SIGNAL-INDUCED SITE-SPECIFIC PHOSPHORYLATION TARGETS I-KAPPA-B-ALPHA TO THE UBIQUITIN-PROTEASOME PATHWAY

The transcription factor NF-kappa B is sequestered in the cytoplasm by the inhibitor protein I kappa B alpha. Extracellular inducers of NF-k appa B activate signal transduction pathways that result in the phosph orylation and subsequent degradation of I kappa B alpha. At present, t he link between phosphorylation of I kappa B alpha and its degradation is not understood. In this report we provide evidence that phosphoryl ation of serine residues 32 and 36 of I kappa B alpha targets the prot ein to the ubiquitin-proteasome pathway. I kappa B alpha is ubiquitina ted in vivo and in vitro following phosphorylation, and mutations that abolish phosphorylation and degradation of I kappa B alpha in vivo pr event ubiquitination in vitro. Ubiquitinated I kappa B alpha remains a ssociated with NF-kappa B, and the bound I kappa B alpha is degraded b y the 26S proteasome. Thus, ubiquitination provides a mechanistic link between phosphorylation and degradation of I kappa B alpha.