Pathway Human Homo sapiens

Neddylation

R-HSA-8951664 in Reactome release 97: under Post-translational protein modification, with 234 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-8951664 (mouse), R-RNO-8951664 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-8951664.7
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2017-03-27
Last updated: 2022-12-07
Events inside: 44, counted from the record

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 Reactome attaches

Covalent modification of all members of human cullin family proteins by NEDD8Oncogene, 1999, vol. 18, p. 6829-34PubMed 10597293
The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and TherapyGenes Cancer, 2010, vol. 1, p. 708-16PubMed 21779466
Building and remodelling Cullin-RING E3 ubiquitin ligasesEMBO Rep., 2013, vol. 14, p. 1050-61PubMed 24232186
Cullin E3 ligases and their rewiring by viral factorsBiomolecules, 2014, vol. 4, p. 897-930PubMed 25314029
A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitinationProc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, p. 4579-84PubMed 10781063
Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalphaMol. Cell. Biol., 2000, vol. 20, p. 2326-33PubMed 10713156
Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerizationJ. Biol. Chem., 2000, vol. 275, p. 32317-24

Reactome's record lists 14 orthologous events, R-RNO-8951664 (Rattus norvegicus), R-MMU-8951664 (Mus musculus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Neddylation". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-8951664 with StableID: R-HSA-8951664.7 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 234 genes in this human pathway; showing 101 to 200, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 2 of 3
Gene	Authority id	Mapping file id	Evidence codes
GeneFBXO17	AuthorityHGNC:18754	Mapping file id115290 NCBI file	EvidenceTAS
GeneFBXO2	AuthorityHGNC:13581	Mapping file id26232 NCBI file	EvidenceTAS
GeneFBXO21	AuthorityHGNC:13592	Mapping file id23014 NCBI file	EvidenceTAS
GeneFBXO22	AuthorityHGNC:13593	Mapping file id26263 NCBI file	EvidenceTAS
GeneFBXO27	AuthorityHGNC:18753	Mapping file id126433 NCBI file	EvidenceTAS
GeneFBXO30	AuthorityHGNC:15600	Mapping file id84085 NCBI file	EvidenceTAS
GeneFBXO31	AuthorityHGNC:16510	Mapping file id79791 NCBI file	EvidenceTAS
GeneFBXO32	AuthorityHGNC:16731	Mapping file id114907 NCBI file	EvidenceTAS
GeneFBXO4	AuthorityHGNC:13583	Mapping file id26272 NCBI file	EvidenceTAS
GeneFBXO40	AuthorityHGNC:29816	Mapping file id51725 NCBI file	EvidenceTAS
GeneFBXO41	AuthorityHGNC:29409	Mapping file id150726 NCBI file	EvidenceTAS
GeneFBXO44	AuthorityHGNC:24847	Mapping file id93611 NCBI file	EvidenceTAS
GeneFBXO6	AuthorityHGNC:13585	Mapping file id26270 NCBI file	EvidenceTAS
GeneFBXO7	AuthorityHGNC:13586	Mapping file id25793 NCBI file	EvidenceTAS
GeneFBXO9	AuthorityHGNC:13588	Mapping file id26268 NCBI file	EvidenceTAS
GeneFBXW10	AuthorityHGNC:1211	Mapping file id10517 NCBI file	EvidenceTAS
GeneFBXW11	AuthorityHGNC:13607	Mapping file id23291 NCBI file	EvidenceTAS
GeneFBXW12	AuthorityHGNC:20729	Mapping file id285231 NCBI file	EvidenceTAS
GeneFBXW2	AuthorityHGNC:13608	Mapping file id26190 NCBI file	EvidenceTAS
GeneFBXW4	AuthorityHGNC:10847	Mapping file id6468 NCBI file	EvidenceTAS
GeneFBXW5	AuthorityHGNC:13613	Mapping file id54461 NCBI file	EvidenceTAS
GeneFBXW7	AuthorityHGNC:16712	Mapping file id55294 NCBI file	EvidenceTAS
GeneFBXW8	AuthorityHGNC:13597	Mapping file id26259 NCBI file	EvidenceTAS
GeneFBXW9	AuthorityHGNC:28136	Mapping file id84261 NCBI file	EvidenceTAS
GeneFEM1A	AuthorityHGNC:16934	Mapping file id55527 NCBI file	EvidenceTAS
GeneFEM1B	AuthorityHGNC:3649	Mapping file id10116 NCBI file	EvidenceTAS
GeneFEM1C	AuthorityHGNC:16933	Mapping file id56929 NCBI file	EvidenceTAS
GeneGAN	AuthorityHGNC:4137	Mapping file id8139 NCBI file	EvidenceTAS
GeneGPR75-ASB3	AuthorityHGNC:40043	Mapping file id100302652 NCBI file	EvidenceTAS
GeneGPS1	AuthorityHGNC:4549	Mapping file id2873 NCBI file	EvidenceTAS
GeneHIF1A	AuthorityHGNC:4910	Mapping file id3091 NCBI file	EvidenceTAS
GeneHIF3A	AuthorityHGNC:15825	Mapping file id64344 NCBI file	EvidenceTAS
GeneKBTBD13	AuthorityHGNC:37227	Mapping file id390594 NCBI file	EvidenceTAS
GeneKBTBD6	AuthorityHGNC:25340	Mapping file id89890 NCBI file	EvidenceTAS
GeneKBTBD7	AuthorityHGNC:25266	Mapping file id84078 NCBI file	EvidenceTAS
GeneKBTBD8	AuthorityHGNC:30691	Mapping file id84541 NCBI file	EvidenceTAS
GeneKCTD6	AuthorityHGNC:22235	Mapping file id200845 NCBI file	EvidenceTAS
GeneKCTD7	AuthorityHGNC:21957	Mapping file id154881 NCBI file	EvidenceTAS
GeneKEAP1	AuthorityHGNC:23177	Mapping file id9817 NCBI file	EvidenceTAS
GeneKLHL11	AuthorityHGNC:19008	Mapping file id55175 NCBI file	EvidenceTAS
GeneKLHL13	AuthorityHGNC:22931	Mapping file id90293 NCBI file	EvidenceTAS
GeneKLHL2	AuthorityHGNC:6353	Mapping file id11275 NCBI file	EvidenceTAS
GeneKLHL20	AuthorityHGNC:25056	Mapping file id27252 NCBI file	EvidenceTAS
GeneKLHL21	AuthorityHGNC:29041	Mapping file id9903 NCBI file	EvidenceTAS
GeneKLHL22	AuthorityHGNC:25888	Mapping file id84861 NCBI file	EvidenceTAS
GeneKLHL25	AuthorityHGNC:25732	Mapping file id64410 NCBI file	EvidenceTAS
GeneKLHL3	AuthorityHGNC:6354	Mapping file id26249 NCBI file	EvidenceTAS
GeneKLHL41	AuthorityHGNC:16905	Mapping file id10324 NCBI file	EvidenceTAS
GeneKLHL42	AuthorityHGNC:29252	Mapping file id57542 NCBI file	EvidenceTAS
GeneKLHL5	AuthorityHGNC:6356	Mapping file id51088 NCBI file	EvidenceTAS
GeneKLHL9	AuthorityHGNC:18732	Mapping file id55958 NCBI file	EvidenceTAS
GeneLMO7	AuthorityHGNC:6646	Mapping file id4008 NCBI file	EvidenceTAS
GeneLRR1	AuthorityHGNC:19742	Mapping file id122769 NCBI file	EvidenceTAS
GeneLRRC41	AuthorityHGNC:16917	Mapping file id10489 NCBI file	EvidenceTAS
GeneMUL1	AuthorityHGNC:25762	Mapping file id79594 NCBI file	EvidenceTAS
GeneNAE1	AuthorityHGNC:621	Mapping file id8883 NCBI file	EvidenceTAS
GeneNEDD8	AuthorityHGNC:7732	Mapping file id4738 NCBI file	EvidenceTAS
GeneNEURL2	AuthorityHGNC:16156	Mapping file id140825 NCBI file	EvidenceTAS
GeneNFE2L2	AuthorityHGNC:7782	Mapping file id4780 NCBI file	EvidenceTAS
GeneNPLOC4	AuthorityHGNC:18261	Mapping file id55666 NCBI file	EvidenceTAS
GeneNUB1	AuthorityHGNC:17623	Mapping file id51667 NCBI file	EvidenceTAS
GeneOBSL1	AuthorityHGNC:29092	Mapping file id23363 NCBI file	EvidenceTAS
GenePALB2	AuthorityHGNC:26144	Mapping file id79728 NCBI file	EvidenceTAS
GenePSMA1	AuthorityHGNC:9530	Mapping file id5682 NCBI file	EvidenceTAS
GenePSMA2	AuthorityHGNC:9531	Mapping file id5683 NCBI file	EvidenceTAS
GenePSMA3	AuthorityHGNC:9532	Mapping file id5684 NCBI file	EvidenceTAS
GenePSMA4	AuthorityHGNC:9533	Mapping file id5685 NCBI file	EvidenceTAS
GenePSMA5	AuthorityHGNC:9534	Mapping file id5686 NCBI file	EvidenceTAS
GenePSMA6	AuthorityHGNC:9535	Mapping file id5687 NCBI file	EvidenceTAS
GenePSMA7	AuthorityHGNC:9536	Mapping file id5688 NCBI file	EvidenceTAS
GenePSMB1	AuthorityHGNC:9537	Mapping file id5689 NCBI file	EvidenceTAS
GenePSMB2	AuthorityHGNC:9539	Mapping file id5690 NCBI file	EvidenceTAS
GenePSMB3	AuthorityHGNC:9540	Mapping file id5691 NCBI file	EvidenceTAS
GenePSMB4	AuthorityHGNC:9541	Mapping file id5692 NCBI file	EvidenceTAS
GenePSMB5	AuthorityHGNC:9542	Mapping file id5693 NCBI file	EvidenceTAS
GenePSMB6	AuthorityHGNC:9543	Mapping file id5694 NCBI file	EvidenceTAS
GenePSMB7	AuthorityHGNC:9544	Mapping file id5695 NCBI file	EvidenceTAS
GenePSMC1	AuthorityHGNC:9547	Mapping file id5700 NCBI file	EvidenceTAS
GenePSMC2	AuthorityHGNC:9548	Mapping file id5701 NCBI file	EvidenceTAS
GenePSMC3	AuthorityHGNC:9549	Mapping file id5702 NCBI file	EvidenceTAS
GenePSMC4	AuthorityHGNC:9551	Mapping file id5704 NCBI file	EvidenceTAS
GenePSMC5	AuthorityHGNC:9552	Mapping file id5705 NCBI file	EvidenceTAS
GenePSMC6	AuthorityHGNC:9553	Mapping file id5706 NCBI file	EvidenceTAS
GenePSMD1	AuthorityHGNC:9554	Mapping file id5707 NCBI file	EvidenceTAS
GenePSMD11	AuthorityHGNC:9556	Mapping file id5717 NCBI file	EvidenceTAS
GenePSMD12	AuthorityHGNC:9557	Mapping file id5718 NCBI file	EvidenceTAS
GenePSMD13	AuthorityHGNC:9558	Mapping file id5719 NCBI file	EvidenceTAS
GenePSMD14	AuthorityHGNC:16889	Mapping file id10213 NCBI file	EvidenceTAS
GenePSMD2	AuthorityHGNC:9559	Mapping file id5708 NCBI file	EvidenceTAS
GenePSMD3	AuthorityHGNC:9560	Mapping file id5709 NCBI file	EvidenceTAS
GenePSMD6	AuthorityHGNC:9564	Mapping file id9861 NCBI file	EvidenceTAS
GenePSMD7	AuthorityHGNC:9565	Mapping file id5713 NCBI file	EvidenceTAS
GenePSMD8	AuthorityHGNC:9566	Mapping file id5714 NCBI file	EvidenceTAS
GenePUM2	AuthorityHGNC:14958	Mapping file id23369 NCBI file	EvidenceTAS
GeneRBBP5	AuthorityHGNC:9888	Mapping file id5929 NCBI file	EvidenceTAS
GeneRBBP7	AuthorityHGNC:9890	Mapping file id5931 NCBI file	EvidenceTAS
GeneRBX1	AuthorityHGNC:9928	Mapping file id9978 NCBI file	EvidenceTAS
GeneRNF7	AuthorityHGNC:10070	Mapping file id9616 NCBI file	EvidenceTAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSEM1	AuthorityHGNC:10845	Mapping file id7979 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Post-translational protein modificationR-HSA-5975921,507 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.