Affinage

CUL5

Cullin-5 · UniProt Q93034

Length
780 aa
Mass
91.0 kDa
Annotated
2026-04-28
66 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CUL5 is the scaffold subunit of Cullin-RING E3 ubiquitin ligase 5 (CRL5) complexes, which assemble with RBX2, ElonginB/C, and diverse SOCS-box substrate receptors to ubiquitinate a broad range of substrates, thereby controlling antiviral defense, apoptosis, T cell differentiation, hematopoiesis, cell migration, and autophagy. CRL5 complexes are activated by NEDD8 conjugation to CUL5, which allosterically exposes binding sites for the co-E3 ARIH2 and sequesters the NEDD8 E2 (UBE2F) site on RBX2, relieving ARIH2 autoinhibition to initiate substrate ubiquitination (PMID:34518685, PMID:33268465). Substrate specificity is dictated by interchangeable SOCS-box receptors—including CIS, ASB6, ASB9, ASB11, Rab40b, PCMTD2, LRRC41, Wsb2, and HIV-1 Vif—that recruit substrates such as phospho-JAK1, Noxa, Bim, BIK, Rap2, free histones H3/H4, PTBP1, p62, and APOBEC3G/3F for K48/K63-linked polyubiquitination and proteasomal degradation (PMID:14564014, PMID:35293963, PMID:35589717, PMID:38242867, PMID:40569692, PMID:41260500). PKA-dependent phosphorylation at S730 negatively regulates CUL5 neddylation and thereby modulates its activity, while a nuclear localization signal (640-PKLKRQ-646) is required for nuclear CUL5 function and growth-regulatory effects (PMID:19917606, PMID:27834018).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2000 Medium

    Before CUL5's E3 ligase function was defined, overexpression studies revealed that CUL5 (then called VACM-1) modulates second messenger signaling—inhibiting cAMP and stimulating IP3 production—in a PKA phosphorylation-dependent manner, suggesting a signaling-regulatory role.

    Evidence Stable overexpression in cells with cAMP/IP3 assays and S730A mutagenesis

    PMID:10898738

    Open questions at the time
    • No direct substrate or ubiquitination mechanism identified
    • Overexpression system without loss-of-function confirmation
    • Relationship to E3 ligase activity unknown at the time
  2. 2001 High

    Biochemical reconstitution established that CUL5 assembles with BC-box proteins (MUF1, Elongin A, SOCS1, WSB1) and Rbx1 to form functional E3 ubiquitin ligases, defining CUL5 as a scaffold for a modular Cullin-RING ligase family.

    Evidence Purification from rat liver and in vitro reconstitution of ubiquitin ligase activity

    PMID:11384984

    Open questions at the time
    • Endogenous substrates not yet identified
    • Specificity determinants distinguishing CUL2 vs CUL5 complexes unknown
  3. 2003 High

    The discovery that HIV-1 Vif hijacks CUL5-ElonginB/C to form an E3 ligase that polyubiquitinates APOBEC3G for proteasomal degradation established the first physiologically critical CRL5 substrate and revealed viral subversion of CUL5 as an immune evasion strategy.

    Evidence Co-IP, ubiquitination assays, dominant-negative CUL5, and Vif point mutants in human cells

    PMID:14564014

    Open questions at the time
    • Structural basis of Vif–CUL5 selectivity unknown
    • Whether CUL5 targets other APOBEC family members unresolved
  4. 2004 High

    Systematic domain-swap and knockdown experiments resolved how SOCS-box proteins achieve selective recruitment of CUL5-RBX2 versus CUL2-RBX1 through distinct Cul5-box and Cul2-box sequences, and identified conserved cysteine residues in Vif as an additional CUL5-specificity determinant.

    Evidence Domain-swap mutagenesis, Co-IP with endogenous proteins, RNAi epistasis, functional assays

    PMID:15574592 PMID:15574593 PMID:15601820

    Open questions at the time
    • Three-dimensional structural basis of selectivity not yet determined
    • Full repertoire of CUL5 substrate receptors not catalogued
  5. 2005 High

    Extension of the Vif–CUL5 paradigm showed that APOBEC3F is also targeted for degradation by the same CUL5-containing ligase, and that Vif itself is autoubiquitinated and degraded by CUL5, establishing CUL5 as a regulator of both substrate and adaptor turnover.

    Evidence RNAi of CUL5, dominant-negative CUL5, ubiquitination and protein stability assays

    PMID:16014920

    Open questions at the time
    • Kinetics of Vif autoubiquitination versus substrate ubiquitination unresolved
    • Physiological consequence of Vif autoregulation for viral fitness unclear
  6. 2006 High

    Identification of Vif as a zinc-binding protein with an HCCH motif, and mapping of the Vif-binding region to the N-terminal Cullin repeat of CUL5 (the most divergent region from CUL2), provided a structural rationale for why Vif selectively recruits CUL5 over CUL2.

    Evidence Zinc-binding assays, mutagenesis, Co-IP, deletion mapping of CUL5

    PMID:16530799

    Open questions at the time
    • Atomic-resolution structure of the Vif–CUL5 interface not yet available
  7. 2008 High

    Systematic biochemical reconstitution of multiple CRL complexes validated generalizable rules for Cul2-box/Cul5-box specificity, including the LPφP motif in Cul5-boxes and tolerance for variable spacing between BC- and Cullin-boxes.

    Evidence Biochemical reconstitution of a panel of BC-box protein–Cullin complexes with mutagenesis

    PMID:18187417

    Open questions at the time
    • In vivo validation of predicted CUL5 substrates based on these rules not performed
    • Role of post-translational modifications in modulating box specificity unknown
  8. 2009 Medium

    PKA-dependent phosphorylation of CUL5 at S730 was shown to suppress CUL5 neddylation, linking kinase signaling to CRL5 activation status and explaining how cAMP/PKA signaling modulates CUL5 function.

    Evidence Co-IP with anti-phospho-PKA-substrate antibody, Western blot for Nedd8-CUL5, forskolin treatment, S730A mutagenesis

    PMID:19917606

    Open questions at the time
    • Direct kinase assay showing PKA phosphorylates CUL5 at S730 not provided
    • Downstream substrates affected by neddylation changes not identified
    • Single lab finding
  9. 2013 High

    Crystal structures of the ASB9–ElonginB/C complex and the CUL5 N-terminal domain revealed a unique rigid-body rotation between CUL5 Cullin repeats compared to other Cullins, providing the first atomic-level view of CRL5 architecture.

    Evidence X-ray crystallography and structural modeling

    PMID:23806657

    Open questions at the time
    • Full-length CRL5 complex structure not determined
    • Structural basis for neddylation-dependent activation of CUL5 unknown
  10. 2014 High

    The crystal structure of the complete Vif–CBFβ–CUL5–ELOB–ELOC pentameric complex revealed how Vif mimics SOCS2 to contact CUL5 and ELOC cooperatively, confirmed the zinc-finger stabilization of Vif's α-domain, and showed that CBFβ binding by Vif competes with RUNX1.

    Evidence X-ray crystallography of the pentameric complex, ITC binding measurements, mutagenesis with functional viral assays

    PMID:24402281 PMID:24422669

    Open questions at the time
    • How APOBEC3G is positioned relative to the E3 for ubiquitin transfer not structurally resolved
    • Structure of an endogenous (non-hijacked) CRL5 with a natural SOCS-box receptor and substrate not available
  11. 2016 Medium

    A nuclear localization signal (640-PKLKRQ-646) in CUL5 was found to be required for its nuclear localization and its growth-regulatory effects, demonstrating that CUL5 function is compartment-dependent.

    Evidence Site-directed mutagenesis of NLS residues with immunocytochemistry and proliferation assays

    PMID:27834018

    Open questions at the time
    • Nuclear substrates of CUL5 not identified
    • Whether nuclear neddylation is functionally distinct from cytoplasmic neddylation unclear
    • Single lab finding
  12. 2019 High

    Genome-wide CRISPR screens and targeted knockouts revealed that CRL5 components (CUL5, RNF7/SAG, UBE2F) control levels of pro-apoptotic BH3-only proteins Noxa and Bim, and that a separate CUL5–ASB11 complex ubiquitinates BIK during the adaptive UPR via XBP1s-driven ASB11 upregulation, establishing CRL5 as a major regulator of apoptotic priming.

    Evidence Genome-wide CRISPR screen with flow cytometry, CRISPR KO, Co-IP of CUL5–ASB11, ubiquitination assays, ER stress and apoptosis functional readouts

    PMID:31294695 PMID:31387940

    Open questions at the time
    • Whether CUL5 directly ubiquitinates Noxa/Bim or acts through an intermediate not fully resolved
    • Relative contribution of different substrate receptors to apoptotic regulation in different tissues unknown
  13. 2020 High

    Gossypol was identified as a direct inhibitor of CUL5 neddylation that binds the SAG–CUL5 interface (dependent on CUL5-H572), providing a pharmacological tool to block CRL5 activation and confirming that neddylation is essential for CRL5 substrate turnover in cells.

    Evidence AlphaScreen HTS, biochemical neddylation assay, mutagenesis of H572, substrate accumulation readout

    PMID:32145688

    Open questions at the time
    • Selectivity for CUL5 over CUL1 neddylation not fully characterized
    • In vivo pharmacokinetics and target engagement not evaluated
  14. 2020 Medium

    KLHDC1, operating as a CUL5-type E3 ligase, was shown to target truncated selenoproteins (SELENOS) produced by failed UGA/Sec decoding for proteasomal degradation, linking CRL5 to selenoprotein quality control.

    Evidence Co-IP, ubiquitination assay, RNAi with cell death and ROS readouts

    PMID:32200094

    Open questions at the time
    • Whether CUL5 is the only Cullin partner for KLHDC1 not confirmed
    • Generality to other truncated selenoproteins not tested
    • Single lab study
  15. 2021 High

    Cryo-EM structures and HDX-MS revealed the allosteric activation mechanism of CRL5: NEDD8 conjugation to CUL5 does not directly recruit ARIH2 (unlike CUL1/ARIH1) but instead causes conformational changes in CUL5 that expose cryptic ARIH2-binding sites, which then relieve ARIH2 autoinhibition for substrate ubiquitination.

    Evidence Cryo-EM structures, HDX-MS, biochemical reconstitution with ASB9-CRL5-ARIH2-UBE2L3 ubiquitinating CKB

    PMID:33268465 PMID:34518685

    Open questions at the time
    • Whether all CRL5 substrate receptors use the ARIH2 co-E3 pathway not established
    • Full catalytic cycle including polyubiquitin chain extension not structurally resolved
  16. 2021 Medium

    Identification of p62/SQSTM1 as a CUL5–ASB6 substrate linked CRL5 to autophagy regulation, as CUL5 or ASB6 depletion caused p62 accumulation and altered autophagy and proliferation.

    Evidence Co-IP, ubiquitination assay, RNAi and overexpression with proliferation and autophagy readouts

    PMID:34164402

    Open questions at the time
    • Ubiquitin chain type on p62 not determined
    • Whether this is the primary p62 degradation pathway versus selective autophagy not resolved
    • Single lab study
  17. 2022 High

    CUL5 was established as a key regulator of immune cell differentiation: in CD4+ T cells, CUL5–CIS ubiquitinates phospho-JAK1 to set the IL-4 receptor signaling threshold controlling Treg vs Th9 fate, and in CD8+ T cells, CUL5–PCMTD2 restrains TCR and IL-2 signaling to limit effector function.

    Evidence Conditional KO mice, Co-IP of CUL5–CIS–pJak1 and CUL5–PCMTD2, CRISPR screening, neddylation inhibitor, tumor and allergy models

    PMID:35589717 PMID:38242867

    Open questions at the time
    • Full set of CUL5 substrates in T cells not catalogued
    • Whether CUL5 regulation differs across T cell subsets beyond CD4/CD8 unknown
  18. 2022 High

    Rab40b was identified as a GTPase-containing CUL5 substrate receptor that ubiquitinates Rap2 to regulate its activation and endolysosomal recycling to lamellipodia, establishing a CRL5-dependent mechanism controlling cell migration and invasion.

    Evidence Co-IP, in vitro ubiquitination, live-cell imaging of Rap2 localization, migration/invasion assays with mutants

    PMID:35293963

    Open questions at the time
    • Ubiquitin chain type on Rap2 not determined
    • Whether other Rab40 family members function similarly not tested
  19. 2025 High

    The ASB9–CUL5 complex was shown to polyubiquitinate free histones H3 and H4 (but not nucleosomal or chaperone-bound histones) via K48 and K63 chains without requiring the ARIH2 co-E3, revealing an ARIH2-independent CRL5 ubiquitination pathway and a role in histone proteostasis.

    Evidence In vitro ubiquitination with purified components, binding affinity measurements, polyubiquitin linkage analysis by mass spectrometry

    PMID:41260500

    Open questions at the time
    • Physiological context for free histone ubiquitination (e.g., replication stress, histone overexpression) not defined
    • Whether this pathway operates in vivo not shown
  20. 2025 High

    Hematopoietic-specific CUL5 deletion revealed that CUL5 is required for steady-state hematopoiesis; CUL5–LRRC41 complexes regulate JAK/STAT signaling in HSPCs, and loss causes STAT5/LRRC41 accumulation, myeloid bias, and increased HSC proliferation normalized by JAK inhibition.

    Evidence Conditional KO (Cul5-Vav-Cre), Co-IP of CUL5–LRRC41, HSPC proteomics, ruxolitinib rescue

    PMID:40569692

    Open questions at the time
    • Whether LRRC41 is the sole substrate receptor in HSPCs or additional receptors contribute
    • Direct ubiquitination target (STAT5 or other JAK/STAT components) not biochemically confirmed
  21. 2025 Medium

    Wsb2 was identified as a CUL5 substrate receptor that uses BCL2 anti-apoptotic proteins (Bcl-xL, Bcl-w, Mcl1) as co-receptors to recruit Bim for CRL5-mediated ubiquitination, revealing a co-receptor mechanism in CRL5 substrate recognition.

    Evidence Co-IP, mutagenesis of Bcl-xL and Wsb2, ubiquitination assay, knockdown with apoptosis readout (preprint)

    PMID:40832228

    Open questions at the time
    • Not yet peer-reviewed
    • Structural basis of the co-receptor mechanism not determined
    • Whether this pathway operates in specific tissues or is ubiquitous unknown
  22. 2026 Medium

    CUL5 was linked to cancer immune evasion through ubiquitination of the splicing factor PTBP1, which controls RUBCN alternative splicing; CUL5 loss stabilizes PTBP1, shifts RUBCN splicing to inhibit autophagy, and reduces CD8+ T cell-mediated killing of bladder cancer cells.

    Evidence Genome-wide CRISPR screen under T cell pressure, CUL5 KO with PTBP1 ubiquitination assay, splicing analysis, in vivo xenograft with anti-PD-1

    PMID:41662369

    Open questions at the time
    • Substrate receptor mediating PTBP1 ubiquitination by CUL5 not identified
    • Whether CUL5–PTBP1 axis is generalizable beyond bladder cancer unknown
    • Single study without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural and functional map of the CRL5 substrate receptor repertoire, including identification of the full complement of endogenous substrates for each receptor and the in vivo physiological contexts requiring ARIH2-dependent versus ARIH2-independent ubiquitination, remains to be established.
  • Systematic identification of all CUL5 substrates across cell types not performed
  • Structural basis for co-receptor mechanisms (e.g., Wsb2–BCL2) not determined
  • How PKA-dependent phosphorylation at S730 integrates with neddylation dynamics in physiological settings unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016874 ligase activity 6
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 1
Partners
ARIH2ASB11ASB9ELOBELOCLRRC41PCMTD2RBX2
Complex memberships
CRL5 (CUL5-RBX2-ElonginB/C)CRL5-ARIH2

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 HIV-1 Vif interacts with CUL5, Elongin B/C, and Rbx1 to form an SCF-like E3 ubiquitin ligase complex that induces polyubiquitination and proteasomal degradation of APOBEC3G. A Vif mutant that bound APOBEC3G but not CUL5-SCF was functionally inactive, establishing that CUL5-SCF function is required for Vif-mediated APOBEC3G suppression. Co-immunoprecipitation, ubiquitination assay, dominant-negative CUL5 mutant overexpression, Vif point mutants Science High 14564014
2004 SOCS-box proteins (with a BC box followed by a Cul5 box) specifically associate with CUL5-Rbx2, whereas VHL-box proteins associate with CUL2-Rbx1. Domain-swapping analyses showed the specificity of interaction is determined by the Cul2/Cul5 box sequences. RNAi knockdown of CUL5-Rbx2 did not affect VHL-mediated HIF-2α degradation, confirming functional distinction of the two modules. Co-immunoprecipitation with endogenous proteins, domain-swap mutagenesis, RNAi knockdown with substrate degradation readout Genes & development High 15601820
2004 HIV-1 Vif contains a novel SOCS box that mediates interaction with ElonginC, but selective assembly with CUL5 (versus CUL2) additionally requires two conserved cysteine residues outside the SOCS box that interact directly with CUL5. Mutagenesis, Co-immunoprecipitation, functional assays for APOBEC3G suppression Genes & development High 15574593
2004 Vif assembles a CUL5-EloB-EloC SCF-like E3 ubiquitin ligase through a novel SOCS box that binds EloC; Vif binding to EloC is negatively regulated by serine phosphorylation in the BC-box motif. CUL5 promotes Vif autoubiquitination within the assembled complex, analogous to F-box protein autoubiquitination in SCF complexes. Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, phosphorylation mutagenesis Genes & development High 15574592
2001 MUF1, a novel leucine-rich repeat BC-box protein, assembles with CUL5 and Rbx1 to reconstitute E3 ubiquitin ligase activity in vitro. Other BC-box proteins (Elongin A, SOCS1, WSB1) also assemble with CUL5/Rbx1 to form potential E3 ubiquitin ligases. Biochemical purification from rat liver, in vitro reconstitution of ubiquitin ligase activity, Co-immunoprecipitation The Journal of biological chemistry High 11384984
2005 HIV-1 Vif suppresses APOBEC3F by binding it and inducing its polyubiquitination and degradation through the CUL5-containing E3 ubiquitin ligase. Depletion of CUL5 by RNAi or overexpression of CUL5 mutants blocked Vif-mediated APOBEC3F suppression. Interference with CUL5-E3 also stabilized Vif itself, indicating Vif is also a substrate regulated by CUL5-E3 ligase. RNAi knockdown, dominant-negative CUL5 overexpression, ubiquitination assay, protein stability assay Journal of virology High 16014920
2006 HIV-1 Vif is a zinc-binding protein containing an H-x5-C-x17-18-C-x3-5-H (HCCH) motif distinct from known zinc fingers. Zinc-binding stabilizes a conserved hydrophobic interface in this motif required for Vif-CUL5 E3 assembly. An N-terminal region of the first Cullin repeat of CUL5 (dispensable for ElonginC binding, and most divergent between CUL2 and CUL5) is required for Vif interaction, providing a structural basis for selective CUL5 recruitment. Mutagenesis, zinc-binding assays, Co-immunoprecipitation, deletion mapping of CUL5 Virology High 16530799
2008 Detailed structure-function studies of BC-box proteins define Cul2-box and Cul5-box sequences that determine recruitment of CUL2-Rbx1 versus CUL5-Rbx2 modules; the LPPhiP motif conserved in most Cul5-boxes is compatible with CUL2 interaction, and spacing between BC- and Cullin-boxes is flexible (3–80 amino acids). Biochemical reconstitution of a larger collection of CRL complexes validated these rules. Biochemical purification, reconstitution of ubiquitin ligases, structure-function mutagenesis The Journal of biological chemistry High 18187417
2010 HIV-1 Vif binds ElonginB/C (EloBC) at two sites via an induced-folding mechanism: the BC box of Vif binds EloC, and a conserved Pro-Pro-Leu-Pro motif of Vif binds the C-terminal domain of EloB. Both interactions are required to form a functional CUL5-containing ligase complex. Purified protein in vitro binding assays, isothermal titration calorimetry, NMR spectroscopy, cell-based functional assays PLoS pathogens High 20532212
2013 Crystal structures of the ASB9-ElonginB/C ternary complex and the N-terminal domain of CUL5 reveal a distinct architecture where the ankyrin domain of ASB9 is coaxial to the SOCS box-ElonginB/C complex and perpendicular to other repeat-protein complexes; CUL5 itself shows a unique rigid-body rotation between Cullin repeats compared to other Cullins. X-ray crystallography, structural modeling of the full CUL5-based E3 ligase Journal of molecular biology High 23806657
2014 Crystal structure of the Vif-CBF-β-CUL5-ELOB-ELOC pentameric complex reveals that Vif organizes the complex through two domains: an α/β domain that binds CBF-β (competing with RUNX1 binding), and an α-domain whose interactions with ELOC and CUL5 are cooperative and mimic those of SOCS2. A unique zinc-finger motif in Vif stabilizes the α-domain conformation required for CUL5 interaction. X-ray crystallography of the pentameric complex Nature High 24402281
2014 An N-terminal region of Vif (residues 25-30, motif 25VXHXMY30) is required for the Vif-CUL5 interaction; single alanine substitutions in this region reduced CUL5 binding (measured by ITC) and abrogated APOBEC3G/3F degradation and HIV infectivity rescue without disrupting CBF-β or EloB/C binding. Pull-down assays, isothermal titration calorimetry, circular dichroism, size-exclusion chromatography, functional viral infectivity assays Retrovirology High 24422669
2019 The CUL5-RNF7-UBE2F E3 ubiquitin ligase complex (CRL5) proteasomally regulates the levels of BH3-only pro-apoptotic proteins Bim and Noxa. CRISPR knockout of CUL5, RNF7, or UBE2F components accumulated Noxa (responsible for re-sensitization to CDK9 inhibitor) and re-sensitized lung cancer cells to MCL1 and CDK9 inhibitors. Genome-wide CRISPR screens (flow cytometry-based), CRISPR KO with protein level measurement, functional apoptosis assays eLife High 31294695
2019 Cul5-ASB11 functions as the E3 ubiquitin ligase that ubiquitinates the pro-apoptotic protein BIK for degradation. During ER stress, XBP1s (activated by IRE1α) transcriptionally upregulates ASB11, stimulating BIK ubiquitination, interaction with p97/VCP, and proteolysis, thereby promoting cell survival during the adaptive UPR phase. Genotoxic stress suppresses this axis, stabilizing BIK. Co-immunoprecipitation to identify Cul5-ASB11 complex, ubiquitination assays, RNAi knockdown, IRE1α inhibitor experiments, XBP1s overexpression The Journal of cell biology High 31387940
2020 Gossypol inhibits CUL5 neddylation by directly binding to the SAG-CUL5 complex; CUL5-H572 plays a key role in gossypol binding. Biochemical studies showed gossypol blocked neddylation of both CUL5 and CUL1, causing accumulation of NOXA and MCL1 substrates in cancer cells. AlphaScreen high-throughput screen, biochemical neddylation assay, direct binding studies, substrate accumulation in cells Neoplasia High 32145688
2020 The Cul5-type ubiquitin ligase KLHDC1 targets truncated SELENOS (produced by failed UGA/Sec decoding) for proteasomal degradation. Knockdown of KLHDC1 in U2OS cells decreased ER stress-induced cell death, linked to altered ROS levels. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown with functional readout (cell death, ROS) iScience Medium 32200094
2021 Cryo-EM/structural and biochemical analyses reveal that ARIH2 autoinhibition is relieved upon assembly with neddylated CUL5-RBX2. Unlike CUL1-linked NEDD8 which directly recruits ARIH1, CUL5-linked NEDD8 activates ARIH2 allosterically: NEDD8 contacts covalently linked CUL5, eliciting structural rearrangements that expose cryptic ARIH2-binding sites on CUL5. Cryo-EM structures, biochemical reconstitution, structural comparison Nature chemical biology High 34518685
2021 CUL5 neddylation allosterically exposes its ARIH2-binding site, promoting high-affinity ARIH2 binding, while sequestering the NEDD8 E2 (UBE2F) binding site on RBX2. Once ARIH2 binds, helices near its Ariadne domain active site are exposed, relieving autoinhibition. The ASB9-CRL5-ARIH2-UBE2L3 complex ubiquitylates CKB (creatine kinase B), which is also polyubiquitylated by UBE2R1 or UBE2D2. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), in vitro ubiquitination assay with purified components, mass spectrometry site mapping Molecular & cellular proteomics High 33268465
2021 CUL5-ASB6 forms an E3 ubiquitin ligase complex that ubiquitinates p62/SQSTM1 for degradation. Depletion of CUL5 or ASB6 induced p62 accumulation; overexpression of ASB6 promoted ubiquitination and degradation of p62 and inhibited cell proliferation and autophagy. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown and overexpression with proliferation/autophagy readouts Frontiers in cell and developmental biology Medium 34164402
2022 The Rab40b/CUL5 E3 ubiquitin ligase complex ubiquitylates Rap2 (a Ras-like small GTPase). Ubiquitylation regulates Rap2 activation and its recycling from the endolysosomal compartment to lamellipodia of migrating breast cancer cells, thereby controlling Rap2-dependent actin dynamics at the leading edge required for cell migration and invasion. Co-immunoprecipitation, in vitro ubiquitination assay, live-cell imaging of Rap2 localization, cell migration/invasion assays with mutants The Journal of cell biology High 35293963
2022 CUL5 in CD4+ T cells determines fate selection between T helper and T regulatory cells by regulating IL-4 receptor signaling. CUL5 forms a complex with CIS and phospho-Jak1 (pJak1) following T cell activation; CUL5 deletion reduces ubiquitination and degradation of pJak1, leading to increased pJak1 and pSTAT6 levels, which lowers the IL-4 receptor signaling threshold and diverts cells from Treg to Th9 differentiation. Conditional knockout mice (Cul5 deleted in T cells), Co-immunoprecipitation (CUL5-CIS-pJak1 complex), Western blotting of pJak1/pSTAT6, T cell differentiation assays, in vivo allergy/asthma model Nature communications High 35589717
2024 CUL5 negatively regulates central signaling pathways in CD8+ T cells. CUL5 is upregulated by TCR stimulation and forms a complex with PCMTD2 (a SOCS-box-containing protein) to inhibit TCR and IL-2 signaling. Knockout of CUL5 broadly enhances TCR and cytokine signaling and effector functions; neddylation inhibition (required for CUL5 activation) mimics this enhancement. CRISPR-based stepwise screening, conditional KO in CD8+ T cells, Co-immunoprecipitation (CUL5-PCMTD2), proteomic analysis, chemical neddylation inhibition, tumor growth assays Nature communications High 38242867
2000 VACM-1/CUL5 expression in cells inhibits cAMP production (basal and stimulated by forskolin/vasopressin) and stimulates inositol trisphosphate production. This inhibitory effect on cAMP is reversed by mutation of the PKA-dependent phosphorylation site S730A, and is modulated by PKA and PKC inhibitors. Stable cell line expression, cAMP assays, PKA/PKC inhibitors, site-directed mutagenesis (S730A) American journal of physiology. Cell physiology Medium 10898738
2009 PKA-dependent phosphorylation of VACM-1/CUL5 at S730 controls its neddylation status; mutation S730A increases Nedd8 modification of CUL5, and induction of PKA activity with forskolin reduces CUL5 neddylation. Neddylated CUL5 is associated with the proliferative (S730A) phenotype, while PKA phosphorylation of CUL5 suppresses its neddylation and its growth-promoting activity. Co-immunoprecipitation with anti-pPKA antibody, Western blot for Nedd8-modified CUL5, RNAi, PKA activator (forskolin), mutagenesis The Journal of biological chemistry Medium 19917606
2016 A nuclear localization signal (NLS, 640PKLKRQ646) in VACM-1/CUL5 is required for its nuclear localization and its antiproliferative effect. Mutation of NLS residues (K642G, K644G) significantly reduced nuclear localization and compromised growth-inhibitory activity. The NLS is also required for the pro-proliferative effect of the S730A mutant, and nuclear NEDD8 signal but not total neddylation was decreased. Site-directed mutagenesis, immunocytochemistry, cell proliferation assays, Western blot for nuclear fractions Cell and tissue research Medium 27834018
2025 The ASB9-CUL5 E3 ligase complex polyubiquitylates free histones H3 and H4 (but not H2A or H2B) via K48 and K63 chains, driving their degradation. Neddylated ASB9-CRL5 binds histones with highest affinity; histones in nucleosomes or bound to chaperone Asf1 are not ubiquitylated. This is the first example of CUL5-mediated ubiquitylation that does not require an ARIH2 RBR co-E3. In vitro ubiquitination assay with purified components, binding affinity measurements, polyubiquitin chain linkage analysis by mass spectrometry Molecular & cellular proteomics High 41260500
2025 CUL5 is required for steady-state hematopoiesis; mice lacking CUL5 in hematopoietic cells show increased HSPCs, myeloid/megakaryocyte bias, increased HSC proliferation, and reduced CXCR4 surface expression. CUL5 forms a complex with LRRC41 (identified by Co-IP), and CUL5 deletion causes LRRC41 and STAT5 accumulation during IL-3 stimulation; JAK1/2 inhibition with ruxolitinib normalized hematopoiesis, placing CUL5 upstream of JAK/STAT in HSCs. Conditional knockout (Cul5Vav-Cre), Co-immunoprecipitation of CUL5-LRRC41, whole-cell proteomics of HSPCs, JAK inhibitor (ruxolitinib) rescue The Journal of clinical investigation High 40569692
2025 Wsb2 (a SOCS-box substrate receptor of CUL5) uses BCL2 anti-apoptotic proteins as co-receptors to recruit Bim to the Cul5-Wsb2 E3 ligase for ubiquitination and degradation. Wsb2 recognizes Bcl-xl through a conserved motif (shared with Bcl-w and Bcl2 but not Mcl1); mutation of either Bcl-xl or Wsb2 blocks Wsb2 binding to the Bcl-xl/Bim dimer. Wsb2 also associates with the Mcl1/Bim dimer through a separate interface. Co-immunoprecipitation, mutagenesis of Bcl-xl and Wsb2, ubiquitination assay, knockdown with apoptosis readout bioRxivpreprint Medium 40832228
2026 CUL5 ubiquitinates PTBP1; CUL5 loss reduces PTBP1 ubiquitination, which alters alternative splicing of RUBCN pre-mRNA, increasing levels of the RUBCN-S isoform and inhibiting autophagy, thereby reducing immune evasion of bladder cancer cells from CD8+ T cell killing. Genome-wide CRISPR-Cas9 KO screen under CD8+ T cell pressure, CUL5 KO with ubiquitination assay of PTBP1, alternative splicing analysis, in vivo xenograft model with anti-PD-1 PLoS biology Medium 41662369
2021 CUL5 interacts with NAMPT (visfatin) as identified by Co-IP, and CUL5 overexpression inhibits NAMPT expression in H2O2-stimulated human coronary artery endothelial cells, reducing VEGF, MMP2, and phosphorylation of p38 and Akt. Co-immunoprecipitation, overexpression experiments, Western blot Journal of cardiovascular pharmacology Low 34596622

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science (New York, N.Y.) 1006 14564014
2004 VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes & development 409 15601820
2004 Selective assembly of HIV-1 Vif-Cul5-ElonginB-ElonginC E3 ubiquitin ligase complex through a novel SOCS box and upstream cysteines. Genes & development 267 15574593
2004 Phosphorylation of a novel SOCS-box regulates assembly of the HIV-1 Vif-Cul5 complex that promotes APOBEC3G degradation. Genes & development 254 15574592
2014 Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif. Nature 177 24402281
2008 Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. The Journal of biological chemistry 164 18187417
2001 Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase. The Journal of biological chemistry 137 11384984
2005 Regulation of Apobec3F and human immunodeficiency virus type 1 Vif by Vif-Cul5-ElonB/C E3 ubiquitin ligase. Journal of virology 133 16014920
2006 Assembly of HIV-1 Vif-Cul5 E3 ubiquitin ligase through a novel zinc-binding domain-stabilized hydrophobic interface in Vif. Virology 117 16530799
2012 RETRACTED: MicroRNA-19a and -19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5. Cancer letters 112 22561557
2010 The SOCS-box of HIV-1 Vif interacts with ElonginBC by induced-folding to recruit its Cul5-containing ubiquitin ligase complex. PLoS pathogens 68 20532212
2007 Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. European journal of cancer (Oxford, England : 1990) 59 17449237
2021 CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Nature chemical biology 54 34518685
2013 Downregulation of miR-7 upregulates Cullin 5 (CUL5) to facilitate G1/S transition in human hepatocellular carcinoma cells. IUBMB life 49 24339204
1997 Identification and analysis of expression of human VACM-1, a cullin gene family member located on chromosome 11q22-23. Genome research 49 9037604
2003 Analysis of CUL-5 expression in breast epithelial cells, breast cancer cell lines, normal tissues and tumor tissues. Molecular cancer 47 14641918
2007 Polymorphisms of CUL5 are associated with CD4+ T cell loss in HIV-1 infected individuals. PLoS genetics 45 17257057
2015 Downregulation of MicroRNA-145 Caused by Hepatitis B Virus X Protein Promotes Expression of CUL5 and Contributes to Pathogenesis of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 26512974
2000 VACM-1, a cullin gene family member, regulates cellular signaling. American journal of physiology. Cell physiology 34 10898738
2004 T47D breast cancer cell growth is inhibited by expression of VACM-1, a cul-5 gene. Biochemical and biophysical research communications 33 15184056
2013 Molecular architecture of the ankyrin SOCS box family of Cul5-dependent E3 ubiquitin ligases. Journal of molecular biology 30 23806657
2003 VACM-1, a cul-5 gene, inhibits cellular growth by a mechanism that involves MAPK and p53 signaling pathways. American journal of physiology. Cell physiology 29 12917106
2020 Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes. Neoplasia (New York, N.Y.) 28 32145688
2019 The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells. eLife 28 31294695
2006 Estrogen-dependent growth and estrogen receptor (ER)-alpha concentration in T47D breast cancer cells are inhibited by VACM-1, a cul 5 gene. Molecular and cellular biochemistry 28 17186378
1999 VACM-1 receptor is specifically expressed in rabbit vascular endothelium and renal collecting tubule. The American journal of physiology 26 9950950
2018 MicroRNA-19a regulates the proliferation, migration and invasion of human gastric cancer cells by targeting CUL5. Archives of biochemistry and biophysics 23 30521783
2022 Ubiquitylation by Rab40b/Cul5 regulates Rap2 localization and activity during cell migration. The Journal of cell biology 22 35293963
2011 Effect of HIV-1 Vif variability on progression to pediatric AIDS and its association with APOBEC3G and CUL5 polymorphisms. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 22 21571098
2001 Expression of VACM-1 protein in cultured rat adrenal endothelial cells is linked to the cell cycle. Endothelium : journal of endothelial cell research 22 11409851
2021 The Mechanism of NEDD8 Activation of CUL5 Ubiquitin E3 Ligases. Molecular & cellular proteomics : MCP 21 33268465
2019 BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress. The Journal of cell biology 21 31387940
2022 The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation. Nature communications 19 35589717
2007 Expression of VACM-1/cul5 mutant in endothelial cells induces MAPK phosphorylation and maspin degradation and converts cells to the angiogenic phenotype. Microvascular research 19 17950367
2009 Granulocytic differentiation of HL-60 promyelocytic leukemia cells is associated with increased expression of Cul5. In vitro cellular & developmental biology. Animal 18 19118439
2020 Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding. iScience 17 32200094
2009 Phosphorylation of VACM-1/Cul5 by protein kinase A regulates its neddylation and antiproliferative effect. The Journal of biological chemistry 17 19917606
2024 The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells. Nature communications 16 38242867
2001 Vasopressin-activated calcium-mobilizing (VACM-1) receptor mRNA is present in peripheral organs and the central nervous system of the laboratory rat. Endocrine research 16 11794467
2016 Nuclear localization signal sequence is required for VACM-1/CUL5-dependent regulation of cellular growth. Cell and tissue research 15 27834018
2014 HIV-1 Vif N-terminal motif is required for recruitment of Cul5 to suppress APOBEC3. Retrovirology 15 24422669
2012 APOBEC3-mediated editing in HIV type 1 from pediatric patients and its association with APOBEC3G/CUL5 polymorphisms and Vif variability. AIDS research and human retroviruses 15 22145963
2010 Resveratrol enhances anti-proliferative effect of VACM-1/cul5 in T47D cancer cells. Cell biology and toxicology 15 20949323
2010 Reduced cul-5 activity causes aberrant follicular morphogenesis and germ cell loss in Drosophila oogenesis. PloS one 14 20140218
2021 CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy. Frontiers in cell and developmental biology 13 34164402
2010 Essential role for the d-Asb11 cul5 Box domain for proper notch signaling and neural cell fate decisions in vivo. PloS one 13 21124961
2003 Osmotic stress increases cullin-5 (cul-5) mRNA in the rat cerebral cortex, hypothalamus and kidney. Neuroscience research 11 12631466
2020 miR-19a promotes the metastasis and EMT through CUL5 in prostate cancer cell line PC3. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 9 33099949
2021 CUL5-Mediated Visfatin (NAMPT) Degradation Blocks Endothelial Proliferation and Angiogenesis via the MAPK/PI3K-AKT Signaling. Journal of cardiovascular pharmacology 8 34596622
2011 Mutational analysis of VACM-1/cul5 exons in cancer cell lines. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 8 21635549
2012 VACM-1/cul5 expression in vascular tissue in vivo is induced by water deprivation and its expression in vitro regulates aquaporin-1 concentrations. Cell and tissue research 7 22581383
2012 Aquaporin-2 levels in vitro and in vivo are regulated by VACM-1, a cul 5 gene. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 7 23171819
2022 Cul5 mediates taurine-stimulated mTOR mRNA expression and proliferation of mouse mammary epithelial cells. Amino acids 6 36449095
2018 CUL5 is required for thalidomide-dependent inhibition of cellular proliferation. PloS one 6 29746508
2018 Comparative Analysis of cul5 and rbx2 Expression in the Developing and Adult Murine Brain and Their Essentiality During Mouse Embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 5 30269386
2014 New insights into the mechanism for VACM-1/cul5 expression in vascular tissue in vivo. International review of cell and molecular biology 5 25376490
2006 Truncated form of VACM-1/cul-5 with an extended 3' untranslated region stimulates cell growth via a MAPK-dependent pathway. Biochemical and biophysical research communications 4 16581022
2025 The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice. The Journal of clinical investigation 3 40569692
2021 Retraction notice to "MicroRNA-19a and -19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5" [Canc. Lett. 322 (2012) 148-158]. Cancer letters 1 34274168
2017 CUL5 and APOBEC3G Polymorphisms are Partially Implicated in HIV-1 Infection and Antiretroviral Therapy in a Brazilian Population. Current HIV research 1 28302043
2026 CUL5 E3 ubiquitin ligase regulates the evasion of bladder cancer cells to CD8+ T cell-mediated killing by inhibiting autophagy. PLoS biology 0 41662369
2026 Regulation of Cellular Signaling by CUL5 is Dependent on Its Neddylation Status. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 0 41797611
2025 The Mechanism of Histone Ubiquitylation by the ASB9-CUL5 Ubiquitin Ligase. bioRxiv : the preprint server for biology 0 40501794
2025 Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation. bioRxiv : the preprint server for biology 0 40832228
2025 The Mechanism of Histone Ubiquitylation by the ASB9-CUL5 Ubiquitin Ligase. Molecular & cellular proteomics : MCP 0 41260500
2024 Selection and characterization of aptamers targeting the Vif-CBFβ-ELOB-ELOC-CUL5 complex. Journal of biochemistry 0 38740386