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 1 to 100, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 3
Gene	Authority id	Mapping file id	Evidence codes
GeneADRM1	AuthorityHGNC:15759	Mapping file id11047 NCBI file	EvidenceTAS
GeneAMER1	AuthorityHGNC:26837	Mapping file id139285 NCBI file	EvidenceTAS
GeneANKRD9	AuthorityHGNC:20096	Mapping file id122416 NCBI file	EvidenceTAS
GeneASB1	AuthorityHGNC:16011	Mapping file id51665 NCBI file	EvidenceTAS
GeneASB10	AuthorityHGNC:17185	Mapping file id136371 NCBI file	EvidenceTAS
GeneASB11	AuthorityHGNC:17186	Mapping file id140456 NCBI file	EvidenceTAS
GeneASB12	AuthorityHGNC:19763	Mapping file id142689 NCBI file	EvidenceTAS
GeneASB13	AuthorityHGNC:19765	Mapping file id79754 NCBI file	EvidenceTAS
GeneASB14	AuthorityHGNC:19766	Mapping file id142686 NCBI file	EvidenceTAS
GeneASB15	AuthorityHGNC:19767	Mapping file id142685 NCBI file	EvidenceTAS
GeneASB16	AuthorityHGNC:19768	Mapping file id92591 NCBI file	EvidenceTAS
GeneASB17	AuthorityHGNC:19769	Mapping file id127247 NCBI file	EvidenceTAS
GeneASB18	AuthorityHGNC:19770	Mapping file id401036 NCBI file	EvidenceTAS
GeneASB2	AuthorityHGNC:16012	Mapping file id51676 NCBI file	EvidenceTAS
GeneASB3	AuthorityHGNC:16013	Mapping file id51130 NCBI file	EvidenceTAS
GeneASB4	AuthorityHGNC:16009	Mapping file id51666 NCBI file	EvidenceTAS
GeneASB5	AuthorityHGNC:17180	Mapping file id140458 NCBI file	EvidenceTAS
GeneASB6	AuthorityHGNC:17181	Mapping file id140459 NCBI file	EvidenceTAS
GeneASB7	AuthorityHGNC:17182	Mapping file id140460 NCBI file	EvidenceTAS
GeneASB8	AuthorityHGNC:17183	Mapping file id140461 NCBI file	EvidenceTAS
GeneASB9	AuthorityHGNC:17184	Mapping file id140462 NCBI file	EvidenceTAS
GeneBIRC5	AuthorityHGNC:593	Mapping file id332 NCBI file	EvidenceTAS
GeneBRCA1	AuthorityHGNC:1100	Mapping file id672 NCBI file	EvidenceTAS
GeneBTBD1	AuthorityHGNC:1120	Mapping file id53339 NCBI file	EvidenceTAS
GeneBTBD6	AuthorityHGNC:19897	Mapping file id90135 NCBI file	EvidenceTAS
GeneBTRC	AuthorityHGNC:1144	Mapping file id8945 NCBI file	EvidenceTAS
GeneCAND1	AuthorityHGNC:30688	Mapping file id55832 NCBI file	EvidenceTAS
GeneCCDC22	AuthorityHGNC:28909	Mapping file id28952 NCBI file	EvidenceTAS
GeneCCDC8	AuthorityHGNC:25367	Mapping file id83987 NCBI file	EvidenceTAS
GeneCCNF	AuthorityHGNC:1591	Mapping file id899 NCBI file	EvidenceTAS
GeneCDKN1A	AuthorityHGNC:1784	Mapping file id1026 NCBI file	EvidenceTAS
GeneCISH	AuthorityHGNC:1984	Mapping file id1154 NCBI file	EvidenceTAS
GeneCOMMD1	AuthorityHGNC:23024	Mapping file id150684 NCBI file	EvidenceTAS
GeneCOMMD10	AuthorityHGNC:30201	Mapping file id51397 NCBI file	EvidenceTAS
GeneCOMMD2	AuthorityHGNC:24993	Mapping file id51122 NCBI file	EvidenceTAS
GeneCOMMD3	AuthorityHGNC:23332	Mapping file id23412 NCBI file	EvidenceTAS
GeneCOMMD4	AuthorityHGNC:26027	Mapping file id54939 NCBI file	EvidenceTAS
GeneCOMMD5	AuthorityHGNC:17902	Mapping file id28991 NCBI file	EvidenceTAS
GeneCOMMD6	AuthorityHGNC:24015	Mapping file id170622 NCBI file	EvidenceTAS
GeneCOMMD7	AuthorityHGNC:16223	Mapping file id149951 NCBI file	EvidenceTAS
GeneCOMMD8	AuthorityHGNC:26036	Mapping file id54951 NCBI file	EvidenceTAS
GeneCOMMD9	AuthorityHGNC:25014	Mapping file id29099 NCBI file	EvidenceTAS
GeneCOP1	AuthorityHGNC:17440	Mapping file id64326 NCBI file	EvidenceTAS
GeneCOPS2	AuthorityHGNC:30747	Mapping file id9318 NCBI file	EvidenceTAS
GeneCOPS3	AuthorityHGNC:2239	Mapping file id8533 NCBI file	EvidenceTAS
GeneCOPS4	AuthorityHGNC:16702	Mapping file id51138 NCBI file	EvidenceTAS
GeneCOPS5	AuthorityHGNC:2240	Mapping file id10987 NCBI file	EvidenceTAS
GeneCOPS6	AuthorityHGNC:21749	Mapping file id10980 NCBI file	EvidenceTAS
GeneCOPS7A	AuthorityHGNC:16758	Mapping file id50813 NCBI file	EvidenceTAS
GeneCOPS7B	AuthorityHGNC:16760	Mapping file id64708 NCBI file	EvidenceTAS
GeneCOPS8	AuthorityHGNC:24335	Mapping file id10920 NCBI file	EvidenceTAS
GeneCUL1	AuthorityHGNC:2551	Mapping file id8454 NCBI file	EvidenceTAS
GeneCUL2	AuthorityHGNC:2552	Mapping file id8453 NCBI file	EvidenceTAS
GeneCUL3	AuthorityHGNC:2553	Mapping file id8452 NCBI file	EvidenceTAS
GeneCUL4A	AuthorityHGNC:2554	Mapping file id8451 NCBI file	EvidenceTAS
GeneCUL4B	AuthorityHGNC:2555	Mapping file id8450 NCBI file	EvidenceTAS
GeneCUL5	AuthorityHGNC:2556	Mapping file id8065 NCBI file	EvidenceTAS
GeneCUL7	AuthorityHGNC:21024	Mapping file id9820 NCBI file	EvidenceTAS
GeneCUL9	AuthorityHGNC:15982	Mapping file id23113 NCBI file	EvidenceTAS
GeneDCAF10	AuthorityHGNC:23686	Mapping file id79269 NCBI file	EvidenceTAS
GeneDCAF11	AuthorityHGNC:20258	Mapping file id80344 NCBI file	EvidenceTAS
GeneDCAF13	AuthorityHGNC:24535	Mapping file id25879 NCBI file	EvidenceTAS
GeneDCAF16	AuthorityHGNC:25987	Mapping file id54876 NCBI file	EvidenceTAS
GeneDCAF17	AuthorityHGNC:25784	Mapping file id80067 NCBI file	EvidenceTAS
GeneDCAF4	AuthorityHGNC:20229	Mapping file id26094 NCBI file	EvidenceTAS
GeneDCAF5	AuthorityHGNC:20224	Mapping file id8816 NCBI file	EvidenceTAS
GeneDCAF6	AuthorityHGNC:30002	Mapping file id55827 NCBI file	EvidenceTAS
GeneDCAF7	AuthorityHGNC:30915	Mapping file id10238 NCBI file	EvidenceTAS
GeneDCAF8	AuthorityHGNC:24891	Mapping file id50717 NCBI file	EvidenceTAS
GeneDCUN1D1	AuthorityHGNC:18184	Mapping file id54165 NCBI file	EvidenceTAS
GeneDCUN1D2	AuthorityHGNC:20328	Mapping file id55208 NCBI file	EvidenceTAS
GeneDCUN1D3	AuthorityHGNC:28734	Mapping file id123879 NCBI file	EvidenceTAS
GeneDCUN1D4	AuthorityHGNC:28998	Mapping file id23142 NCBI file	EvidenceTAS
GeneDCUN1D5	AuthorityHGNC:28409	Mapping file id84259 NCBI file	EvidenceTAS
GeneDDA1	AuthorityHGNC:28360	Mapping file id79016 NCBI file	EvidenceTAS
GeneDDB1	AuthorityHGNC:2717	Mapping file id1642 NCBI file	EvidenceTAS
GeneDDB2	AuthorityHGNC:2718	Mapping file id1643 NCBI file	EvidenceTAS
GeneDPP3	AuthorityHGNC:3008	Mapping file id10072 NCBI file	EvidenceTAS
GeneDTL	AuthorityHGNC:30288	Mapping file id51514 NCBI file	EvidenceTAS
GeneELOB	AuthorityHGNC:11619	Mapping file id6923 NCBI file	EvidenceTAS
GeneELOC	AuthorityHGNC:11617	Mapping file id6921 NCBI file	EvidenceTAS
GeneEPAS1	AuthorityHGNC:3374	Mapping file id2034 NCBI file	EvidenceTAS
GeneERCC8	AuthorityHGNC:3439	Mapping file id1161 NCBI file	EvidenceTAS
GeneFBXL12	AuthorityHGNC:13611	Mapping file id54850 NCBI file	EvidenceTAS
GeneFBXL13	AuthorityHGNC:21658	Mapping file id222235 NCBI file	EvidenceTAS
GeneFBXL14	AuthorityHGNC:28624	Mapping file id144699 NCBI file	EvidenceTAS
GeneFBXL15	AuthorityHGNC:28155	Mapping file id79176 NCBI file	EvidenceTAS
GeneFBXL16	AuthorityHGNC:14150	Mapping file id146330 NCBI file	EvidenceTAS
GeneFBXL18	AuthorityHGNC:21874	Mapping file id80028 NCBI file	EvidenceTAS
GeneFBXL19	AuthorityHGNC:25300	Mapping file id54620 NCBI file	EvidenceTAS
GeneFBXL20	AuthorityHGNC:24679	Mapping file id84961 NCBI file	EvidenceTAS
GeneFBXL22	AuthorityHGNC:27537	Mapping file id283807 NCBI file	EvidenceTAS
GeneFBXL3	AuthorityHGNC:13599	Mapping file id26224 NCBI file	EvidenceTAS
GeneFBXL4	AuthorityHGNC:13601	Mapping file id26235 NCBI file	EvidenceTAS
GeneFBXL5	AuthorityHGNC:13602	Mapping file id26234 NCBI file	EvidenceTAS
GeneFBXL7	AuthorityHGNC:13604	Mapping file id23194 NCBI file	EvidenceTAS
GeneFBXL8	AuthorityHGNC:17875	Mapping file id55336 NCBI file	EvidenceTAS
GeneFBXO10	AuthorityHGNC:13589	Mapping file id26267 NCBI file	EvidenceTAS
GeneFBXO11	AuthorityHGNC:13590	Mapping file id80204 NCBI file	EvidenceTAS
GeneFBXO15	AuthorityHGNC:13617	Mapping file id201456 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.