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Gene Review

NEDD8  -  neural precursor cell expressed,...

Homo sapiens

Synonyms: NEDD-8, Nedd-8, Neddylin, Neural precursor cell expressed developmentally down-regulated protein 8, Ubiquitin-like protein Nedd8
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Disease relevance of NEDD8


Psychiatry related information on NEDD8


High impact information on NEDD8


Biological context of NEDD8

  • To examine the biological role of NEDD8 conjugation, this dominant-negative form of UBC12 was applied to a cell growth assay [9].
  • This reduction is not due to down-regulation of NEDD8 transcription, but due to post-transcriptional mechanism [10].
  • To identify proteins that are involved in the NEDD8-conjugation and de-conjugation pathway, the yeast two-hybrid system was used to screen a human heart cDNA library using NEDD8 as a bait [11].
  • The NEDD8/Rub1 class of ubiquitin-like proteins has been implicated in progression of the cell cycle from G1 into S phase [12].
  • Mutational studies revealed that at least three Leu residues in the conserved sequence are required for binding with NEDD8 [13].

Anatomical context of NEDD8

  • Here we report that all Hs-Cul family proteins, such as Cul-1, Cul-2, Cul-3, Cul-4B, and Cul-5, in addition to Cul-4A, were modified by covalent attachment of NEDD8 in rabbit reticulocyte lysates [14].
  • All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium [15].
  • However, the conjugation pattern of NEDD8 is entirely different from that of ubiquitin in all cell lines tested [16].
  • In adult tissues, NEDD8 expression was mostly restricted to the heart and skeletal muscle [16].
  • Immunocytochemical analysis showed that NEDD8 expression was highly enriched in the nucleus and was much weaker in the cytosol [16].

Associations of NEDD8 with chemical compounds

  • This mutant, with a single Cys-to-Ser substitution at the conserved Cys residue in the E2 family, could specifically inhibit NEDD8 conjugation [9].
  • Bacterially expressed NEDP1 is capable of processing NEDD8 in vitro to expose the diglycine motif required for conjugation and can deconjugate NEDD8 from modified substrates [17].
  • We now report the X-ray structures of the human Nedd8-specific protease, Den1, in a complex with the inhibitor Nedd8 aldehyde, thus revealing a model for the tetrahedral transition state intermediate generated during proteolysis [18].
  • A chimeric tetramer composed of three ubiquitins and one histidine-tagged NEDD8 binds to the 26 S proteasome with an affinity similar to that of tetraubiquitin [12].
  • Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase [19].

Physical interactions of NEDD8


Regulatory relationships of NEDD8

  • Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha [22].
  • The C-terminal domain of ISG15 was superimposed on the structure of Nedd8 (r.m.s.d. = 0.84 A) bound to its AppBp1-Uba3 activating enzyme to model ISG15 binding to UbE1L [23].

Other interactions of NEDD8

  • We report here that the highly conserved C-terminal sequence in CUL1 is dually required, both for nuclear localization and for modification by NEDD8 [24].
  • The coexpression of NUB1L enhanced the degradation rate of FAT10 8-fold, whereas NEDD8 degradation was only accelerated 2-fold [20].
  • Structure of a complex between Nedd8 and the Ulp/Senp protease family member Den1 [18].
  • APP-BP1, first identified as a protein that interacts with the carboxyl (C) terminus of the amyloid precursor protein (APP), is one-half of the bipartite activating enzyme for the ubiquitin-like protein NEDD8 [25].
  • We also show that ASPP2 activates nuclear factor-kappaB (NF-kappaB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-kappaB activity [25].

Analytical, diagnostic and therapeutic context of NEDD8


  1. The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERalpha-positive breast cancer cells. Fan, M., Bigsby, R.M., Nephew, K.P. Mol. Endocrinol. (2003) [Pubmed]
  2. NEDD8 protein is involved in ubiquitinated inclusion bodies. Dil Kuazi, A., Kito, K., Abe, Y., Shin, R.W., Kamitani, T., Ueda, N. J. Pathol. (2003) [Pubmed]
  3. Accumulation of NEDD8 in neuronal and glial inclusions of neurodegenerative disorders. Mori, F., Nishie, M., Piao, Y.S., Kito, K., Kamitani, T., Takahashi, H., Wakabayashi, K. Neuropathol. Appl. Neurobiol. (2005) [Pubmed]
  4. Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8. Walden, H., Podgorski, M.S., Schulman, B.A. Nature (2003) [Pubmed]
  5. A new NEDD8-ligating system for cullin-4A. Osaka, F., Kawasaki, H., Aida, N., Saeki, M., Chiba, T., Kawashima, S., Tanaka, K., Kato, S. Genes Dev. (1998) [Pubmed]
  6. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. Liu, J., Furukawa, M., Matsumoto, T., Xiong, Y. Mol. Cell (2002) [Pubmed]
  7. APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain. Chen, Y., Liu, W., McPhie, D.L., Hassinger, L., Neve, R.L. J. Cell Biol. (2003) [Pubmed]
  8. A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Podust, V.N., Brownell, J.E., Gladysheva, T.B., Luo, R.S., Wang, C., Coggins, M.B., Pierce, J.W., Lightcap, E.S., Chau, V. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  9. A dominant-negative UBC12 mutant sequesters NEDD8 and inhibits NEDD8 conjugation in vivo. Wada, H., Yeh, E.T., Kamitani, T. J. Biol. Chem. (2000) [Pubmed]
  10. NUB1, a NEDD8-interacting protein, is induced by interferon and down-regulates the NEDD8 expression. Kito, K., Yeh, E.T., Kamitani, T. J. Biol. Chem. (2001) [Pubmed]
  11. Cleavage of the C-terminus of NEDD8 by UCH-L3. Wada, H., Kito, K., Caskey, L.S., Yeh, E.T., Kamitani, T. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  12. Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes. Whitby, F.G., Xia, G., Pickart, C.M., Hill, C.P. J. Biol. Chem. (1998) [Pubmed]
  13. Regulation of the NEDD8 conjugation system by a splicing variant, NUB1L. Tanaka, T., Kawashima, H., Yeh, E.T., Kamitani, T. J. Biol. Chem. (2003) [Pubmed]
  14. Covalent modification of all members of human cullin family proteins by NEDD8. Hori, T., Osaka, F., Chiba, T., Miyamoto, C., Okabayashi, K., Shimbara, N., Kato, S., Tanaka, K. Oncogene (1999) [Pubmed]
  15. Hypoxia-inducible Factors in the First Trimester Human Lung. Groenman, F., Rutter, M., Caniggia, I., Tibboel, D., Post, M. J. Histochem. Cytochem. (2007) [Pubmed]
  16. Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. Kamitani, T., Kito, K., Nguyen, H.P., Yeh, E.T. J. Biol. Chem. (1997) [Pubmed]
  17. NEDP1, a highly conserved cysteine protease that deNEDDylates Cullins. Mendoza, H.M., Shen, L.N., Botting, C., Lewis, A., Chen, J., Ink, B., Hay, R.T. J. Biol. Chem. (2003) [Pubmed]
  18. Structure of a complex between Nedd8 and the Ulp/Senp protease family member Den1. Reverter, D., Wu, K., Erdene, T.G., Pan, Z.Q., Wilkinson, K.D., Lima, C.D. J. Mol. Biol. (2005) [Pubmed]
  19. Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase. Amir, R.E., Haecker, H., Karin, M., Ciechanover, A. Oncogene (2004) [Pubmed]
  20. NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation. Hipp, M.S., Raasi, S., Groettrup, M., Schmidtke, G. J. Biol. Chem. (2004) [Pubmed]
  21. Interaction of NUB1 with the proteasome subunit S5a. Tanji, K., Tanaka, T., Kamitani, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. Read, M.A., Brownell, J.E., Gladysheva, T.B., Hottelet, M., Parent, L.A., Coggins, M.B., Pierce, J.W., Podust, V.N., Luo, R.S., Chau, V., Palombella, V.J. Mol. Cell. Biol. (2000) [Pubmed]
  23. Crystal structure of the interferon-induced ubiquitin-like protein ISG15. Narasimhan, J., Wang, M., Fu, Z., Klein, J.M., Haas, A.L., Kim, J.J. J. Biol. Chem. (2005) [Pubmed]
  24. The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1. Furukawa, M., Zhang, Y., McCarville, J., Ohta, T., Xiong, Y. Mol. Cell. Biol. (2000) [Pubmed]
  25. ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis. Chen, Y., Liu, W., Naumovski, L., Neve, R.L. J. Neurochem. (2003) [Pubmed]
  26. Proteomic analysis of normal and malignant prostate tissue to identify novel proteins lost in cancer. Meehan, K.L., Holland, J.W., Dawkins, H.J. Prostate (2002) [Pubmed]
  27. Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor. Antenos, M., Casper, R.F., Brown, T.J. J. Biol. Chem. (2002) [Pubmed]
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