Reactome | Neddylation

Neddylation

Stable Identifier

R-HSA-8951664

DOI

10.3180/R-HSA-8951664.4

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

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