Regulation of NF-κB by ubiquitination and degradation of the IκBs

The nuclear factor-?B (NF-?B) signaling pathway is a busy ground for the action of the ubiquitinproteasome 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 (I?Bs) that bind NF-?B 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 I?B kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and I?B degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF beta-TrCP. The F-box component of this E3, beta-TrCP, recognizes the I?B degron formed following phosphorylation by IKK and thus couples I?B phosphorylation to ubiquitination. SCF beta-TrCP-mediated I?B ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor I?Ba within a few minutes of cell stimulation. In vivo ablation of beta-TrCP results in accumulation of all the I?Bs and complete NF-?B inhibition. As many details of I?B-beta-TrCP interaction have been worked out, the development of beta-TrCP inhibitors might be a feasible therapeutic approach for NF-?B-associated human disease. However, we may still need to advance our understanding of the mechanism of I?B degradation as well as of the diverse functions of beta-TrCP in vivo.