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Homo sapiens
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NEDD8 is a small ubiquitin-like molecule that is conjugated to substrate proteins through an E1 to E3 enzyme cascade similar to that for ubiquitin. The best characterized target of neddylation is the cullin scaffold subunit of cullin-RING E3 ubiquitin ligases (CRLs), which themselves target numerous cellular proteins for degradation by the proteasome (Hori et al, 1999; reviewed in Soucy et al, 2010; Lyedeard et al, 2013). The multisubunit CRL complexes are compositionally diverse, but each contains a scaffolding cullin protein (CUL1, 2, 3, 4A, 4B, 5, 7 or 9) and a RING box-containing E3 ligase subunit RBX, along with other adaptor and substrate-interacting subunits. RBX2 (also known as RNF7) interacts preferentially with CUL5, while RBX1 is the primary E3 for most other cullin family members (reviewed in Mahon et al, 2014). Neddylation of the cullin subunit increases the ubiquitination activity of the CRL complex (Podust et al, 2000; Read et al, 2000; Wu et al, 2000; Kawakami et al, 2001; Ohh et al, 2002; Yu et al, 2015). In addition to CRL complexes, a number of other less-well characterized NEDD8 targets have been identified. These include other E3 ubiquitin ligases such as SMURF1 and MDM2, receptor tyrosine kinases such as EGFR and TGF beta RII, and proteins that contribute to transcriptional regulation, among others (Xie et al, 2014; Watson et al, 2010; Oved et al, 2006; Zuo et al, 2013; Xirodimas et al, 2004; Singh et al, 2007; Abida et al, 2007; Liu et al 2010; Watson et al, 2006; Loftus et al, 2012; Aoki et al, 2013; reviewed in Enchev et al, 2015).
Like ubiquitin, NEDD8 undergoes post-translational processing to generate the mature form. UCHL3- or SENP8-mediated proteolysis removes the C-terminal 5 amino acids of NEDD8, generating a novel C-terminal glycine residue for conjugation to the cysteine residues in the E1, E2 enzymes or lysine residues in the substrate protein, usually the E3 NEDD8 ligase itself (Wada et al, 1998; reviewed in Enchev et al, 2015). Most substrates in vivo appear to be singly neddylated on one or more lysine residues, but NEDD8 chains have been formed on cullin substrates in vitro and on histone H4 in cultured human cells after DNA damage (Jones et al, 2008; Ohki et al, 2009; Xirodimas et al, 2008; Jeram et al, 2010; Ma et al, 2013; reviewed in Enchev et al, 2015). The significance of NEDD8 chains is still not clear.
NEDD8 has a single heterodimeric E1 enzyme, consisting of NAE1 (also known as APPBP1) and UBA3, and two E2 enzymes, UBE2M and UBE2F, which are N-terminally acetylated (Walden et al, 2003; Bohnsack et al, 2003; Huang et al, 2004; Huang et al, 2005; Huang et al, 2009; Scott et al, 2011a; Monda et al, 2013; reviewed in Enchev et al, 2015). All NEDD8 E3 enzymes reported to date also function as E3 ubiquitin ligases, and most belong to the RING domain class. The best characterized NEDD8 E3 enzymes are the CRL complexes described above. RBX1-containing complexes interact preferentially with UBE2M, while UBE2F is the E2 for RBX2-containing complexes (Huang et al, 2009; Monda et al, 2013).
Neddylation is regulated in vivo by interaction with DCUN1D proteins (also called DCNLs). The 5 human DCUN1D proteins interact both with cullins and with the NEDD8 E2 proteins and thereby increase the kinetic efficiency of neddylation (Kurz et al, 2005; Kurz et al, 2008; Scott et al, 2010; Scott et al, 2011a; Scott et al, 2014; Monda et al, 2013). Glomulin (GLMN) is another regulator of CRL function that binds to the neddylated cullin and competitively inhibits interaction with the ubiquitin E2 enzyme (Arai et al, 2003; Tron et al, 2012; Duda et al, 2012; reviewed in Mahon et al, 2014).
The multisubunit COP9 signalosome is the only cullin deneddylase, while SENP8 (also known as DEN1) contributes to deneddylation of other non-cullin NEDD8 targets (Cope et al, 2002; Emberley et al, 2012; Chan et al, 2008; Wu et al, 2003; reviewed in Wei et al, 2008; Enchev et al, 2015). In the deneddylated state, cullins bind to CAND1 (cullin associated NEDD8-dissociated protein1), which displaces the COP9 signalosome and promotes the exchange of the ubiquitin substrate-specific adaptor. This allows CRL complexes to be reconfigured to target other subtrates for ubiquitination (Liu et al, 2002; Schmidt et al, 2009; Pierce et al, 2013; reviewed in Mahon et al, 2014).

Literature References
PubMed ID Title Journal Year
15242646 Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity

Lane, DP, Saville, MK, Hay, RT, Xirodimas, DP, Bourdon, JC

Cell 2004
17301054 Hetero-oligomerization with MdmX rescues the ubiquitin/Nedd8 ligase activity of RING finger mutants of Mdm2

Iyappan, S, Singh, RK, Scheffner, M

J. Biol. Chem. 2007
18206966 Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation

Chou, YC, Willems, AR, Meyer-Schaller, N, Sicheri, F, Tyers, M, Peter, M, Hecht, ML, Kurz, T

Mol. Cell 2008
17098746 FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity

Gu, W, Abida, WM, Nikolaev, A, Zhang, W, Zhao, W

J. Biol. Chem. 2007
23290524 c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-? type II receptor

Chen, Y, Deng, H, Zuo, W, Zhang, T, Luo, S, Ding, Y, Gao, C, Feng, XH, Huang, F, Chen, YG, Du, J, Chiang, YJ, Jeong, LS, Lee, HW, Li, M

Mol. Cell 2013
12504025 NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases

Furukawa, M, Liu, J, Xiong, Y, Matsumoto, T

Mol. Cell 2002
18782863 DEN1 deneddylates non-cullin proteins in vivo

Pan, KT, Wu, JT, Chan, Y, Yim, J, Kim, HJ, Yoon, J, Chien, CT

J. Cell. Sci. 2008
21940857 N-terminal acetylation acts as an avidity enhancer within an interconnected multiprotein complex

Bennett, EJ, Schulman, BA, Harper, JW, Scott, DC, Monda, JK

Science 2011
16980297 Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function

Ohh, M, Watson, IR, Blanch, A, Irwin, MS, Lin, DC

J. Biol. Chem. 2006
19250909 E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification

Borg, LA, Huang, DT, Duda, DM, Hunt, HW, Murray, PJ, Schulman, BA, Roussel, MF, Neale, G, Ayrault, O, Taherbhoy, AM, Scott, DC

Mol. Cell 2009
25314029 Cullin E3 ligases and their rewiring by viral factors

Pick, E, Mahon, C, Krogan, NJ, Craik, CS

Biomolecules 2014
10597293 Covalent modification of all members of human cullin family proteins by NEDD8

Kato, S, Shimbara, N, Miyamoto, C, Osaka, F, Okabayashi, K, Chiba, T, Tanaka, K, Hori, T

Oncogene 1999
12740388 Conservation in the mechanism of Nedd8 activation by the human AppBp1-Uba3 heterodimer

Haas, AL, Bohnsack, RN

J. Biol. Chem. 2003
19748355 F-box-directed CRL complex assembly and regulation by the CSN and CAND1

Hofmann, K, Wee, S, Schmidt, MW, McQuary, PR, Wolf, DA

Mol. Cell 2009
25531226 Protein neddylation: beyond cullin-RING ligases

Schulman, BA, Enchev, RI, Peter, M

Nat. Rev. Mol. Cell Biol. 2015
26906416 Characterization of the mammalian family of DCN-type NEDD8 E3 ligases

Keuss, MJ, Mcarthur, R, Wood, NT, Knebel, A, Thomas, Y, Kurz, T

J. Cell. Sci. 2016
22767593 Deconjugation of Nedd8 from Cul1 is directly regulated by Skp1-F-box and substrate, and the COP9 signalosome inhibits deneddylated SCF by a noncatalytic mechanism

Emberley, ED, Mosadeghi, R, Deshaies, RJ

J. Biol. Chem. 2012
10921923 Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization

Wu, K, Pan, ZQ, Chen, A

J. Biol. Chem. 2000
16735510 Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases

Cesareni, G, Zwang, Y, Kochupurakkal, BS, Santonico, E, Yarden, Y, Katz, M, Marmor, MD, Oved, S, Lavi, S, Mosesson, Y, Shtiegman, K

J. Biol. Chem. 2006
11483504 NEDD8 recruits E2-ubiquitin to SCF E3 ligase

Shimbara, N, Hidaka, Y, Yamanaka, K, Iwai, K, Kawakami, T, Minato, N, Suzuki, H, Osaka, F, Omata, M, Chiba, T, Tanaka, K, Suzuki, T

EMBO J. 2001
23201271 Structural conservation of distinctive N-terminal acetylation-dependent interactions across a family of mammalian NEDD8 ligation enzymes

Bennett, EJ, Miller, DJ, Schulman, BA, Harper, JW, King, D, Lydeard, J, Scott, DC, Monda, JK

Structure 2013
19245792 The mechanism of poly-NEDD8 chain formation in vitro

Chiba, T, Konishi, N, Ohki, Y, Funatsu, N

Biochem. Biophys. Res. Commun. 2009
10713156 Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha

Podust, VN, Parent, LA, Palombella, VJ, Chau, V, Luo, RS, Read, MA, Coggins, MB, Gladysheva, TB, Brownell, JE, Pierce, JW, Hottelet, M

Mol. Cell. Biol. 2000
22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7

Tron, AE, Duda, DM, Kuwabara, H, Bahamon, BN, Schulman, BA, Signoretti, S, Fujiwara, Y, Arai, T, Olszewski, JL, DeCaprio, JA

Mol. Cell 2012
11818338 An intact NEDD8 pathway is required for Cullin-dependent ubiquitylation in mammalian cells

Kaelin, WG, Ohh, M, Read, MA, Chen, Y, Kim, WY, Moslehi, JJ, Chau, V

EMBO Rep. 2002
19784069 Chemotherapy induces NEDP1-mediated destabilization of MDM2

Li, BK, Watson, IR, Ohh, M, Roche, O, Irwin, MS, Blanch, A

Oncogene 2010
23453757 Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins

Hess, S, Zheng, N, Graham, RL, Clurman, BE, Sweredoski, MJ, Shan, SO, Rome, M, Pierce, NW, Larimore, EA, Deshaies, RJ, Liu, X, Lee, JE

Cell 2013
14690597 The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1

Miller, DW, Huang, DT, Howard, RJ, Schulman, BA, Holton, JM, Minor, DL, Walden, H, Podgorski, MS

Mol. Cell 2003
15694336 Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1

Huang, DT, Schulman, BA, Holton, JM, Paydar, A, Waddell, MB, Zhuang, M

Mol. Cell 2005
18247557 A targeted proteomic analysis of the ubiquitin-like modifier nedd8 and associated proteins

Guerrero, C, Yang, Y, Wu, K, Nillegoda, N, Jones, J, Pan, ZQ, Huang, L

J. Proteome Res. 2008
20832729 A dual E3 mechanism for Rub1 ligation to Cdc53

Duda, DM, Schulman, BA, Grace, CR, Scott, DC, Kriwacki, RW, Monda, JK, Kurz, T

Mol. Cell 2010
21779466 The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy

Brownell, JE, Dick, LR, Soucy, TA, Milhollen, MA, Smith, PG

Genes Cancer 2010
15361859 A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8

Miller, DW, Huang, DT, Cassell, R, Schulman, BA, Roussel, MF, Holton, JM, Mathew, R

Nat. Struct. Mol. Biol. 2004
20029837 An improved SUMmOn-based methodology for the identification of ubiquitin and ubiquitin-like protein conjugation sites identifies novel ubiquitin-like protein chain linkages

Srikumar, T, Zhang, XD, Raught, B, Anne Eisenhauer, H, Jeram, SM, Matunis, M, Rogers, R, Pedrioli, PG

Proteomics 2010
9790970 Cleavage of the C-terminus of NEDD8 by UCH-L3

Kamitani, T, Wada, H, Yeh, ET, Caskey, LS, Kito, K

Biochem. Biophys. Res. Commun. 1998
12759363 DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1

Yamoah, K, Wu, K, Gan-Erdene, T, Wei, N, Wilkinson, KD, Wang, R, Pan, ZQ, Tan, P, Lee, CG, Chen, A, Dolios, G

J. Biol. Chem. 2003
24821572 The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

Liu, P, Deng, H, Wang, J, Xing, G, Chai, N, Zhang, M, Chen, Y, Cao, Y, Wu, J, Lu, Y, Wang, S, Wang, HR, He, S, Zhao, F, Cui, Y, Lu, K, Xie, P, He, F, Li, Y, Zhang, L

Nat Commun 2014
22748924 Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface

Tron, AE, Duda, DM, Lambert, LJ, Mittag, T, Schulman, BA, Waddell, MB, Hammel, M, Olszewski, JL, DeCaprio, JA

Mol. Cell 2012
24949976 Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8

Schulman, BA, Lydeard, JR, Cho, SE, Sviderskiy, VO, Harper, JW, Scott, DC, Monda, JK

Cell 2014
10781063 A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination

Brownell, JE, Podust, VN, Lightcap, ES, Wang, C, Pierce, JW, Luo, RS, Coggins, MB, Chau, V, Gladysheva, TB

Proc. Natl. Acad. Sci. U.S.A. 2000
18926707 The COP9 signalosome: more than a protease

Wei, N, Serino, G, Deng, XW

Trends Biochem. Sci. 2008
12904573 Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis

Ali, SH, Skaar, JR, Arai, T, Kasper, JS, DeCaprio, JA, Takahashi, C

Proc. Natl. Acad. Sci. U.S.A. 2003
23394999 RNF111-dependent neddylation activates DNA damage-induced ubiquitination

Ma, T, Yang, CY, Yu, X, Zhang, F, Chen, Y, Wang, S

Mol. Cell 2013
24232186 Building and remodelling Cullin-RING E3 ubiquitin ligases

Schulman, BA, Lydeard, JR, Harper, JW

EMBO Rep. 2013
18274552 Ribosomal proteins are targets for the NEDD8 pathway

Shen, L, Hay, RT, Xirodimas, DP, Nakamura, A, Botting, C, Sundqvist, A

EMBO Rep. 2008
23001041 NEDDylation controls the target specificity of E2F1 and apoptosis induction

Higuchi, M, Gotoh, Y, Aoki, I

Oncogene 2013
12183637 Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1

Koonin, EV, Aravind, L, Suh, GS, Zipursky, SL, Cope, GA, Schwarz, SE, Deshaies, RJ

Science 2002
26632597 Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8

Zheng, N, Mao, H, Rychnovsky, SD, Novitsky, EJ, Huang, L, Yu, C, Tang, X

Nat Commun 2015
22836579 NEDDylation regulates E2F-1-dependent transcription

La Thangue, NB, Munro, S, Liu, G, Loftus, SJ, Carr, SM

EMBO Rep. 2012
20101219 NUB1 promotes cytoplasmic localization of p53 through cooperation of the NEDD8 and ubiquitin pathways

Xirodimas, DP, Liu, G

Oncogene 2010
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