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

Activation of NF-kappa B transcription factors requires phosphorylation and ubiquitin-proteasome-dependent degradation of I kappa B proteins. We provide evidence that a human F-box protein, h-beta TrCP, a component of Skp1-Cullin-F-box protein (SCF) complexes, a new class of E3 ubiquitin ligases, is essential for inducible degradation of I kappa B alpha. beta TrCP associates with Ser(32)-Ser(36) phosphorylated, but not with unmodified I kappa B alpha or Ser(32)-Ser(36) phosphorylation-deficient mutants. Expression of a F-box-deleted beta TrCP inhibits I kappa B alpha degradation, promotes accumulation of phosphorylated Ser(32)-Ser(36) I kappa B alpha, and prevents NF-kappa B-dependent transcription. Our findings indicate that beta TrCP is the adaptor protein required for I kappa B alpha recognition by the SCFbeta TrCP E3 complex that ubiquitinates I kappa B alpha and makes it a substrate for the proteasome.