Affinage

NEDD8

Ubiquitin-like protein NEDD8 · UniProt Q15843

Length
81 aa
Mass
9.1 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEDD8 is a ubiquitin-like protein that, through covalent conjugation to cullin scaffolds, serves as the master activating switch for cullin-RING ligases (CRLs) and thereby controls regulated protein degradation, cell cycle progression, and signaling (PMID:9353319, PMID:10713156, PMID:11696557). Its C-terminus is proteolytically processed to expose Gly-76, after which it is activated by the heterodimeric E1 APP-BP1/UBA3, transferred to the E2 UBC12 (UBE2M) or UBE2F, and ligated to conserved cullin lysines by RING E3s such as ROC1/RBX1 and by DCNL-family co-E3 ligases (PMID:9353319, PMID:9694792, PMID:10207026, PMID:19250909, PMID:26906416). A single residue (Ala-72) distinguishes NEDD8 from ubiquitin and enforces use of its dedicated E1, maintaining pathway specificity (PMID:9857030). Neddylation of cullins (e.g. Cul-1 at K720) is required for CRL-mediated ubiquitination and proteasomal turnover of substrates including IkBalpha, NF-kB precursor p105, p27Kip1, beta-catenin, and CDT1, coupling the pathway to cell cycle control, DNA replication licensing, and inflammatory signaling (PMID:10713156, PMID:10781063, PMID:11696557, PMID:11953428, PMID:21487042, PMID:21159650, PMID:28522566). Cryo-EM of trapped reaction intermediates shows NEDD8 acts as a structural nexus, undergoing local remodeling that, combined with large cullin domain movements, juxtaposes substrate with the RING-activated ubiquitin-charged E2 and allosterically recruits accessory E3s such as ARIH1/ARIH2 in a cullin-specific manner (PMID:32051583, PMID:34518685). Conjugation is reversed by the NEDD8-specific protease NEDP1/SENP8, whose structure reveals discrimination of NEDD8 from ubiquitin and which also processes pre-NEDD8 and limits poly-NEDD8 chain formation (PMID:15775960, PMID:28475037, PMID:31577950). Beyond cullins, NEDD8 modifies non-cullin substrates: Mdm2 neddylates p53 and TAp73 to inhibit their transcriptional activity and alter localization, c-Cbl neddylates EGFR to promote its lysosomal degradation, and the HECT ligase Smurf1 is activated by auto-neddylation (PMID:15242646, PMID:16980297, PMID:16735510, PMID:24821572). Unanchored trimeric NEDD8 directly binds and inhibits PARP-1, and S65-phosphorylated NEDD8 allosterically activates Parkin and stimulates HSP70, defining conjugation-independent signaling roles (PMID:30804002, PMID:34642328). Under stress and free-ubiquitin depletion, the ubiquitin E1 Ube1 drives atypical neddylation and formation of hybrid NEDD8-ubiquitin chains (PMID:22370482, PMID:33472076). The pathway is pharmacologically blockable by the NAE inhibitor MLN4924, which disrupts CRL function and induces DNA re-replication and apoptosis in cancer cells (PMID:19360080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1997 High

    Established that NEDD8 is a bona fide ubiquitin-like modifier requiring C-terminal processing to Gly-76 for covalent conjugation, defining it as a distinct conjugation system.

    Evidence Mutational analysis and immunocytochemistry of HA-tagged NEDD8 in COS cells

    PMID:9353319

    Open questions at the time
    • Did not identify the activating/conjugating enzymes
    • No physiological substrate identified
  2. 1998 High

    Defined the dedicated enzymatic cascade (APP-BP1/hUba3 E1, hUbc12 E2) and identified cullins as the principal substrate, anchoring NEDD8 to CRL biology.

    Evidence In vitro reconstitution with purified components; identification of Cul-4A as substrate

    PMID:9694792

    Open questions at the time
    • E3 ligase for cullin neddylation not yet defined
    • Functional consequence for CRL activity not shown
  3. 1998 High

    Crystal structure and Ala-72 mutagenesis explained how NEDD8 is structurally ubiquitin-like yet maintains E1 specificity, resolving how the two pathways stay separate.

    Evidence X-ray crystallography at 1.6 A plus in vitro E1 activation assays and Ala-72 mutant

    PMID:9857030

    Open questions at the time
    • Did not address E2/E3 specificity determinants
  4. 1998 Medium

    Identified UCH-L3 as a C-terminal hydrolase that processes/cleaves NEDD8, addressing how pro-NEDD8 is matured and deconjugated.

    Evidence Yeast two-hybrid, GST pull-down, in vitro cleavage assay

    PMID:9790970

    Open questions at the time
    • Single lab; in vivo relevance versus NEDP1 not delineated
    • Substrate selectivity not quantified
  5. 1999 High

    Demonstrated thioester intermediates for both UBA3 (E1) and UBC12 (E2), confirming the biochemical mechanism of NEDD8 activation and transfer.

    Evidence GST pulldown, thioester conjugate formation assays, co-precipitation

    PMID:10207026

    Open questions at the time
    • E3 ligation step not reconstituted here
  6. 2000 High

    Showed that cullin neddylation is functionally required for CRL substrate ubiquitination, linking NEDD8 directly to degradation of IkBalpha, p27Kip1, and other SCF substrates.

    Evidence In vivo co-IP, in vitro ubiquitination with dominant-negative Ubc12 and non-neddylatable Cul-1 K720R / SCF(Skp2) reconstitution

    PMID:10713156 PMID:10781063

    Open questions at the time
    • Structural basis of CRL activation by NEDD8 not yet known
    • Did not address non-cullin substrates
  7. 2000 Medium

    Characterized UBC12(C111S) as a dominant-negative that sequesters NEDD8, providing a tool to block the pathway and showing neddylation supports cell growth.

    Evidence Co-expression, denaturing SDS-PAGE, cell growth assays in U2OS/HEK293

    PMID:10828074

    Open questions at the time
    • Single lab; growth defect mechanism indirect
  8. 2001 High

    Genetic knockout of Uba3 in mice established the NEDD8 pathway as essential for cell cycle progression and embryonic viability via SCF-dependent substrate degradation.

    Evidence Uba3-/- knockout mice, cell cycle analysis, immunostaining for cyclin E, p57, beta-catenin

    PMID:11696557

    Open questions at the time
    • Phenotype attributable to multiple CRL substrates collectively
    • Non-cullin functions not separable in this model
  9. 2001 Medium

    Identified NUB1 as an adaptor that targets NEDD8 and its conjugates to the 26S proteasome, revealing a route for clearance of NEDD8-modified species.

    Evidence GST pull-down with S5a, co-IP, proteasome inhibitor treatment

    PMID:11585840

    Open questions at the time
    • Single lab; physiological substrate scope unclear
    • Interplay with deNEDDylation not addressed
  10. 2002 High

    Extended the NEDD8-CRL axis to additional substrates and processes — NF-kB precursor p105 processing and ERalpha degradation — broadening the regulatory reach of cullin neddylation.

    Evidence Cell-free/reconstituted ubiquitination assays with Cul-1 K720R; co-expression and proteasome inhibitor assays in MCF7

    PMID:11953428 PMID:12554766

    Open questions at the time
    • ERalpha study single lab and indirect
    • E3 adaptor specificity for each substrate not fully mapped
  11. 2002 High

    C. elegans genetics revealed an in vivo developmental role for NEDD8 in cytoskeletal regulation via cullin-dependent turnover of katanin.

    Evidence RNAi/loss-of-function in C. elegans embryos with live cytoskeletal imaging

    PMID:11847342

    Open questions at the time
    • Direct biochemical demonstration of katanin as CRL substrate not shown
    • Mammalian conservation not tested here
  12. 2003 Medium

    Identified ASPP2 as a negative regulator binding APP-BP1 to inhibit cullin neddylation, introducing a layer of pathway regulation upstream of conjugation.

    Evidence Endogenous co-IP, cullin-1 neddylation assay, proliferation/apoptosis assays

    PMID:12694406

    Open questions at the time
    • Single lab; structural basis of inhibition unknown
  13. 2003 Medium

    Established ROC1/RBX1 as the RING E3 for cullin neddylation and showed neddylation feeds back to trigger cullin autoubiquitination, coupling activation to turnover.

    Evidence In vitro neddylation with Cul1/Roc1, Roc1 RING mutant (H77A), pulse-chase degradation

    PMID:12565873

    Open questions at the time
    • Single lab
    • Distinction between E3 vs ubiquitin-ligase autoactivity roles not fully resolved
  14. 2004 High

    Demonstrated non-cullin neddylation of p53 by Mdm2 that represses p53 transcriptional activity, expanding NEDD8 function beyond CRL activation.

    Evidence Temperature-sensitive NEDD8 E2 cell line (TS-41), p53 3NKR non-neddylatable mutant, reporter assays

    PMID:15242646

    Open questions at the time
    • Structural site/mechanism of repression not defined
    • Stress-context regulation addressed only later
  15. 2005 High

    Structurally defined NEDP1 as the NEDD8-specific deconjugating protease, explaining substrate discrimination and providing the enzymatic basis for CRL recycling.

    Evidence X-ray transition-state complex with NEDD8, mutagenesis, deconjugation assays, in vivo NEDP1 mutant analysis

    PMID:15775960

    Open questions at the time
    • Regulation of NEDP1 activity in vivo not addressed
    • Full substrate repertoire unknown
  16. 2006 Medium

    Broadened non-cullin neddylation to TAp73 (Mdm2-dependent, NEDP1-reversible) and EGFR (c-Cbl-dependent), linking NEDD8 to transcription-factor localization and receptor trafficking.

    Evidence Co-expression with NEDP1, subcellular fractionation, reporter assays; co-IP, mutational analysis, lysosomal degradation assay

    PMID:16735510 PMID:16980297

    Open questions at the time
    • Single-lab studies
    • Quantitative stoichiometry of these modifications unclear
  17. 2009 High

    MLN4924 provided a selective NAE inhibitor establishing the NEDD8 pathway as a druggable anticancer target acting through CRL disruption and S-phase deregulation.

    Evidence Enzymatic inhibition assay, cell-based assays, mouse xenografts

    PMID:19360080

    Open questions at the time
    • Did not define which CRL substrates drive each phenotype
  18. 2009 High

    Identified UBE2F as a second NEDD8 E2 with RBX2 and resolved poly-NEDD8 chain assembly mechanics, establishing hierarchical E2-E3 specificity in the cascade.

    Evidence In vitro NEDD8 conjugation, crystallography, ROC1 mutant chain-transfer assays

    PMID:19245792 PMID:19250909

    Open questions at the time
    • Biological role of poly-NEDD8 chains on cullins not yet defined here
  19. 2010 High

    Revealed that bacterial deamidases (Cif/CHBP) target Gln40 of NEDD8 to inactivate neddylated CRLs, demonstrating pathogen subversion of the pathway and pinpointing a functional residue.

    Evidence In vitro deamidation, infection experiments, ubiquitination/MS assays; Y2H, co-IP, in vitro ubiquitylation

    PMID:20688984 PMID:20941356

    Open questions at the time
    • Host countermeasures not addressed
    • Structural basis resolved in later work
  20. 2011 High

    Established CDT1 stabilization as the principal driver of DNA re-replication caused by NAE inhibition, mechanistically tying NEDD8-CRL activity to replication licensing control.

    Evidence siRNA knockdown epistasis (CDT1 knockdown suppresses rereplication), cell cycle/synchrony experiments

    PMID:21159650 PMID:21487042

    Open questions at the time
    • Contribution of other CRL substrates to genotoxicity not fully quantified
  21. 2012 High

    Showed NEDD8 conjugation links CRL activity to the p97 extraction machinery via UBXD7, and that under stress the ubiquitin E1 Ube1 drives atypical neddylation and hybrid chains.

    Evidence Neddylation-selective co-IP and UIM mutant degradation assay; Ube1 siRNA, MS of NEDD8 proteome, free-ubiquitin depletion

    PMID:22370482 PMID:22466964

    Open questions at the time
    • Ube1 study single lab/Medium confidence
    • Functional consequences of hybrid chains not fully resolved
  22. 2012 High

    Structures of Cif/NEDD8 complexes detailed the molecular recognition driving Gln40 deamidation, and NAE inhibition was shown to suppress the Fanconi anemia DNA repair pathway.

    Evidence X-ray crystallography, mutagenesis, native PAGE; siRNA/MLN4924 with FANCD2 and CHK1 readouts

    PMID:22219386 PMID:22691497

    Open questions at the time
    • FA-pathway link single lab/Medium confidence
    • Direct CRL target controlling FANCD2 not identified
  23. 2014 High

    Demonstrated that the HECT ligase Smurf1 is activated by auto-neddylation, expanding NEDD8's role to direct enzymatic activation of a non-cullin ubiquitin ligase.

    Evidence Co-IP, thioester intermediate assay, C426A active-site mutant, ubiquitin E2 recruitment assay; conserved in yeast Rsp5

    PMID:24821572

    Open questions at the time
    • Physiological signals triggering Smurf1 neddylation not defined
  24. 2016 Medium

    Defined DCNL co-E3 ligases that require a substrate adaptor and dictate cullin neddylation by subcellular localization, refining spatial control of CRL activation.

    Evidence Complex purification, in vitro neddylation, subcellular localization

    PMID:26906416

    Open questions at the time
    • Single lab
    • In vivo contribution of each DCNL paralog not quantified
  25. 2017 High

    Showed SENP8/DEN1 deconjugates Ubc12 auto-neddylation to keep the conjugation machinery functional, and that neddylated Cul-5 activates TRAF6/NF-kB inflammatory signaling.

    Evidence Deconjugation-resistant NEDD8 mutant, SENP8-deficient cells, cell cycle analysis; Cul-5 KO mice, LPS challenge, neddylation-specific co-IP

    PMID:28475037 PMID:28522566

    Open questions at the time
    • Cul-5/TRAF6 study single lab/Medium confidence
    • Full set of NEDP1/SENP8 in vivo substrates incomplete
  26. 2019 High

    Uncovered conjugation-independent NEDD8 signaling: NEDP1-controlled NEDD8 chain status is sensed by HSP70 to drive APAF1-dependent apoptosis, and unanchored tri-NEDD8 directly inhibits PARP-1.

    Evidence In vitro ATPase and APAF1 oligomerization assays with NEDP1 KO; PARP-1 zinc-finger pull-down, NEDP1 deletion, H2O2 treatment, MS of acetylation, PARP-1 activity

    PMID:30804002 PMID:31577950

    Open questions at the time
    • APAF1 arm single lab/Medium confidence
    • Physiological abundance of unanchored chains under normal conditions unclear
  27. 2020 High

    Cryo-EM of a trapped CRL1(beta-TRCP) ubiquitylation intermediate provided the definitive mechanism by which NEDD8 activates ubiquitin transfer, acting as a structural nexus that juxtaposes substrate and E2 active site.

    Evidence Cryo-EM of chemically trapped ubiquitylation intermediate with phospho-IkBalpha

    PMID:32051583

    Open questions at the time
    • Generalization across all cullin scaffolds inferred rather than directly shown for each
  28. 2021 High

    Resolved cullin-specific allosteric regulation (CUL5-NEDD8 exposing cryptic ARIH2 sites vs CUL1-NEDD8 recruiting ARIH1) and defined the NEDDylated proteome, distinguishing canonical from atypical (Ube1-driven) targets and chain types.

    Evidence Cryo-EM/X-ray of E3-E3 assemblies with biochemical assays; NEDD8 R74K + anti-diGly MS proteomics

    PMID:33472076 PMID:34518685

    Open questions at the time
    • Functional significance of many newly identified non-cullin sites not validated
    • NEDD8-SUMO-2 chain biology largely undefined
  29. 2021 High

    Demonstrated S65 phosphorylation of NEDD8 generates a signaling molecule that allosterically activates Parkin and engages a distinct HSP70 interactome, defining a PTM-driven conjugation-independent role.

    Evidence NMR structural analysis, in vitro Parkin activation, MS interactome, HSP70 ATPase assays

    PMID:34642328

    Open questions at the time
    • Cellular kinase generating pNEDD8 and its physiological context not established
    • In vivo abundance of pNEDD8 unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the balance between canonical CRL-directed neddylation, atypical stress neddylation, and conjugation-independent NEDD8 signaling is integrated in vivo — and the functional roles of the hundreds of non-cullin sites and hybrid/branched chains — remains open.
  • Physiological triggers partitioning canonical vs atypical neddylation unresolved
  • Function of most mapped non-cullin NEDDylation sites unvalidated
  • In vivo regulation of unanchored and phospho-NEDD8 species unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0031386 protein tag activity 4
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CUL1MDM2NEDP1NUB1RBX1UBA3UBE2FUBE2M
Complex memberships
Cullin-RING ligase (CRL/SCF)NEDD8-activating E1 (APP-BP1/UBA3)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 NEDD8 is a ubiquitin-like protein that is covalently conjugated to other proteins; its C-terminus is cleaved to expose Gly-76, which is required for conjugation. NEDD8 is enriched in the nucleus relative to ubiquitin, and mutational analysis showed Gly-76 is essential for conjugation. Mutational analysis, immunocytochemistry, Western blot of HA-tagged NEDD8 in COS cells The Journal of biological chemistry High 9353319
1998 The NEDD8 conjugation pathway uses a dedicated E1-like heterodimeric complex (APP-BP1/hUba3) to activate NEDD8, followed by transfer to the E2 conjugating enzyme hUbc12, with the major identified substrate being cullin-4A (Cul-4A). In vitro biochemical reconstitution with purified components, identification of Cul-4A as neddylation substrate Genes & development High 9694792
1998 Crystal structure of human NEDD8 at 1.6-Å resolution shows close structural similarity to ubiquitin. A single conserved residue, Ala-72 (Arg in ubiquitin), prevents NEDD8 from being efficiently activated by the ubiquitin E1 enzyme, thereby maintaining pathway specificity. NEDD8 can be transferred from E1 to E2-25K, which adds it to polyubiquitin chains, and chimeric NEDD8-containing tetramers bind the 26S proteasome. X-ray crystallography (1.6 Å), in vitro activation assay with ubiquitin E1, mutational analysis of Ala-72 The Journal of biological chemistry High 9857030
1998 UCH-L3 (but not UCH-L1) cleaves the C-terminus of NEDD8 in vitro and binds NEDD8 directly, identifying UCH-L3 as a C-terminal hydrolase/processing enzyme for NEDD8. Yeast two-hybrid screen, GST pull-down, in vitro cleavage assay Biochemical and biophysical research communications Medium 9790970
1999 Human UBA3 forms the catalytic subunit of the NEDD8-activating E1 complex (with APP-BP1) and forms a beta-mercaptoethanol-sensitive (thioester) conjugate with NEDD8. Human UBC12 forms a thiol-ester linkage with NEDD8 in the presence of the activating enzyme, identifying both E1 and E2 components of the NEDD8 pathway. GST pulldown (UBA3 with NEDD8 vs. ubiquitin/sentrin-1), thioester conjugate formation assay, co-precipitation The Journal of biological chemistry High 10207026
2000 Nedd8 modification of Cul-1 is required for SCF(β-TrCP)-mediated ubiquitination of IκBα. The Nedd8-conjugated form of Cul-1 is selectively enriched in active SCF complexes in vivo, and a K720R Cul-1 mutant that cannot be neddylated shows markedly reduced IκBα ubiquitination activity. In vivo co-immunoprecipitation, in vitro ubiquitination assay with dominant-negative Ubc12, K720R Cul-1 mutant analysis Molecular and cellular biology High 10713156
2000 The Nedd8 conjugation pathway is required for SCF(Skp2)-mediated ubiquitination and subsequent proteasomal degradation of p27Kip1. A dominant-negative UBC12(C111S) mutant blocks p27 ubiquitination and degradation in cell extracts, and recombinant SCF(Skp2) requires Nedd8 pathway components for p27 ubiquitination activity. In vitro ubiquitination assay with cell extracts and recombinant SCF(Skp2), dominant-negative UBC12(C111S) Proceedings of the National Academy of Sciences of the United States of America High 10781063
2000 UBC12(C111S), a dominant-negative mutant of the NEDD8 E2 conjugating enzyme, sequesters NEDD8 by forming a stable non-reducible heterodimeric conjugate, thereby inhibiting NEDD8 transfer to substrates including cullin-1 and cullin-2. Overexpression of this mutant inhibits cell growth in U2OS and HEK293 cells. Co-expression, SDS-PAGE under denaturing conditions, cell growth assay The Journal of biological chemistry Medium 10828074
2001 NUB1 (NEDD8 Ultimate Buster-1), an interferon-inducible protein, interacts with NEDD8 and recruits NEDD8 and its conjugates to the 26S proteasome via binding to the S5a subunit (PA700), leading to proteasomal degradation of NEDD8 conjugates. Proteasome inhibitors block this NUB1-mediated down-regulation. GST pull-down with S5a, co-immunoprecipitation, proteasome inhibitor treatment The Journal of biological chemistry Medium 11585840
2001 The NEDD8 system is essential for cell cycle progression in both mitotic and endoreduplicative cycles in mice. Uba3 knockout mice die at peri-implantation, with inner cell mass apoptosis and failure of trophoblastic cells to enter S phase, accompanied by aberrant cyclin E and p57(Kip2) expression. β-catenin, a SCF substrate, accumulates in the cytoplasm and nucleus of Uba3−/− cells, confirming loss of SCF-mediated degradation. Gene knockout (Uba3−/−) in mice, cell cycle analysis, immunostaining for cyclin E, p57, β-catenin The Journal of cell biology High 11696557
2002 The NEDD8 pathway is required for proteasome-mediated degradation of estrogen receptor alpha (ERα). Uba3 co-expression increases ERα turnover via the 26S proteasome; inhibition of NEDD8 activation reduces ERα polyubiquitination and stabilizes the receptor. Loss of the NEDD8 pathway impairs ICI 182,780-induced ERα degradation and antiproliferative activity in MCF7 cells. Co-expression and proteasome inhibitor assays, dominant-negative NEDD8 pathway, cell proliferation assay Molecular endocrinology (Baltimore, Md.) Medium 12554766
2002 The NEDD8 pathway is required for SCF(β-TrCP)-mediated ubiquitination and processing of the NF-κB precursor p105. In cell-free and reconstituted systems, all three NEDD8 pathway components (E1, E2, NEDD8) stimulate p105 ubiquitination, and a non-neddylatable Cul-1 K720R mutant cannot support p105 ubiquitination/processing. Cell-free ubiquitination assay, reconstituted system, dominant-negative UBC12, Cul-1 K720R mutant The Journal of biological chemistry High 11953428
2002 The Nedd8 pathway in C. elegans regulates cytoskeletal organization: Nedd8 conjugation negatively regulates microfilament cortical contractility during pronuclear migration and cytokinesis, and is required to down-regulate katanin (a microtubule-severing complex) to permit assembly of the large mitotic spindle, likely via cullin-based E3 ligase-mediated degradation of katanin. Genetic analysis (RNAi and loss-of-function) in C. elegans embryos, live imaging of cytoskeletal dynamics Science (New York, N.Y.) High 11847342
2003 ASPP2 specifically interacts with APP-BP1 (the non-catalytic subunit of the NEDD8 E1 complex), inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1, and blocks APP-BP1-induced cell proliferation and neuronal apoptosis, identifying ASPP2 as a negative regulator of the neddylation pathway. Co-immunoprecipitation in non-transfected cells, neddylation assay of cullin-1, functional proliferation/apoptosis assays Journal of neurochemistry Medium 12694406
2003 Roc1 (a RING-finger protein in SCF) binds Ubc12 (NEDD8 E2) via its RING domain and functions as a NEDD8 E3 ligase toward Cul1 in vitro. A RING mutant (H77A) abolishes Ubc12 binding. Neddylation of Cul1 also triggers its own ubiquitination and proteasomal degradation; non-neddylatable Cul1-K720R is more stable than wild-type. In vitro neddylation assay with bacterially expressed Cul1/Roc1, Roc1 RING mutant, pulse-chase degradation assay Biochemical and biophysical research communications Medium 12565873
2004 Mdm2 acts as an E3 ligase for NEDD8 modification of p53, and Mdm2-dependent neddylation of p53 inhibits its transcriptional activity. Using a temperature-sensitive NEDD8 conjugation pathway cell line and a p53 mutant (3NKR) that cannot be neddylated, neddylation was shown to suppress p53-dependent transcription. Mdm2 itself is also modified with NEDD8. Temperature-sensitive cell line (TS-41) with mutant NEDD8 conjugation, 3NKR p53 mutant, transcriptional reporter assays, Western blot Cell High 15242646
2005 Crystal structure of NEDP1 (the NEDD8-specific deconjugating cysteine protease of the Ulp family) in isolation and in a transition-state complex with NEDD8 at atomic resolution. NEDD8 binding induces a dramatic conformational change in a flexible loop that locks the NEDD8 C-terminus in an extended β-structure for catalysis. A single residue difference between NEDD8 and ubiquitin C-termini underlies NEDP1's ability to discriminate between them. NEDP1 processes pre-NEDD8 and deconjugates NEDD8 from substrates including p53 and cullins. X-ray crystallography (transition-state complex), site-directed mutagenesis, biochemical deconjugation assay, in vivo analysis of NEDP1 mutants The EMBO journal High 15775960
2006 Mdm2 promotes NEDD8 modification of TAp73 (but not ΔNp73) in an Mdm2-dependent manner. The deNEDDylating enzyme NEDP1 reverses this modification. Neddylated TAp73 is preferentially localized to the cytoplasm, and blocking the NEDD8 pathway increases TAp73 transactivation activity. Co-expression with NEDP1, subcellular fractionation, transcriptional reporter assay The Journal of biological chemistry Medium 16980297
2006 The ubiquitin ligase c-Cbl mediates NEDD8 modification of the EGF receptor (EGFR). EGF stimulates receptor neddylation at multiple lysines in the kinase domain, which enhances subsequent ubiquitylation and lysosomal sorting/degradation of EGFR. Clathrin coat-associated ubiquitin-binding proteins also bind Nedd8. Co-immunoprecipitation, mutational analysis, lysosomal degradation assay The Journal of biological chemistry Medium 16735510
2009 MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme (NAE) that acts as an adenosine sulfamate analog, disrupts cullin-RING ligase-mediated protein turnover, and induces apoptosis in cancer cells via deregulation of S-phase DNA synthesis. Enzymatic inhibition assay, cell-based assays, mouse xenograft models Nature High 19360080
2009 UBE2F is a second NEDD8-conjugating E2 enzyme, distinct from UBE2M (UBC12). Structural and biochemical analyses show that UBE2M/RBX1 and UBE2F/RBX2 have distinct cullin substrate specificities, establishing hierarchical E2-E3 (RING) specificity in the NEDD8 conjugation cascade. In vitro NEDD8 conjugation assay, structural analysis (crystallography), biochemical specificity assays Molecular cell High 19250909
2009 Poly-NEDD8 chain formation on Cullin-1 occurs via buildup on the catalytic Cys of Ubc12, and ROC1 is essential for transfer of the poly-NEDD8 chain from Ubc12 to Cul-1 (but not for chain formation itself). A ROC1 ubiquitin ligase-inactive mutant enhances poly-NEDD8 chain formation. In vitro reconstituted NEDD8 conjugation system with purified components, ROC1 mutant analysis Biochemical and biophysical research communications Medium 19245792
2010 The bacterial effector CHBP (and the related Cif from EPEC) functions as a deamidase that specifically deamidates Gln40 in both ubiquitin and NEDD8 in vitro and during infection. Deamidation of NEDD8 at Gln40 abolishes the activity of neddylated cullin-RING ligases (CRLs), blocking ubiquitination and degradation of multiple CRL substrates. In vitro deamidation assay, infection experiments, ubiquitination assays, mass spectrometry Science (New York, N.Y.) High 20688984
2010 The bacterial effector Cif targets NEDD8-conjugated cullins, co-localizing with NEDD8 in the host nucleus and inducing accumulation of neddylated cullins. Cif directly inhibits neddylated CUL1-associated ubiquitin ligase activity in an in vitro ubiquitylation assay, modulating turnover of multiple CRL substrates (including p21 and p27). Yeast two-hybrid, co-immunoprecipitation, in vitro ubiquitylation assay, cell infection PLoS pathogens High 20941356
2011 Inhibition of NAE by siRNA or MLN4924 leads to CDT1 accumulation, which is the primary mediator of the DNA rereplication phenotype observed upon NAE inhibition. siRNA knockdown of cullins responsible for CDT1 turnover recapitulates rereplication, while CDT1 knockdown suppresses it. siRNA knockdown, cell cycle analysis, synchrony experiments Cancer research High 21159650 21487042
2012 The ubiquitin E1 enzyme Ube1 (not the canonical NEDD8 E1) mediates NEDD8 conjugation under stress conditions (proteasome inhibition, heat shock, oxidative stress). This is triggered by depletion of free ubiquitin. Under stress, NEDDylated proteins are simultaneously ubiquitinated and mixed NEDD8-ubiquitin chains form. NEDD8 modification of p53 upon stress is mainly mediated through Ube1. Ube1 siRNA knockdown, mass spectrometry of NEDD8 proteome, immunoprecipitation, free ubiquitin depletion experiments Cell cycle (Georgetown, Tex.) Medium 22370482
2012 The p97 cofactor UBXD7 (and its yeast ortholog Ubx5) selectively associates with the active, NEDD8-modified form of cullins through its ubiquitin-interacting motif (UIM), linking neddylated CRL activity to the p97 pathway for substrate extraction/degradation. Disruption of the UIM abolishes CRL binding and impedes degradation of a Cul3 substrate. Co-immunoprecipitation (selective for neddylated cullin), UIM mutation, yeast substrate degradation assay Nature structural & molecular biology High 22466964
2012 Crystal structures of two Cif/NEDD8 complexes reveal the conserved molecular interface for enzyme-substrate recognition at Gln40 of NEDD8. Shape complementarity rather than specific individual contacts drives recognition. The 'occluding loop' in Cif forces a conformational change in the NEDD8 C-terminus to position Gln40 in the active site. X-ray crystallography of Cif/NEDD8 complexes, mutagenesis, native PAGE activity assay Proceedings of the National Academy of Sciences of the United States of America High 22691497
2012 NAE inhibition by MLN4924 increases cellular sensitivity to DNA interstrand cross-linking agents by suppressing FANCD2 monoubiquitination and CHK1 phosphorylation, thereby inhibiting the Fanconi anemia DNA repair pathway. siRNA knockdown of NEDD8 conjugating enzymes, MLN4924 treatment, immunoblot for FANCD2 monoubiquitination and CHK1 phosphorylation Molecular cancer research : MCR Medium 22219386
2014 The HECT E3 ubiquitin ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and catalyzes its own neddylation on multiple lysines via its active site Cys426. Neddylation of Smurf1 enhances ubiquitin E2 recruitment and augments Smurf1 ubiquitin ligase activity. This activation mechanism is conserved in yeast Rsp5. Co-immunoprecipitation, thioester intermediate assay, active-site mutant (C426A), neddylation assay, ubiquitin E2 recruitment assay Nature communications High 24821572
2016 DCN-like (DCNL) proteins form stable stoichiometric complexes with CAND1 and cullins and function as NEDD8 E3 ligases that can only neddylate cullins in the presence of a substrate adaptor. Different DCNL proteins have distinct subcellular localizations, determining which subpopulation of a given cullin they neddylate. Biochemical complex purification, in vitro neddylation assay, subcellular localization experiments Journal of cell science Medium 26906416
2017 SENP8/DEN1 deconjugates auto-neddylation of Ubc12 (the NEDD8 E2 conjugating enzyme). Loss of SENP8 leads to aberrant neddylation of Ubc12 and other NEDD8 conjugation pathway components, resulting in accumulation of CRL substrates and defective cell cycle progression. Deconjugation-resistant NEDD8 mutant, SENP8-deficient cells, identification of Ubc12 auto-neddylation, cell cycle analysis eLife High 28475037
2017 Nedd8 modification of Cullin-5 following LPS exposure induces Cul-5 interaction with TRAF6, promoting TRAF6 polyubiquitination and NF-κB activation. Cul-5-deficient mice show reduced lung injury in response to LPS, linking NEDD8-dependent CRL activation to TLR4-TRAF6 inflammatory signaling. Cul-5 knockout mice, LPS challenge model, co-immunoprecipitation (neddylated Cul-5 with TRAF6), cytokine measurement American journal of physiology. Lung cellular and molecular physiology Medium 28522566
2019 Upon DNA damage, the deneddylating enzyme NEDP1 is induced and restricts formation of NEDD8 chains (mainly K11/K48-linked). The resulting balance shift from poly- to mono-NEDDylation is sensed by HSP70, which binds NEDD8. In vitro, conversion of NEDD8 chains to mono-NEDD8 stimulates HSP70 ATPase activity, promoting APAF1 oligomerization and apoptosis induction. In vitro ATPase assay with NEDD8 chain vs. monomer, NEDP1 knockout/knockdown, APAF1 oligomerization assay Cell reports Medium 31577950
2019 Unanchored trimeric NEDD8 (tri-NEDD8), which accumulates upon oxidative stress (H2O2) due to NEDP1 inhibition, specifically binds the second zinc finger domain of PARP-1 and attenuates PARP-1 activation. In NEDP1-deleted cells, constitutive tri-NEDD8 inhibits PARP-1 and protects from PARP-1-dependent cell death. The NEDD8 trimers are additionally acetylated, and de-acetylase overexpression reduces tri-NEDD8 binding to PARP-1. Pull-down with PARP-1 zinc finger domain, NEDP1 deletion, H2O2 treatment, mass spectrometry for acetylation, PARP-1 activity assay The EMBO journal High 30804002
2020 Cryo-EM structure of the ubiquitylation intermediate reveals how neddylated CRL1β-TRCP catalyzes ubiquitin transfer from UBE2D to phosphorylated IκBα. NEDD8 acts as a nexus, binding disparate cullin elements and RING-activated ubiquitin-linked UBE2D. Local NEDD8 structural remodeling combined with large-scale CRL domain movements juxtapose substrate and active site, explaining how NEDD8 activates CRL ubiquitylation activity. Cryo-electron microscopy structure of chemically trapped ubiquitylation intermediate Nature High 32051583
2021 NEDD8 can be phosphorylated at S65 (the same site as ubiquitin). S65 phosphorylation alters NEDD8's structural dynamics similarly to pUb. Both pNEDD8 and pUb can allosterically activate Parkin, but pNEDD8 has a distinct protein interactome including HSP70 family members. pNEDD8 stimulates HSP70 ATPase activity more strongly than unmodified NEDD8, independent of conjugation to other proteins. NMR structural analysis, in vitro Parkin activation assay, mass spectrometry interactome, HSP70 ATPase assay Nature communications High 34642328
2021 CUL5-linked NEDD8 activates ARIH2 via an allosteric mechanism distinct from CUL1-linked NEDD8. While CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2 directly; instead, it contacts CUL5 and induces conformational rearrangements that expose cryptic ARIH2-binding sites. This reveals cullin-specific allosteric regulation by NEDD8. Cryo-EM/X-ray structures of E3-E3 assemblies, biochemical binding and ubiquitylation assays Nature chemical biology High 34518685
2021 Proteome-wide identification of 1,101 unique NEDDylation sites on 620 proteins using NEDD8 R74K mutant combined with anti-diGly antibodies reveals distinct proteomes for canonical (NEDD8-specific enzymes; targets include spliceosome/mRNA surveillance/DNA replication components) versus atypical (ubiquitin enzymes; targets include ribosome/proteasome) NEDDylation. Poly-NEDD8, hybrid NEDD8-ubiquitin, and NEDD8-SUMO-2 chains were identified; NEDD8-SUMO-2 chains are induced by proteotoxic stress via K11 NEDDylation of SUMO-2. NEDD8 R74K mutant, anti-diGly antibody enrichment, mass spectrometry, bioinformatics Cell reports High 33472076

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 1711 19360080
2004 Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 459 15242646
1997 Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. The Journal of biological chemistry 455 9353319
2004 Nedd8 on cullin: building an expressway to protein destruction. Oncogene 366 15021886
2000 Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. Molecular and cellular biology 327 10713156
2010 MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood 295 20525923
2010 NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer research 251 21159650
2009 E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Molecular cell 241 19250909
1999 Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. The Journal of biological chemistry 238 10207026
2010 Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 234 20203261
2000 A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 226 10781063
2020 NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 220 32051583
1998 A new NEDD8-ligating system for cullin-4A. Genes & development 220 9694792
2012 The Nedd8-activating enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver cancer cell growth. Cancer research 218 22562464
2001 The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice. The Journal of cell biology 190 11696557
2010 The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy. Genes & cancer 188 21779466
1998 Crystal structure of the human ubiquitin-like protein NEDD8 and interactions with ubiquitin pathway enzymes. The Journal of biological chemistry 187 9857030
2014 The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis. Nature communications 186 24821572
2018 Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood 173 29348128
2010 Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science (New York, N.Y.) 172 20688984
2002 Cytoskeletal regulation by the Nedd8 ubiquitin-like protein modification pathway. Science (New York, N.Y.) 169 11847342
2012 MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy. Expert opinion on investigational drugs 166 22799561
2008 Novel substrates and functions for the ubiquitin-like molecule NEDD8. Biochemical Society transactions 165 18793140
2011 NEDD8 pathways in cancer, Sine Quibus Non. Cancer cell 163 21316600
2006 Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases. The Journal of biological chemistry 140 16735510
2011 Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer research 139 21487042
1998 Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochemical and biophysical research communications 137 9790970
2001 Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1. The Journal of biological chemistry 125 11585840
2014 The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clinical cancer research : an official journal of the American Association for Cancer Research 116 24634471
2020 NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Current opinion in structural biology 115 33160249
2002 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. Molecular endocrinology (Baltimore, Md.) 111 12554766
2006 Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. The Journal of biological chemistry 100 16980297
2005 Accumulation of NEDD8 in neuronal and glial inclusions of neurodegenerative disorders. Neuropathology and applied neurobiology 99 15634231
2005 Structural basis of NEDD8 ubiquitin discrimination by the deNEDDylating enzyme NEDP1. The EMBO journal 98 15775960
2012 The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions. Cell cycle (Georgetown, Tex.) 97 22370482
2001 NUB1, a NEDD8-interacting protein, is induced by interferon and down-regulates the NEDD8 expression. The Journal of biological chemistry 94 11259415
2012 Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. Cancer research 89 23100467
2004 NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation. The Journal of biological chemistry 86 14757770
2003 Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability. Biochemical and biophysical research communications 82 12565873
2010 Control of cullin-ring ubiquitin ligase activity by nedd8. Sub-cellular biochemistry 79 21222272
2012 A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. Cell reports 74 22832224
2018 NEDD8-its role in the regulation of Cullin-RING ligases. Current opinion in plant biology 72 29909289
2010 Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS pathogens 70 20941356
2004 Regulation of cullin-based ubiquitin ligases by the Nedd8/RUB ubiquitin-like proteins. Seminars in cell & developmental biology 70 15209382
2004 Cullin-based ubiquitin ligase and its control by NEDD8-conjugating system. Current protein & peptide science 68 15180522
2003 NEDD8 protein is involved in ubiquitinated inclusion bodies. The Journal of pathology 68 12533840
2012 NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway. Nature structural & molecular biology 67 22466964
2002 The NEDD8 pathway is essential for SCF(beta -TrCP)-mediated ubiquitination and processing of the NF-kappa B precursor p105. The Journal of biological chemistry 67 11953428
2000 A dominant-negative UBC12 mutant sequesters NEDD8 and inhibits NEDD8 conjugation in vivo. The Journal of biological chemistry 67 10828074
2022 The NEDD8-activating enzyme inhibitor MLN4924 reduces ischemic brain injury in mice. Proceedings of the National Academy of Sciences of the United States of America 66 35101976
2018 Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors. Investigational new drugs 64 29781056
2014 Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic. Endocrine-related cancer 61 25504797
2012 Inhibition of the Nedd8 system sensitizes cells to DNA interstrand cross-linking agents. Molecular cancer research : MCR 59 22219386
2011 Quantitative proteomic analysis of cellular protein modulation upon inhibition of the NEDD8-activating enzyme by MLN4924. Molecular & cellular proteomics : MCP 59 21873567
2021 CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Nature chemical biology 58 34518685
2019 Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer. EBioMedicine 57 31208947
2017 Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target. Cell death & disease 57 28569775
2019 TAS4464, A Highly Potent and Selective Inhibitor of NEDD8-Activating Enzyme, Suppresses Neddylation and Shows Antitumor Activity in Diverse Cancer Models. Molecular cancer therapeutics 56 31092565
2021 Proteome-wide identification of NEDD8 modification sites reveals distinct proteomes for canonical and atypical NEDDylation. Cell reports 55 33472076
2009 Characterization and structural studies of the Plasmodium falciparum ubiquitin and Nedd8 hydrolase UCHL3. The Journal of biological chemistry 53 20042598
2007 Control of cell proliferation via elevated NEDD8 conjugation in oral squamous cell carcinoma. Molecular and cellular biochemistry 53 17660949
2023 Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions. Journal of hematology & oncology 51 37525282
2014 The NEDD8 modification pathway in plants. Frontiers in plant science 50 24711811
2012 Inhibition of NEDD8-conjugation pathway by novel molecules: potential approaches to anticancer therapy. Molecular oncology 50 22306028
2017 Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing. European journal of medicinal chemistry 49 29232579
2002 The activating enzyme of NEDD8 inhibits steroid receptor function. Molecular endocrinology (Baltimore, Md.) 49 11818503
2015 Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells. Cancer biology & therapy 48 25782162
2012 Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma. Molecular cancer therapeutics 48 22246439
2018 Ubiquitin, SUMO, and NEDD8: Key Targets of Bacterial Pathogens. Trends in cell biology 47 30107971
2014 Nedd8-activating enzyme inhibitor MLN4924 provides synergy with mitomycin C through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics pathways. Molecular cancer therapeutics 45 24672057
2014 The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and augments the efficacy of cytarabine. Clinical cancer research : an official journal of the American Association for Cancer Research 44 25388161
2019 The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity. Cell reports 42 31577950
2016 Characterization of the mammalian family of DCN-type NEDD8 E3 ligases. Journal of cell science 41 26906416
2015 NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 40 26156395
2017 SENP8 limits aberrant neddylation of NEDD8 pathway components to promote cullin-RING ubiquitin ligase function. eLife 39 28475037
2015 NEDD8-mediated neddylation is required for human endometrial stromal proliferation and decidualization. Human reproduction (Oxford, England) 39 26003431
2019 Unanchored tri-NEDD8 inhibits PARP-1 to protect from oxidative stress-induced cell death. The EMBO journal 37 30804002
2017 Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis. Molecular cancer therapeutics 36 28468780
2011 The NEDD8-activating enzyme inhibitor, MLN4924, cooperates with TRAIL to augment apoptosis through facilitating c-FLIP degradation in head and neck cancer cells. Molecular cancer therapeutics 36 21914854
2020 Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells. Leukemia 33 32203139
2017 Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury. American journal of physiology. Lung cellular and molecular physiology 33 28522566
2012 A metal-based inhibitor of NEDD8-activating enzyme. PloS one 33 23185368
2003 ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis. Journal of neurochemistry 32 12694406
2021 TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia. Oncogene 30 33420360
2023 NEDD8-conjugating enzyme E2s: critical targets for cancer therapy. Cell death discovery 29 36690633
2021 Structural and functional consequences of NEDD8 phosphorylation. Nature communications 29 34642328
2019 Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site. Journal of neuroinflammation 29 31882005
2016 SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation. The Journal of biological chemistry 29 27756846
2015 NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins. The Journal of biological chemistry 29 26260793
2015 Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo. Blood 29 26675347
2012 The molecular basis of ubiquitin-like protein NEDD8 deamidation by the bacterial effector protein Cif. Proceedings of the National Academy of Sciences of the United States of America 29 22691497
2009 The mechanism of poly-NEDD8 chain formation in vitro. Biochemical and biophysical research communications 29 19245792
2005 Expression, purification, and characterization of the E1 for human NEDD8, the heterodimeric APPBP1-UBA3 complex. Methods in enzymology 29 16275315
2020 Old and New Concepts in Ubiquitin and NEDD8 Recognition. Biomolecules 28 32272761
2010 De novo DNA methyltransferase DNMT3b interacts with NEDD8-modified proteins. The Journal of biological chemistry 28 20847044
2018 The Nedd8-activating enzyme inhibitor MLN4924 (TAK-924/Pevonedistat) induces apoptosis via c-Myc-Noxa axis in head and neck squamous cell carcinoma. Cell proliferation 27 30341788
2017 The Nedd8 Non-covalent Binding Region in the Smurf HECT Domain is Critical to its Ubiquitn Ligase Function. Scientific reports 27 28169289
2016 The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia. Oncotarget 27 26993774
2016 MLN4924, a First-in-Class NEDD8-Activating Enzyme Inhibitor, Attenuates IFN-β Production. Journal of immunology (Baltimore, Md. : 1950) 25 26895833
2021 The nedd-8 activating enzyme gene underlies genetic resistance to infectious pancreatic necrosis virus in Atlantic salmon. Genomics 23 34547402

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