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 proteolytic processes required for activation of the transcription factor NF-kappa B. The p105 precursor of the p50 subunit of NF-kappa B is processed in vitro by an ATP-dependent process that requires proteasomes and ubiquitin conjugation. The C-terminal region of p105 is rapidly degraded, leaving the N-terminal p50 domain. p105 processing can be blocked in intact cells with inhibitors of the proteasome or in yeast with 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 functions not only in the complete degradation of polypeptides, but also in the regulated processing of precursors into active proteins.
Palombella
V J
VJ
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138.
Rando
O J
OJ
Goldberg
A L
AL
Maniatis
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D007976:Leupeptins / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D011480:Protease Inhibitors; D011498:Protein Precursors; D014452:Ubiquitins; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C063261:acetylleucyl-leucyl-norleucinal; D000072000:NF-KappaB Inhibitor alpha; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde