DEN1 Is a Dual Function Protease Capable of Processing the C Terminus of Nedd8 and Deconjugating Hyper-neddylated CUL1

Nedd8 activates ubiquitination by increasing the efficiency of polyubiquitin chain assembly through its covalent conjugation to cullin molecules. Here we report the isolation, cloning, and characterization of a novel human Nedd8-specific protease called DEN1. Human DEN1 is encoded by AAH31411.1, a p...

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Published in:The Journal of biological chemistry 2003-08, Vol.278 (31), p.28882-28891
Main Authors: Wu, Kenneth, Yamoah, Kosj, Dolios, Georgia, Gan-Erdene, Tudeviin, Tan, Peilin, Chen, Angus, Lee, Chee-gun, Wei, Ning, Wilkinson, Keith D., Wang, Rong, Pan, Zhen-Qiang
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Cell Cycle Proteins - metabolism
Cullin Proteins
Electrophoresis, Polyacrylamide Gel
Endopeptidases - chemistry
Endopeptidases - genetics
Endopeptidases - metabolism
HeLa Cells
Humans
Molecular Sequence Data
NEDD8 Protein
Recombinant Proteins - metabolism
Ubiquitin - metabolism
Ubiquitins - metabolism
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Summary:Nedd8 activates ubiquitination by increasing the efficiency of polyubiquitin chain assembly through its covalent conjugation to cullin molecules. Here we report the isolation, cloning, and characterization of a novel human Nedd8-specific protease called DEN1. Human DEN1 is encoded by AAH31411.1, a previously uncharacterized protein of 212 amino acids that shares homology with the Ulp1 cysteinyl SUMO deconjugating enzyme family. Recombinant human DEN1, purified from bacteria, selectively binds to Nedd8 and hydrolyzes C-terminal derivatives of Nedd8. Interestingly, DEN1 deconjugates cullin 1 (CUL1)-Nedd8 in a concentration-dependent manner. At a low concentration, DEN1 processes hyper-neddylated CUL1 to yield a mononeddylated form, which presumably contains the Lys-720CUL1-Nedd8 linkage. At elevated concentrations, DEN1 is able to complete the removal of Nedd8 from CUL1. These activities distinguish DEN1 from the COP9 signalosome, which is capable of efficiently cleaving the Lys-720CUL1-Nedd8 conjugate, but lacks Nedd8 C-terminal hydrolytic activity and poorly processes hyperneddylated CUL1. These results suggest a unique role for DEN1 in regulating the modification of cullins by Nedd8.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M302888200