signaling pathway is a busy ground for the action of the ubiquitin-proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF-κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF(β-TrCP) . The F-box component of this E3, β-TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF(β-TrCP) -mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β-TrCP results in accumulation of all the IκBs and complete NF-κB inhibition. As many details of IκB-β-TrCP interaction have been worked out, the development of β-TrCP inhibitors might be a feasible therapeutic approach for NF-κB-associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β-TrCP in vivo.
authors.affiliation: Lautenberg Centre for Immunology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Kanarek
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
mesh_terms: D000818:Animals; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases