Affinage

CUL3

Cullin-3 · UniProt Q13618

Length
768 aa
Mass
88.9 kDa
Annotated
2026-06-09
100 papers in source corpus 50 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CUL3 is a scaffold cullin that nucleates Cullin-RING E3 ubiquitin ligase (CRL3) complexes, assembling with the RING protein RBX1/ROC1 and one of a large family of BTB-domain substrate adaptors to ubiquitinate structurally diverse substrates across cell-cycle, redox, autophagy, ion-transport, and neuronal programs (PMID:11311237, PMID:13679922, PMID:13679921, PMID:15572695, PMID:15367669). The defining architectural principle of CRL3 is that the BTB protein merges the Skp1 and F-box functions into a single polypeptide: its BTB/3-box module docks onto a hydrophobic groove that requires a unique N-terminal extension of CUL3, while a separate protein-interaction domain (Kelch, MATH) selects the substrate, with adaptor dimerization enabling avid bivalent engagement of multivalent degrons (PMID:13679922, PMID:13679921, PMID:19818708, PMID:23349464, PMID:37156295, PMID:19955409). Through distinct adaptors CUL3 directs substrate-specific fates — KEAP1 targets the oxidative-stress transcription factor Nrf2, an interaction disrupted by electrophilic modification of KEAP1 Cys151 (PMID:15572695, PMID:15367669, PMID:18251510); KLHL3 targets WNK kinases, with Gordon syndrome mutations abolishing complex assembly (PMID:23387299); KLHL9/KLHL13, KLHL21, and KLHL18 control mitotic Aurora kinases, the chromosomal passenger complex, and centrosomal/cytokinetic progression (PMID:17543862, PMID:19995937, PMID:23213400); KLHL20 terminates autophagy by degrading ULK1 and also writes non-degradative K33-linked chains on coronin 7 at the trans-Golgi to drive post-Golgi trafficking (PMID:26687681, PMID:24768539); and SPOP recognizes Ser/Thr-rich degrons to degrade Ci/Gli, Daxx, and other substrates (PMID:19818708, PMID:19955409, PMID:16524876). CUL3 itself constitutively degrades cyclin E to maintain quiescence, as shown by conditional knockout mice that accumulate cyclin E with increased S-phase entry (PMID:17339333). CRL3 activity is switched on by neddylation and requires reiterative neddylation/deneddylation cycles maintained by the COP9 signalosome, which also stabilizes the CUL3 protein; plasma-membrane neddylation is promoted by DCNL3 (PMID:12781129, PMID:16127432, PMID:19617556). In the mammalian nervous system, CUL3 loss-of-function causes autism-like and neuronal migration phenotypes linked to dysregulated substrates including eIF4G1, Plastin3, and 4E-BP1 (PMID:31780330, PMID:34031387, PMID:39301775).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Established that CUL3 forms an active ubiquitin ligase by partnering with the RING protein ROC1, defining the catalytic core that all later CRL3 complexes share.

    Evidence In vitro ubiquitination of cyclin D1 by ROC1-CUL3 immunocomplexes with RING-finger mutagenesis

    PMID:11311237

    Open questions at the time
    • No substrate adaptor identified at this stage
    • Physiological relevance of cyclin D1 as substrate not tested in vivo
  2. 2003 High

    Resolved how CUL3 achieves substrate specificity, showing BTB-domain proteins act as single-polypeptide adaptors that fuse the Skp1 and F-box roles, the founding principle of CRL3 architecture.

    Evidence Reconstitution and Co-IP of C. elegans MEL-26/CUL-3/MEI-1 plus genetic analysis; parallel demonstration that neddylation/deneddylation cycles are required for CUL-3 activity

    PMID:12781129 PMID:13679921 PMID:13679922

    Open questions at the time
    • Structural basis of BTB-CUL3 docking not yet resolved
    • Generality across the BTB family not established at this point
  3. 2004 High

    Connected CUL3 to redox homeostasis by identifying KEAP1 as a BTB adaptor that delivers Nrf2 for ubiquitination and showing the interaction is redox-sensitive through KEAP1 Cys151.

    Evidence In vitro ubiquitination, Co-IP, and C151S mutagenesis; RhoBTB2 identified as both adaptor-like binder and substrate

    PMID:15107402 PMID:15367669 PMID:15572695

    Open questions at the time
    • Mechanism by which Cys151 modification dissociates the complex not yet structurally defined
    • How oxidative signal is sensed remained open
  4. 2005 High

    Defined neddylation/deneddylation as the activity switch for CUL3, with the COP9 signalosome both recycling NEDD8 and stabilizing the CUL3 protein, and showed CRL3 adaptors are themselves subject to autoregulatory turnover.

    Evidence Drosophila CSN-mutant genetics with CUL3 stability/neddylation biochemistry; in vivo ubiquitination of KEAP1 and other BTB-Kelch proteins

    PMID:15983046 PMID:16127432

    Open questions at the time
    • The enzyme(s) recognizing neddylated unstable CUL3 not fully defined
    • Quantitative kinetics of neddylation cycling in vivo unresolved
  5. 2007 High

    Demonstrated that CRL3 controls mitosis and cell-cycle exit, with KLHL9/KLHL13 governing Aurora B dynamics and CUL3 itself maintaining quiescence via constitutive cyclin E degradation.

    Evidence Reconstituted CUL3/KLHL9/KLHL13 ligase with RNAi and live imaging; conditional Cul3 knockout mice for cyclin E; yeast Elongin A-CUL3 RNA Pol II degradation

    PMID:17296727 PMID:17339333 PMID:17543862

    Open questions at the time
    • Whether cyclin E degradation requires a dedicated BTB adaptor not identified
    • Phosphorylation-independence mechanism of cyclin E turnover unexplained
  6. 2009 High

    Established the structural and spatial logic of substrate recruitment — SPOP MATH-domain reads Ser/Thr-rich degrons with dimerization enabling avidity — and expanded CRL3 to mitotic, microtubule, and neuronal substrates.

    Evidence SPOP crystal structures with SAXS and binding assays; Ci/Gli degron mapping in Drosophila; KLHL21-Aurora B and KLHDC5-katanin reconstitution; DCNL3-driven plasma-membrane neddylation

    PMID:19261606 PMID:19617556 PMID:19818708 PMID:19955409 PMID:19995937

    Open questions at the time
    • How spatial pools of adaptors are established remained incompletely defined
    • Substrate handoff dynamics after ubiquitination not resolved
  7. 2013 High

    Provided atomic-resolution mechanism for BTB-CUL3 docking and linked CRL3 to human Mendelian disease, showing KLHL3 mutations and WNK4 degron mutations cause Gordon syndrome by disrupting CRL3 assembly or substrate engagement.

    Evidence Crystal structure of CUL3-KLHL11 BTB-BACK with deletion affinity measurements; reconstituted CUL3-KLHL3-WNK ubiquitination with disease-mutant controls

    PMID:23349464 PMID:23387299

    Open questions at the time
    • Full-length CRL3 holoenzyme architecture not solved
    • How disease mutations alter renal ion transport downstream not addressed biochemically
  8. 2015 High

    Showed CRL3 outputs are not limited to degradation, with KLHL20 both terminating autophagy through K48-linked ULK1 degradation and writing non-degradative K33-linked chains on coronin 7 for Golgi trafficking, and KBTBD6/7 spatially restricting RAC1 signaling.

    Evidence Reconstituted KLHL20 ubiquitination with conditional knockout mice; K33 chain-linkage analysis on Crn7; GABARAP-dependent TIAM1 degradation assays

    PMID:24768539 PMID:25684205 PMID:26687681

    Open questions at the time
    • What determines K48 vs K33 chain output by the same adaptor is unresolved
    • Breadth of non-degradative CRL3 signaling not systematically mapped
  9. 2021 Medium

    Linked CUL3 directly to neurodevelopmental disease mechanism, identifying translation-control and cytoskeletal substrates whose dysregulation underlies CUL3 haploinsufficiency phenotypes.

    Evidence Conditional/haploinsufficient mouse models with proteomics and rescue identifying eIF4G1, Plastin3, and patient-cell evidence for 4E-BP1; plus expanded substrate set (BECN1/KLHL38, ACLY/KLHL25)

    PMID:31780330 PMID:33977871 PMID:34031387 PMID:34491895 PMID:39301775

    Open questions at the time
    • Several disease-relevant substrates rely on proteomic inference without full biochemical reconstitution
    • Adaptors mediating eIF4G1, 4E-BP1, and Plastin3 degradation not all identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cell selects among hundreds of competing BTB adaptors for a limited CUL3 pool, and what governs the choice between degradative and non-degradative ubiquitin output, remains unresolved.
  • No quantitative model of adaptor competition for the CUL3 scaffold
  • Determinants of ubiquitin chain-linkage selection per adaptor not defined
  • Full-length CRL3 holoenzyme structure with substrate not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
DCNL3KEAP1KLHL13KLHL20KLHL3KLHL9RBX1SPOP
Complex memberships
CRL3 (Cullin3-RBX1 E3 ubiquitin ligase)

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 assembles with Cul3 and Rbx1 to form a functional E3 that targets multiple lysine residues in the Neh2 domain of Nrf2 for ubiquitin conjugation both in vivo and in vitro. Oxidative stress and sulforaphane inhibit this ubiquitination and correlate with decreased association of Keap1 with Cul3; a Cys151Ser mutation in Keap1 BTB domain is resistant to this inhibition. In vitro ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis (Keap1 C151S) Molecular and cellular biology High 15367669 15572695
2003 BTB-domain proteins function as substrate-specific adaptors for Cul3-based E3 ubiquitin ligase complexes, merging the functional properties of Skp1 and F-box proteins into a single polypeptide. The BTB protein MEL-26 in C. elegans directly and specifically interacts with CUL-3 and the substrate MEI-1/katanin in vivo and in vitro, targeting MEI-1 for degradation at the meiosis-to-mitosis transition. Biochemical reconstitution, Co-immunoprecipitation, in vitro binding assays, C. elegans genetics Nature High 13679921 13679922
2009 SPOP (a MATH-BTB protein) dimerizes and recruits substrates to Cul3 via a conserved helical '3-box' motif C-terminal to the BTB domain; crystal structures reveal that the MATH domain recognizes a Ser/Thr-rich SPOP-binding consensus (SBC) on substrates (Puc, Ci, MacroH2A), and dimerization may allow avid bivalent engagement of substrates with multiple SBCs. X-ray crystallography, biochemical binding assays, small-angle X-ray scattering Molecular cell High 19818708
2013 Crystal structure of Cul3 N-terminal domain in complex with BTB-BACK domains of KLHL11 (a BTB-Kelch protein) reveals that Cul3 interaction requires a unique N-terminal extension of Cul3 that packs against the 3-box in a hydrophobic groove between the BTB and BACK domains; deletion of this N-terminal region causes ~30-fold loss in binding affinity. X-ray crystallography, quantitative binding assays, deletion mutagenesis The Journal of biological chemistry High 23349464
2023 Crystal structure of the BTB and 3-box domains of human KEAP1 in complex with the CUL3 N-terminal domain reveals a heterotetrameric 2:2 assembly. TR-FRET assays show that the CUL3 N-terminal extension is critical for high-affinity binding. The drug CDDO reduces KEAP1-CUL3 binding affinity but does not fully disrupt the interaction. X-ray crystallography, TR-FRET binding assay, mutagenesis Free radical biology & medicine High 37156295
2003 Neddylation of CUL-3 is required for its E3 ligase activity toward MEI-1/katanin in C. elegans; both neddylation and deneddylation (by the COP9 signalosome) are required, and cycles of neddylation/deneddylation are necessary for in vivo ligase activity. C. elegans RNAi epistasis, biochemical analysis of CUL-3 neddylation status Current biology : CB High 12781129
2005 Neddylation of Cul3 activates its E3 function, while deneddylation by the COP9 signalosome (CSN) stabilizes Cul3 protein; neddylated Cul3 is unstable and degraded, and CSN activity is required to maintain normal Cul3 cellular levels by recycling neddylated Cul3 back to the stable, unneddylated form. Genetic analysis in Drosophila (CSN mutants), biochemical assays, protein stability measurements Nature cell biology High 16127432
2007 A Cul3 E3 ligase complex containing substrate adaptors KLHL9 and KLHL13 ubiquitylates Aurora B in vivo and in vitro. This complex removes Aurora B from mitotic chromosomes, allowing its accumulation on the central spindle during anaphase; loss of this complex causes defects in chromosome alignment, midzone/midbody formation, and cytokinesis. RNAi knockdown, co-immunoprecipitation, in vitro ubiquitination assay with reconstituted Cul3/KLHL9/KLHL13 ligase, live-cell imaging Developmental cell High 17543862
2009 The Cul3-KLHL21 E3 ubiquitin ligase complex directly binds Aurora B via KLHL21 and mediates Aurora B ubiquitination in vitro; KLHL21 localizes to midzone microtubules in anaphase and recruits Aurora B and Cul3 there, distinct from KLHL9/KLHL13 pools of Aurora B. Loss of KLHL21 impairs chromosomal passenger complex translocation and cytokinesis. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, live-cell imaging The Journal of cell biology High 19995937
2015 Cul3-KLHL20 ubiquitin ligase targets ULK1 for K48-linked ubiquitination and proteasomal degradation to terminate autophagy. ULK1 autophosphorylation promotes its recruitment to KLHL20. KLHL20 also governs degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation. Impairment of this pathway potentiates starvation-induced cell death and diabetes-associated muscle atrophy. Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, conditional knockout mice, siRNA knockdown Molecular cell High 26687681
2014 Cul3-KLHL20 E3 ligase catalyzes K33-linked (non-degradative) polyubiquitination on coronin 7 (Crn7) at the trans-Golgi network (TGN). This K33-chain facilitates Crn7 targeting to TGN through a ubiquitin-dependent interaction with Eps15, promoting TGN-pool F-actin assembly and post-Golgi trafficking. In vitro and in vivo ubiquitination assays, co-immunoprecipitation, siRNA knockdown, fluorescence microscopy Molecular cell High 24768539
2013 The Cul3-KLHL3 E3 ligase complex ubiquitylates WNK kinase isoforms. Dominant KLHL3 disease mutations inhibit binding to WNK1 or CUL3; Gordon's syndrome WNK4 mutations abolish KLHL3 interaction; the disease-causing KLHL3[R528H] mutant complex cannot ubiquitylate WNK1 in vitro. siRNA knockdown of CUL3 increases WNK1 protein levels and kinase activity in HeLa cells. Co-immunoprecipitation, in vitro ubiquitination assay with recombinant proteins, siRNA knockdown The Biochemical journal High 23387299
2005 Keap1 itself and three other BTB-Kelch proteins (GAN1, ENC1, Sarcosin) are ubiquitinated by a Cul3-dependent complex. Keap1 ubiquitination increases upon oxidative stress, occurs in parallel with inhibition of Keap1-dependent Nrf2 ubiquitination, and results in proteasome-independent degradation of Keap1. In vivo ubiquitination assays, proteasome inhibitor studies, overexpression and knockdown experiments The Journal of biological chemistry Medium 15983046
2008 Covalent modification of Keap1 Cys151 by the electrophile IAB disrupts Keap1 protein secondary structure and dissociates Keap1 from Cul3 in vitro and in vivo. Quantitative mass spectrometry-based kinetics confirmed Cys151 as one of the most reactive Keap1 residues in vivo and as required for IAB-mediated disruption of the Keap1-CUL3 interaction. CD spectroscopy, in vitro binding assay with recombinant proteins, quantitative MS-based kinetics, C151S mutagenesis Chemical research in toxicology High 18251510
2009 Cul3-KBTBD6/KBTBD7 E3 ligase ubiquitylates and promotes proteasomal degradation of TIAM1, a RAC1-specific GEF. KBTBD6/7 employ ATG8-interacting motifs to bind GABARAP proteins, and TIAM1 ubiquitylation by this complex depends on GABARAP, localizing degradation to membrane-associated pools and spatially restricting RAC1 signaling. Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, siRNA knockdown, actin morphology and invasion assays Molecular cell High 25684205
2004 RhoBTB2 binds to Cul3 via its first BTB domain and is a substrate of a Cul3-based ubiquitin ligase complex in vitro and in vivo. A cancer-associated missense mutant of RhoBTB2 fails to bind Cul3 and is not regulated by the ubiquitin/proteasome system, resulting in increased protein levels. Co-immunoprecipitation, in vitro ubiquitination assay, mutant analysis Genes & development Medium 15107402
2006 SPOP serves as an adaptor for Daxx ubiquitination by a Cul3-based ubiquitin ligase complex, leading to proteasomal degradation of Daxx. Overexpression of SPOP with Cul3 reduced Daxx levels; SPOP knockdown blocked Daxx degradation. Daxx degradation reversed its transcriptional repression and promoted apoptosis. Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, transcription reporter assays, apoptosis assays The Journal of biological chemistry Medium 16524876
2006 Actinfilin, a BTB-Kelch protein, acts as a Cul3 substrate adaptor linking GluR6 kainate receptor subunits to the E3 ubiquitin ligase complex for degradation. Actinfilin interacts with Cul3 via its BTB domain and with GluR6 via its Kelch repeat domain. Reduction of actinfilin or Cul3 elevates synaptic GluR6 surface expression in hippocampal neurons. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown, immunofluorescence, Cul3 dominant-negative in neurons The Journal of biological chemistry Medium 17062563
2006 KEL-8 is a BTB-Kelch substrate receptor for CUL-3 ubiquitin ligase in C. elegans neurons that mediates ubiquitin-dependent turnover of the AMPA-type glutamate receptor subunit GLR-1. Loss of KEL-8 increases synaptic GLR-1 levels and alters locomotion behavior. Genetic screen, co-immunoprecipitation, in vivo ubiquitination assays, behavioral analysis Molecular biology of the cell Medium 16394099
2009 The human DCNL3 protein promotes Cul3 neddylation at the plasma membrane. DCNL3 binds Cul3 via a C-terminal potentiating neddylation (PONY) domain, accumulates at the plasma membrane via a lipid-modified N-terminal motif, recruits Cul3 to membranes, and is required for Cul3 neddylation in vivo. Co-immunoprecipitation, RNAi knockdown, yeast complementation assay, subcellular fractionation, fluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 19617556
2007 Cul3 constitutively degrades cyclin E in vivo via a phosphorylation-independent pathway. Conditional knockout of Cul3 in primary mouse fibroblasts and liver causes dramatic increases in cyclin E protein levels, increased S-phase entry, and increased cell size and ploidy, demonstrating Cul3 maintains cellular quiescence through cyclin E turnover. Conditional gene knockout in mice, Western blot, cell cycle analysis, histology Molecular and cellular biology High 17339333
2009 Prothymosin-alpha mediates nuclear import of the INrf2 (Keap1)/Cul3/Rbx1 complex. The DGR region of Keap1 is required for nuclear import; antioxidant treatment increases nuclear import of the complex. Inside the nucleus, the complex exchanges prothymosin-alpha for Nrf2, ubiquitinating and degrading nuclear Nrf2. Co-immunoprecipitation, nuclear fractionation, RNAi knockdown, fluorescence microscopy The Journal of biological chemistry Medium 19279002
2009 Cul3-Klhdc5 (KLHDC5) E3 ligase targets p60/katanin for ubiquitination and degradation to regulate microtubule dynamics in mammalian cells. Cells deficient in Cul3 or KLHDC5 show increased p60/katanin levels and mitotic defects including persistent microtubule bridges. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, microscopy The Journal of biological chemistry Medium 19261606
2009 Ci/Gli transcription factors are degraded by Cul3-HIB/SPOP using multiple Ser/Thr-rich degrons that cooperatively bind HIB. Both HIB and Ci form dimers/oligomers enabling multivalent interactions. Similar S/T-rich motifs in Gli proteins and SPOP-binding proteins mediate their Cul3-SPOP-dependent degradation. In vitro binding assays, in vivo degradation assays, mutagenesis, Drosophila genetics Proceedings of the National Academy of Sciences of the United States of America High 19955409
2008 BTB protein KLHL12 acts as a Cul3 substrate adaptor to ubiquitinate the dopamine D4 receptor. KLHL12 binds the D4 receptor polymorphic third intracellular loop via its Kelch domain and interacts with Cullin3; overexpression of KLHL12 promotes D4 receptor ubiquitination specifically. Co-immunoprecipitation, in vivo ubiquitination assay The Journal of biological chemistry Medium 18303015
2011 KLHL7 forms a dimer and assembles with Cul3 through BTB and BACK domains to form an active E3 ligase. An autosomal dominant retinitis pigmentosa-causative BACK domain mutation in KLHL7 specifically disrupts Cul3 interaction but not dimerization; incorporation of this mutant as a heterodimer diminishes E3 activity in a dominant-negative manner. Co-immunoprecipitation, in vitro/in vivo ubiquitination assay, disease mutation analysis The Journal of biological chemistry Medium 21828050
2008 PIPKIIbeta and SPOP co-interact at nuclear speckles; SPOP mediates ubiquitylation of PIPKIIbeta by Cul3. Stimulation of the p38 MAPK pathway enhances Cul3-SPOP E3 ligase activity toward multiple substrates. A kinase-dead PIPKIIbeta mutant increases intracellular phosphatidylinositol 5-phosphate (PI5P), and PI5P via p38 stimulates Cul3-SPOP activity. Yeast two-hybrid, co-immunoprecipitation, in vivo ubiquitination assay, kinase inhibitor studies, fluorescence microscopy The Journal of biological chemistry Medium 18218622
2011 Cul3-KLHL18 E3 ligase ubiquitylates Aurora-A in vitro and in vivo; depletion of Cul3 or KLHL18 causes a delay in mitotic entry with delayed centrosomal Aurora-A activation. KLHL18 directly interacts with Aurora-A. Co-immunoprecipitation, in vitro ubiquitination assay with reconstituted CUL3-KLHL18-ROC1 ligase, siRNA knockdown, time-lapse microscopy Biology open Medium 23213400
2007 In yeast, elongin A (Ela1) and Cul3 are required for RNA polymerase II (Rpb1) polyubiquitylation and degradation in DNA-damaged cells. The proposed E3 is composed of Elc1, Ela1, Cul3, and Roc1. Genetic analysis in S. cerevisiae, ubiquitylation assays Molecular and cellular biology Medium 17296727
2017 p97 (VCP) negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, aided by the cofactor UFD1/NPL4 and UBXN7, for efficient proteasomal degradation. Co-immunoprecipitation, RNAi knockdown, in vivo ubiquitination assay Molecular and cellular biology Medium 28115426
2010 Nrf2 controls its own degradation by transcriptionally regulating Cul3 and Rbx1 expression through an antioxidant response element (ARE) in their promoters; increased Cul3-Rbx1 promotes ubiquitination and degradation of Nrf2, forming a feedback autoregulatory loop. Promoter mutagenesis, transcription reporter assays, siRNA knockdown, overexpression studies The Journal of biological chemistry Medium 20452971
2012 Antioxidant treatment induces tyrosine 85 phosphorylation of INrf2 (Keap1), which controls nuclear export of the INrf2-Cul3-Rbx1 complex; mutation of Tyr85 blocks nuclear export of INrf2 and Cul3-Rbx1, leading to nuclear accumulation of Nrf2. Cul3 and Rbx1 require INrf2 for their nuclear export. Site-directed mutagenesis (Y85F), nuclear fractionation, co-immunoprecipitation, siRNA knockdown Journal of cell science Medium 22448038
2014 The Drosophila E3 ligase CUL3/RDX (Rdx is the BTB adaptor) ubiquitylates CENP-A in a CAL1-dependent manner. CAL1 is not itself a substrate but serves as an additional substrate-specifying factor. Ubiquitylation of CENP-A by CUL3/RDX stabilizes CENP-A (non-degradative function); loss of RDX causes rapid degradation of CAL1 and CENP-A and chromosome segregation defects. Co-immunoprecipitation, in vivo ubiquitination assay, RNAi knockdown, cytological analysis Developmental cell Medium 24636256
2001 ROC1-CUL3 immunocomplexes promote polyubiquitination of cyclin D1 in vitro; RING finger mutations of ROC1 eliminate this ubiquitin ligase activity; ubiquitination of cyclin D1 is accompanied by autoubiquitination of Cul3. In vitro ubiquitination assay, co-immunoprecipitation, RING finger mutagenesis FEBS letters Medium 11311237
2017 Drosophila Germ cell-less (GCL), a conserved BTB protein, acts as a substrate-specific adaptor for CUL3, forming CRL3^GCL. This complex promotes degradation of Torso, a receptor tyrosine kinase, in a manner dependent on cell-cycle-triggered release of GCL from the nuclear envelope during mitosis, providing spatiotemporal specificity for RTK degradation. Drosophila genetics, co-immunoprecipitation, in vivo ubiquitination assay, fluorescence microscopy Developmental cell Medium 28743001
2019 CUL3 deficiency in mice causes ASD-like social and anxiety behaviors associated with enhanced glutamatergic transmission. Proteomic analysis identified eIF4G1 (a cap-dependent translation factor) as a potential CUL3 substrate; pharmacological inhibition of eIF4G1 function rescued behavioral and cellular deficits in CUL3-deficient mice. Conditional knockout mice, electrophysiology, proteomic analysis, pharmacological rescue Neuron Medium 31780330
2021 CUL3 constitutively haploinsufficiency disrupts neuronal migration during a critical developmental window in mice. Cul3 controls migration by regulating the abundance of Plastin3 (Pls3), an actin-binding protein. Pls3 levels are inversely proportional to migration speed, and transcriptional activation of the intact Cul3 allele can rescue cellular phenotypes in vitro. Conditional knockout mice, cortical lamination analysis, proteomic analysis, rescue experiments Nature communications Medium 34031387
2021 CUL3 interacts with Beclin 1 (BECN1) and promotes its K48-linked ubiquitination and proteasomal degradation. KLHL38 serves as the substrate adaptor mediating this interaction. CUL3-mediated BECN1 degradation decreases autophagic activity and promotes breast and ovarian cancer cell proliferation. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, overexpression studies Autophagy Medium 33977871
2019 Cul3 and the BTB adaptor insomniac (Inc) rapidly accumulate at postsynaptic compartments at the Drosophila NMJ following acute glutamate receptor inhibition and are required for a local increase in mono-ubiquitination. Peflin, a Ca2+-regulated Cul3 co-adaptor, is necessary for retrograde homeostatic signaling, linking Ca2+ signaling to Cul3/Inc activity. Forward genetic screen, immunofluorescence, genetic knockouts, pharmacological and genetic epistasis Nature communications Medium 31278365
2019 KLHL9 and KLHL13, in complex with CUL3, mediate proteasomal degradation of IRS1, the insulin receptor substrate. ATG16L1 deficiency elevates KLHL9/KLHL13 expression, increasing IRS1 degradation and causing insulin resistance. Knockdown of KLHL9, KLHL13, or CUL3 restores IRS1 levels. BioID proximity labeling, co-immunoprecipitation, siRNA knockdown, insulin signaling assays The Journal of biological chemistry Medium 31515271
2019 Cul3-Klhl18 E3 ligase promotes ubiquitination and proteasomal degradation of Unc119, a rod transducin α-subunit (Tα)-interacting protein, during light/dark adaptation. Klhl18 preferentially recognizes casein kinase 2-phosphorylated Unc119, which is dephosphorylated by Ca2+-dependent calcineurin. Loss of Klhl18 causes Tα mislocalization and suppresses light-induced photoreceptor damage. Knockout mice, in vivo ubiquitination assay, co-immunoprecipitation, immunofluorescence, pharmacological inhibition The EMBO journal High 31696965
2009 Heat shock factor 2 (HSF2) PEST sequences directly interact with Cul3, recruiting HSF2 to the Cul3-RING E3 complex for ubiquitination and degradation—identifying a direct substrate recruitment mechanism via PEST sequences that bypasses the need for a BTB adaptor. Co-immunoprecipitation, in vivo ubiquitination assay Cell stress & chaperones Low 19768582
2011 The Cul3-SPOP complex ubiquitinates and destabilizes BRMS1 (breast cancer metastasis suppressor 1); the SPOP adaptor mediates the interaction between Cul3 and BRMS1. Knockdown of SPOP increases BRMS1 protein and represses expression of BRMS1 target genes OPN and uPA. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown Biochemical and biophysical research communications Low 22085717
2021 CUL3-KLHL25 E3 ligase ubiquitinates and degrades ATP-citrate lyase (ACLY) during iTreg differentiation stimulated by TGFβ1. ACLY degradation reduces malonyl-CoA, thereby relieving inhibition of CPT1 and facilitating a shift from fatty acid synthesis to fatty acid oxidation required for iTreg differentiation. Co-immunoprecipitation, in vivo ubiquitination assay, metabolic assays, iTreg differentiation assays eLife Medium 34491895
2021 G3BP1 acts as a competitive inhibitor of Cul3-SPOP by directly interacting with SPOP, reducing Cul3^SPOP E3 ligase activity and stabilizing SPOP substrates including AR coactivators, thereby promoting prostate cancer progression. AR directly upregulates G3BP1 transcription, forming a feed-forward amplification loop. Co-immunoprecipitation, in vivo ubiquitination assay, transcriptomic analysis, siRNA knockdown, overexpression Nature communications Medium 34795264
2021 CUL3 LoF variants cause decreased ubiquitin-protein conjugate levels in patient T-cells; 4E-BP1 (EIF4EBP1) fails to be targeted for proteasomal degradation in patient-derived cells, establishing 4E-BP1 as a CUL3 substrate relevant to neurodevelopmental disease. Patient-derived cell assays, Western blot for ubiquitin conjugates, protein stability assays Annals of neurology Medium 39301775
2017 CUL3 neddylation accumulates during adipogenic differentiation; Cul3 and Rab18 physically associate at lipid droplet membranes. Downregulation of Cul3 or inhibition of neddylation blocks lipid droplet formation and increases RhoA protein levels, suggesting Cul3 regulates RhoA stability during adipogenesis. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, MLN4924 neddylation inhibition Biochimica et biophysica acta. Molecular cell research Low 28499918
2020 CUL3 directly binds β-catenin, promoting its ubiquitination and degradation; miR-23a-3p suppresses CUL3 expression to reduce β-catenin ubiquitination and stabilize β-catenin, enhancing endometrial receptivity and trophoblast attachment. Co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, siRNA knockdown Journal of molecular endocrinology Low 32716006

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Molecular and cellular biology 1058 15572695
2004 The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Molecular and cellular biology 842 15367669
2008 Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proceedings of the National Academy of Sciences of the United States of America 631 18757741
2003 BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 419 13679922
2009 Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Molecular cell 416 19818708
2003 The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 361 13679921
2005 Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. The Journal of biological chemistry 257 15983046
2013 Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. The Journal of biological chemistry 231 23349464
2007 A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes, regulating mitotic progression and completion of cytokinesis in human cells. Developmental cell 196 17543862
2015 Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. Molecular cell 188 26687681
2013 The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. The Biochemical journal 180 23387299
2006 BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. The Journal of biological chemistry 175 16524876
2021 CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy 173 33977871
2008 Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chemical research in toxicology 172 18251510
2002 Distinct protein degradation mechanisms mediated by Cul1 and Cul3 controlling Ci stability in Drosophila eye development. Genes & development 163 12231629
2005 Neddylation and deneddylation regulate Cul1 and Cul3 protein accumulation. Nature cell biology 150 16127432
2003 Neddylation and deneddylation of CUL-3 is required to target MEI-1/Katanin for degradation at the meiosis-to-mitosis transition in C. elegans. Current biology : CB 150 12781129
2009 Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. The Biochemical journal 144 19489739
2006 Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 x Keap1 x Cul3 complex and recruiting Nrf2 x Maf to the antioxidant response element enhancer. The Journal of biological chemistry 143 16785233
2014 K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase Regulates Protein Trafficking. Molecular cell 139 24768539
2013 CUL3 and NRF2 mutations confer an NRF2 activation phenotype in a sporadic form of papillary renal cell carcinoma. Cancer research 132 23365135
2009 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 130 19955409
2009 Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicology and applied pharmacology 126 19560482
2015 Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. Neuron 122 25695269
2009 The Cul3-KLHL21 E3 ubiquitin ligase targets aurora B to midzone microtubules in anaphase and is required for cytokinesis. The Journal of cell biology 118 19995937
2008 Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction. Toxicology and applied pharmacology 114 18417180
2004 RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex. Genes & development 106 15107402
2016 Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells. Molecular and cellular biology 102 27697860
2019 CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron 95 31780330
2017 p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex. Molecular and cellular biology 95 28115426
2020 CUL3BPM E3 ubiquitin ligases regulate MYC2, MYC3, and MYC4 stability and JA responses. Proceedings of the National Academy of Sciences of the United States of America 87 32123086
2012 Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila. PLoS genetics 86 23055946
2009 Cul3 overexpression depletes Nrf2 in breast cancer and is associated with sensitivity to carcinogens, to oxidative stress, and to chemotherapy. Molecular cancer therapeutics 83 19638449
2009 The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes. Proceedings of the National Academy of Sciences of the United States of America 77 19617556
2008 Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes--evidence for an autoregulatory mechanism. Experimental cell research 73 18835386
2021 CUL3 E3 ligases in plant development and environmental response. Nature plants 71 33452490
2015 CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling. Molecular cell 71 25684205
2006 KEL-8 is a substrate receptor for CUL3-dependent ubiquitin ligase that regulates synaptic glutamate receptor turnover. Molecular biology of the cell 71 16394099
2006 Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway. The Journal of biological chemistry 71 17062563
2007 ELA1 and CUL3 are required along with ELC1 for RNA polymerase II polyubiquitylation and degradation in DNA-damaged yeast cells. Molecular and cellular biology 69 17296727
2008 Coordinated activation of the nuclear ubiquitin ligase Cul3-SPOP by the generation of phosphatidylinositol 5-phosphate. The Journal of biological chemistry 68 18218622
2020 Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2-KEAP1-CUL3 Interactions in Chronic Kidney Disease. Antioxidants (Basel, Switzerland) 66 32854194
2008 BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. The Journal of biological chemistry 66 18303015
2010 An autoregulatory loop between Nrf2 and Cul3-Rbx1 controls their cellular abundance. The Journal of biological chemistry 59 20452971
2019 Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3. Molecular psychiatry 56 31455858
2019 The miR-15a-5p-XIST-CUL3 regulatory axis is important for sepsis-induced acute kidney injury. Renal failure 56 31658856
2009 Prothymosin-alpha mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. The Journal of biological chemistry 55 19279002
2013 Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer. Molecular cancer 53 24138990
2007 Constitutive turnover of cyclin E by Cul3 maintains quiescence. Molecular and cellular biology 53 17339333
2011 Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation. The Journal of biological chemistry 51 21828050
2020 CRL3s: The BTB-CUL3-RING E3 Ubiquitin Ligases. Advances in experimental medicine and biology 50 31898230
2011 Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 50 21795997
2019 Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 49 31319993
2011 Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex. Biochemical and biophysical research communications 49 22085717
2009 The Cul3/Klhdc5 E3 ligase regulates p60/katanin and is required for normal mitosis in mammalian cells. The Journal of biological chemistry 46 19261606
2019 Cul3 and insomniac are required for rapid ubiquitination of postsynaptic targets and retrograde homeostatic signaling. Nature communications 45 31278365
2004 Protein degradation: CUL-3 and BTB--partners in proteolysis. Current biology : CB 43 14738749
2014 Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome). Clinical science (London, England : 1979) 42 24266877
2015 Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor. Molecular cancer research : MCR 41 25995385
2013 Aberrant reduction of MiR-141 increased CD47/CUL3 in Hirschsprung's disease. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 40 24334875
2017 GCL and CUL3 Control the Switch between Cell Lineages by Mediating Localized Degradation of an RTK. Developmental cell 38 28743001
2021 Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature communications 37 34031387
2021 Pyrroloquinoline quinone (PQQ) alleviated sepsis-induced acute liver injury, inflammation, oxidative stress and cell apoptosis by downregulating CUL3 expression. Bioengineered 36 34227919
2014 The E3 ligase CUL3/RDX controls centromere maintenance by ubiquitylating and stabilizing CENP-A in a CAL1-dependent manner. Developmental cell 36 24636256
2012 Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression. Journal of cell science 36 22448038
2005 Requirement of Cul3 for axonal arborization and dendritic elaboration in Drosophila mushroom body neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 15843622
2020 De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms. Journal of human genetics 34 32341456
2019 Deficiency of the autophagy gene ATG16L1 induces insulin resistance through KLHL9/KLHL13/CUL3-mediated IRS1 degradation. The Journal of biological chemistry 34 31515271
2021 Tangeretin maintains antioxidant activity by reducing CUL3 mediated NRF2 ubiquitination. Food chemistry 33 34237577
2021 ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation. eLife 32 34491895
2021 G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer. Nature communications 32 34795264
2019 Cul3-Klhl18 ubiquitin ligase modulates rod transducin translocation during light-dark adaptation. The EMBO journal 31 31696965
2011 The CUL3-KLHL18 ligase regulates mitotic entry and ubiquitylates Aurora-A. Biology open 31 23213400
2017 Cul3 neddylation is crucial for gradual lipid droplet formation during adipogenesis. Biochimica et biophysica acta. Molecular cell research 29 28499918
2019 Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis. Scientific reports 28 30872636
2014 New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases. Biochemical Society transactions 28 24450635
2023 Structural and biochemical characterization establishes a detailed understanding of KEAP1-CUL3 complex assembly. Free radical biology & medicine 27 37156295
2016 Salvianolic acid A ameliorates the integrity of blood-spinal cord barrier via miR-101/Cul3/Nrf2/HO-1 signaling pathway. Brain research 27 28011395
2014 Unique pattern of component gene disruption in the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in serous ovarian cancer. BioMed research international 27 25114896
2022 CUL3/SPOP complex prevents immune escape and enhances chemotherapy sensitivity of ovarian cancer cells through degradation of PD-L1 protein. Journal for immunotherapy of cancer 26 36198437
2017 The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells. Scientific reports 26 28216678
2023 Exo-miR-1290-induced by COX-2 overexpression promotes cancer-associated fibroblasts activation and tumor progression by CUL3-Nrf2 pathway in lung adenocarcinoma. Cell communication and signaling : CCS 25 37723559
2021 Novel CUL3 Variant Causing Familial Hyperkalemic Hypertension Impairs Regulation and Function of Ubiquitin Ligase Activity. Hypertension (Dallas, Tex. : 1979) 25 34878901
2018 Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway. Journal of the American Society of Nephrology : JASN 25 30301860
2021 LZTR1: A promising adaptor of the CUL3 family. Oncology letters 24 34113392
2004 Saccharomyces cerevisiae ubiquitin-like protein Rub1 conjugates to cullin proteins Rtt101 and Cul3 in vivo. The Biochemical journal 24 14519104
2001 In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS letters 24 11311237
2013 CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy. Pediatric nephrology (Berlin, Germany) 23 23689903
2022 The functions and effects of CUL3-E3 ligases mediated non-degradative ubiquitination. Gene 22 35580799
2013 A quantitative proteomic analysis uncovers the relevance of CUL3 in bladder cancer aggressiveness. PloS one 22 23308193
2013 Analysis of dimerization of BTB-IVR domains of Keap1 and its interaction with Cul3, by molecular modeling. Bioinformation 21 23847398
2007 Suppression of Hedgehog signaling by Cul3 ligases in proliferation control of retinal precursors. Developmental biology 21 17559828
2021 SPOP and CUL3 Modulate the Sonic Hedgehog Signal Response Through Controlled Degradation of GLI Family Transcription Factors. Frontiers in cell and developmental biology 20 34395437
2009 PEST sequences mediate heat shock factor 2 turnover by interacting with the Cul3 subunit of the Cul3-RING ubiquitin ligase. Cell stress & chaperones 20 19768582
2007 A Cul3-based E3 ligase regulates mitosis and is required to maintain the spindle assembly checkpoint in human cells. Cell cycle (Georgetown, Tex.) 20 18075312
2024 Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder. Annals of neurology 19 39301775
2022 A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation. Genes & development 19 36328355
2016 Cul3-KLHL20 ubiquitin ligase: physiological functions, stress responses, and disease implications. Cell division 19 27042198
2013 CUL3 and protein kinases: insights from PLK1/KLHL22 interaction. Cell cycle (Georgetown, Tex.) 19 24067371
2020 miR-23a-3p increases endometrial receptivity via CUL3 during embryo implantation. Journal of molecular endocrinology 18 32716006

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