NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Promotes Transfer of NEDD8 to Proteasome for Degradation through the P97UFD1/NPL4 Complex

• Published in: The Journal of biological chemistry 2013-10, Vol.288 (43), p.31339-31349
• Main Authors: Liu, Shuai, Yang, Hui, Zhao, Jian, Zhang, Yu-Hang, Song, Ai-Xin, Hu, Hong-Yu
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino Acid Motifs; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cullin 1; Cullin Proteins - genetics; Cullin Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; NEDD8; NEDD8 Protein; Neddylation; NUB1L; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; P97/VCp Complex; Proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein Degradation; Protein Motifs; Protein Synthesis and Degradation; Protein-Protein Interactions; Proteins - genetics; Proteins - metabolism; Proteolysis; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitination; Ubiquitins - genetics; Ubiquitins - metabolism; Valosin Containing Protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.484816

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 (P97UFD1/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. Background: The NEDD8 protein and neddylation levels in cells are modulated by NUB1L. Results: NUB1L down-regulated the NEDD8 levels by directly interacting with NEDD8 and P97. Conclusion: NUB1L joins to the P97UFD1/NPL4 complex and promotes transfer of NEDD8 to proteasome for degradation. Significance: This study provides a molecular mechanism for modulation of neddylation.