Inducible degradation of IκBα by the proteasome requires interaction with the F-box protein h-βTrCP

Activation of NF-κB transcription factors requires phosphorylation and ubiquitin-proteasome-dependent degradation of IκB proteins. We provide evidence that a human F-box protein, h-βTrCP, a component of Skp1-Cullin-F- box protein (SCF) complexes, a new class of E3 ubiquitin ligases, is essential for inducible degradation of IκBα. βTrCP associates with Ser32-Ser36 phosphorylated, but not with unmodified IκBα or Ser32- Ser36 phosphorylation-deficient mutants. Expression of a F-box-deleted βTrCP inhibits IκBα degradation, promotes accumulation of phosphorylated Ser32-Ser36 IκBα, and prevents NF-κB-dependent transcription. Our findings indicate that βTrCP is the adaptor protein required for IκBα recognition by the SCF(βTrCP) E3 complex that ubiquitinates IκBα and makes it a substrate for the proteasome.