THE UBIQUITIN-PROTEASOME PATHWAY IS REQUIRED FOR PROCESSING THE NF-KAPPA-B1 PRECURSOR PROTEIN AND THE ACTIVATION OF NF-KAPPA-B

We demonstrate an essential role for the proteasome complex in two pro teolytic processes required for activation of the transcription factor NF-kappa B. The p105 precursor of the p50 subunit of NF-kappa B is pr ocessed in vitro by an ATP-dependent process that requires proteasomes and ubiquitin conjugation. The C-terminal region of p105 is rapidly d egraded, leaving the N-terminal p50 domain. p105 processing can be blo cked in intact cells with inhibitors of the proteasome or in yeast wit h proteasome mutants. These inhibitors also block the activation of NF -kappa B and the rapid degradation of I kappa B alpha induced by tumor necrosis factor alpha. Thus, the ubiquitin-proteasome pathway functio ns not only in the complete degradation of polypeptides, but also in t he regulated processing of precursors into active proteins.