Signal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP
Abstract
Signal-induced phosphorylation of IκBα targets this inhibitor of NF-κB for ubiquitination and subsequent degradation, thus allowing NF-κB to enter the nucleus to turn on its target genes. We report here the identification of an IκB–ubiquitin (Ub) ligase complex containing the F-box/WD40-repeat protein, β-TrCP, a vertebrate homolog of Drosophila Slimb. β-TrCP binds to IκBα only when the latter is specifically phosphorylated by an IκB kinase complex. Moreover, immunopurified β-TrCP ubiquitinates phosphorylated IκBα at specific lysines in the presence of Ub-activating (E1) and -conjugating (Ubch5) enzymes. A β-TrCP mutant lacking the F-box inhibits the signal-induced degradation of IκBα and subsequent activation of NF-κB-dependent transcription. Furthermore, Drosophila embryos deficient in slimb fail to activate twist and snail, two genes known to be regulated by the NF-κB homolog, Dorsal. These biochemical and genetic data strongly suggest that Slimb/β-TrCP is the specificity determinant for the signal-induced ubiquitination of IκBα.
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Footnotes
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↵Corresponding author.
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E-MAIL jchen{at}hamon.swmed.edu; FAX (214) 648-1196.
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- Received December 7, 1998.
- Accepted December 18, 1998.
- Cold Spring Harbor Laboratory Press