Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Animals
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Cells, Cultured
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Cysteine Endopeptidases / drug effects
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Cysteine Endopeptidases / metabolism*
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DNA-Binding Proteins / metabolism
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Humans
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I-kappa B Proteins*
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Leupeptins / pharmacology
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Models, Biological
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Molecular Sequence Data
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Multienzyme Complexes / drug effects
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Multienzyme Complexes / metabolism*
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NF-KappaB Inhibitor alpha
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NF-kappa B / biosynthesis*
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit
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Protease Inhibitors / pharmacology
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Proteasome Endopeptidase Complex
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Protein Precursors / metabolism*
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Protein Processing, Post-Translational* / drug effects
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Ubiquitins / metabolism*
Substances
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DNA-Binding Proteins
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I-kappa B Proteins
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Leupeptins
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Multienzyme Complexes
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NF-kappa B
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NF-kappa B p50 Subunit
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NFKBIA protein, human
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Protease Inhibitors
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Protein Precursors
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Ubiquitins
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carbobenzoxy-leucyl-leucyl-norvalinal
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acetylleucyl-leucyl-norleucinal
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NF-KappaB Inhibitor alpha
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Adenosine Triphosphate
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde