Abstract
The NEDD8 protein and neddylation levels in cells are modulated by NUB1L or NUB1 through proteasomal degradation, but the underlying molecular mechanism is not well understood. Here, we report that NUB1L down-regulated the protein levels of NEDD8 and neddylation through specifically recognizing NEDD8 and P97/VCP. NUB1L directly interacted with NEDD8, but not with ubiquitin, on the key residue Asn-51 of NEDD8 and with P97/VCP on its positively charged VCP binding motif. In coordination with the P97-UFD1-NPL4 complex (P97(UFD1/NPL4)), NUB1L promotes transfer of NEDD8 to proteasome for degradation. This mechanism is also exemplified by the canonical neddylation of cullin 1 for SCF (SKP1-cullin1-F-box) ubiquitin E3 ligases that is exquisitely regulated by the turnover of NEDD8.
Keywords:
Cullin 1; NEDD8; NUB1L; Neddylation; P97/VCp Complex; Proteasome; Protein Degradation; Protein Motifs; Protein-Protein Interactions; Ubiquitination.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism*
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Amino Acid Motifs
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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NEDD8 Protein
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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Proteins / genetics
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Proteins / metabolism*
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Proteolysis*
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Ubiquitins / genetics
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Ubiquitins / metabolism*
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Valosin Containing Protein
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Cell Cycle Proteins
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Cullin 1
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Cullin Proteins
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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NEDD8 Protein
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NEDD8 protein, human
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NPLOC4 protein, human
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NUB1 protein, human
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Nuclear Proteins
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Proteins
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Transcription Factors
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UFD1 protein, human
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Ubiquitins
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SKP Cullin F-Box Protein Ligases
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Proteasome Endopeptidase Complex
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Adenosine Triphosphatases
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VCP protein, human
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Valosin Containing Protein