Affinage

CUL5

Cullin-5 · UniProt Q93034

Length
780 aa
Mass
91.0 kDa
Annotated
2026-06-09
68 papers in source corpus 34 papers cited in narrative 34 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

CUL5 is the scaffold subunit of Cullin-RING E3 ubiquitin ligase complexes (CRL5) that target diverse substrates for proteasomal degradation, thereby controlling antiviral defense, apoptosis, T cell and hematopoietic cell fate, cell migration, and proliferation (PMID:14564014, PMID:11384984, PMID:35589717). CUL5 assembles with RBX2/RNF7 and the Elongin B/C adaptor module, which docks SOCS-box-containing substrate receptors via a BC-box, while a distinct Cul5-box determines selective CUL5 (versus CUL2) recruitment (PMID:15601820, PMID:11384984, PMID:18187417). Through this architecture CUL5 partners with a broad family of substrate receptors—including ASB proteins (ASB9, ASB11, ASB6), CIS, WSB2, KLHDC1, gustavus, Rab40b, PCMTD2, and LRRC41—each delivering specific substrates such as creatine kinase, the pro-apoptotic BH3-only proteins BIK, Bim, and Noxa, p62/SQSTM1, truncated SELENOS, the GTPase Rap2, phospho-Jak1, STAT5, and PTBP1 (PMID:23806657, PMID:31294695, PMID:31387940, PMID:35293963, PMID:35589717, PMID:32200094, PMID:34164402, PMID:40569692, PMID:40832228). CRL5 activity is gated by NEDD8 conjugation of CUL5 (at Lys724 and additional sites), which allosterically remodels CUL5 to expose a cryptic binding site for the co-E3 ARIH2 while sequestering the NEDD8 E2 UBE2F site on RBX2, although some substrates such as free histones H3/H4 are ubiquitylated ARIH2-independently (PMID:34518685, PMID:33268465, PMID:41260500, PMID:41797611). HIV-1 Vif hijacks this machinery as a SOCS-box mimic, using a zinc-coordinated HCCH motif, CBF-β binding, and cooperative ELOC/CUL5 contacts to reconstitute a CRL5 that degrades the antiviral cytidine deaminases APOBEC3G and APOBEC3F (PMID:14564014, PMID:16014920, PMID:16530799, PMID:24402281). CUL5 substrate selection is exploited physiologically to set signaling thresholds: CRL5-CIS degrades phospho-Jak1 to bias CD4+ T cell fate, CRL5 restrains TCR/IL-2 signaling in CD8+ T cells via PCMTD2, and CRL5-LRRC41 limits STAT5 to maintain hematopoietic stem cell homeostasis (PMID:35589717, PMID:38242867, PMID:40569692).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Established that CUL5 is a functional E3 ligase scaffold, answering whether it could nucleate ubiquitin ligase activity with substrate receptors.

    Evidence In vitro reconstitution of ubiquitin ligase activity from CUL5/Rbx1 with purified BC-box proteins (MUF1, Elongin A, SOCS1, WSB1) from rat liver

    PMID:11384984

    Open questions at the time
    • Did not define which physiological substrates are targeted
    • Did not establish CUL5-versus-CUL2 specificity determinants
  2. 2003 High

    Showed that HIV-1 Vif coopts a CUL5-Elongin B/C-Rbx1 ligase to degrade APOBEC3G, defining the first biologically critical CRL5 substrate axis.

    Evidence Co-IP, in vivo ubiquitination, dominant-negative CUL5 and Vif point mutants

    PMID:14564014

    Open questions at the time
    • Atomic basis of Vif-CUL5 selectivity unresolved
    • Did not address host substrate receptors
  3. 2004 High

    Defined the molecular code for CUL5-specific receptor recruitment, distinguishing CRL5 from CRL2 assembly.

    Evidence Reciprocal Co-IP, domain-swapping mutagenesis, and RNAi separating Cul5-box/SOCS-box from VHL-box/Cul2-box; characterization of Vif's atypical SOCS box and additional Cys-dependent CUL5 contacts and autoubiquitination

    PMID:15574592 PMID:15574593 PMID:15601820

    Open questions at the time
    • LPPhiP motif alone does not fully dictate Cullin choice
    • Structural mechanism of selectivity not yet visualized
  4. 2006 High

    Pinpointed the zinc-coordinated HCCH motif of Vif and the divergent N-terminal CUL5 region as the basis of selective viral CRL5 assembly.

    Evidence Zinc-binding biochemistry, mutagenesis, and CUL5 deletion analysis with Co-IP

    PMID:16530799

    Open questions at the time
    • Mechanism extended to APOBEC3F via RNAi/dominant-negative but degradation kinetics not resolved [#16014920]
  5. 2008 High

    Systematically defined how BC-box-to-Cullin-box spacing and motif variation govern receptor assembly across the BC-box protein family.

    Evidence Purification of BC-box proteins with structure-function mutagenesis and in vitro ligase reconstitution

    PMID:18187417

    Open questions at the time
    • Did not assign specific physiological substrates to each receptor
  6. 2014 High

    Provided atomic-level visualization of the Vif-CBF-β-CUL5-ELOB-ELOC pentamer, explaining cooperative ELOC/CUL5 engagement and SOCS2 mimicry.

    Evidence X-ray crystallography of the pentameric complex; complemented by earlier ITC/NMR mapping of dual EloBC contacts and ASB9/CUL5 structural architecture

    PMID:20532212 PMID:23806657 PMID:24402281

    Open questions at the time
    • Did not capture the neddylated, catalytically active state
    • Substrate positioning relative to E2 inferred, not directly observed
  7. 2021 High

    Resolved how NEDD8 activates CRL5, establishing a cullin-specific allosteric mechanism distinct from CRL1.

    Evidence Cryo-EM, HDX-MS, and reconstituted ubiquitination showing NEDD8 allosterically exposes the ARIH2 site and sequesters the UBE2F site on RBX2; ASB9-CRL5-ARIH2-UBE2L3 ubiquitylates CKB

    PMID:33268465 PMID:34518685

    Open questions at the time
    • Did not establish which substrates strictly require ARIH2 versus act independently
  8. 2022 High

    Demonstrated CRL5 as a tunable rheostat for immune-cell signaling and cytoskeletal control through receptor-specific substrate choice.

    Evidence Conditional Cul5 knockout mice and Co-IP defining CRL5-CIS-pJak1 control of CD4+ T cell fate; ubiquitination/imaging defining Rab40b-CUL5 control of Rap2 and migration

    PMID:35293963 PMID:35589717

    Open questions at the time
    • In vivo substrate specificity for additional receptors not mapped
    • Direct ubiquitination kinetics in primary cells not resolved
  9. 2024 High

    Established CUL5 as a brake on CD8+ T cell anti-tumor activity, linking neddylation-dependent CRL5 activity to immunotherapy.

    Evidence CRISPR screening, CUL5 knockout, proteomics, CUL5-PCMTD2 Co-IP, MLN4924 treatment, and tumor models

    PMID:38242867

    Open questions at the time
    • Direct PCMTD2 substrate(s) not fully enumerated
    • Relationship to other CRL5 immune substrates unclear
  10. 2025 High

    Extended CRL5 substrate scope to hematopoietic homeostasis and to ARIH2-independent ubiquitylation of free histones.

    Evidence Conditional Cul5 knockout mice with reciprocal CUL5-LRRC41 Co-IP and proteomics linking CUL5 to STAT5/LRRC41; in vitro reconstitution and MS showing neddylated ASB9-CRL5 ubiquitylates free H3/H4 ARIH2-independently

    PMID:40569692 PMID:41260500

    Open questions at the time
    • Whether LRRC41 is a direct substrate or co-receptor not fully resolved
    • Cellular consequences of free-histone ubiquitylation not established in vivo
  11. 2026 Medium

    Connected CRL5 substrate control to mRNA splicing, autophagy, and tumor immune evasion, and refined the neddylation sites governing its growth-regulatory output.

    Evidence CRISPR screen under CD8+ T cell pressure with PTBP1 ubiquitination and RUBCN splicing analysis; site-directed mutagenesis showing Lys724/K727/K728 neddylation dictates antiproliferative activity

    PMID:41662369 PMID:41797611

    Open questions at the time
    • PTBP1 receptor not identified
    • Mechanistic link between neddylation site occupancy and substrate selection incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how individual SOCS-box receptors and upstream signals are coordinated to select among the large CRL5 substrate repertoire in a given cell type, and how non-canonical CUL5 signaling functions (cAMP/IP3 modulation, nuclear localization) integrate with its ligase activity.
  • No unified model linking receptor abundance to substrate prioritization
  • Mechanism of reported nuclear/signaling roles not connected to E3 activity

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0016874 ligase activity 4 GO:0031386 protein tag activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2
Partners
ARIH2ASB11ASB9CISELONGIN B/CLRRC41RBX2/RNF7UBE2F
Complex memberships
ASB9-CRL5-ARIH2 ligaseCRL5 (CUL5-RBX2/RNF7-Elongin B/C E3 ubiquitin ligase)Vif-CBF-β-CUL5-ELOB-ELOC complex

Evidence

Reading pass · 34 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 ubiquitinates and degrades APOBEC3G/CEM15. A Vif mutant that retained APOBEC3G binding but lost CUL5-SCF interaction was functionally inactive, establishing CUL5-SCF as required for Vif-mediated APOBEC3G degradation. Co-immunoprecipitation, ubiquitination assay, dominant-negative CUL5 mutants, Vif point mutants Science High 14564014
2004 SOCS-box proteins (containing a BC box and downstream Cul5-box) specifically assemble with CUL5-Rbx2, whereas VHL-box proteins assemble with Cul2-Rbx1. Domain-swapping showed that the Cul5-box and Cul2-box sequences determine which Cullin-Rbx module is recruited. RNAi knockdown of Cul5-Rbx2 did not affect VHL-mediated HIF-2α degradation, confirming functional distinction. Co-immunoprecipitation, domain-swapping mutagenesis, RNAi knockdown Genes & development High 15601820
2004 HIV-1 Vif contains a novel SOCS-box in which alanine replaces the consensus cysteine; this SOCS box mediates interaction with Elongin C, but two conserved Cys residues outside the SOCS box are additionally required for interaction with CUL5 (not Elongin C), establishing that selective CUL5 assembly requires protein interfaces beyond the SOCS-box–Elongin C interaction. Mutagenesis, co-immunoprecipitation, pulldown assays Genes & development High 15574593
2004 Vif recruits CUL5-EloB-EloC through a novel SOCS-box that binds EloC. Serine phosphorylation in the BC-box motif negatively regulates Vif binding to EloC. Vif itself is autoubiquitinated within the assembled Vif-CUL5 complex, analogous to F-box protein autoubiquitination within SCF complexes. Co-immunoprecipitation, in vitro and in vivo ubiquitination assays, phosphorylation analysis, mutagenesis Genes & development High 15574592
2005 HIV-1 Vif exploits the CUL5-E3 ligase to ubiquitinate and degrade both APOBEC3F and APOBEC3G. Depletion of CUL5 by RNAi or overexpression of dominant-negative CUL5 mutants blocked Vif-mediated suppression of APOBEC3F. Vif stability itself is also regulated by CUL5-E3 ligase, suggesting the viral substrate receptor is itself a CUL5 substrate. RNA interference, dominant-negative CUL5 mutants, co-immunoprecipitation, ubiquitination assay Journal of virology High 16014920
2006 HIV-1 Vif is a zinc-binding protein containing an H-x(5)-C-x(17-18)-C-x(3-5)-H (HCCH) motif. Zinc coordination stabilizes a conserved hydrophobic interface within the HCCH motif critical for Vif-CUL5 E3 assembly. An N-terminal region of the first Cullin repeat of CUL5, dispensable for Elongin C binding, is required for Vif interaction, and this region is the most divergent between CUL2 and CUL5. Zinc-binding characterization, mutagenesis, co-immunoprecipitation, deletion analysis of CUL5 Virology High 16530799
2001 MUF1, a novel leucine-rich repeat BC-box protein purified from rat liver, assembles with CUL5 and Rbx1 to reconstitute ubiquitin ligase activity in vitro. Elongin A, SOCS1, and WSB1 were also shown to assemble with the CUL5/Rbx1 module to reconstitute potential E3 ligases. Protein purification from rat liver, in vitro reconstitution of ubiquitin ligase activity, biochemical assembly assays The Journal of biological chemistry High 11384984
2008 Structure-function studies of BC-box proteins define CUL5-box and CUL2-box sequences in detail. The spacing between BC-box and Cullin-box can vary widely (3 to ~80 amino acids). The LPPhiP motif conserved in most Cul5-boxes is also compatible with Cul2 interaction, indicating the motif alone does not determine Cullin specificity. Purification of BC-box proteins, structure-function mutagenesis, biochemical reconstitution of ubiquitin ligases The Journal of biological chemistry High 18187417
2010 HIV-1 Vif binds ElonginBC (EloBC) at two locations via an induced-folding mechanism: (1) the established BC-box binding to EloC, and (2) a novel interaction between the conserved Pro-Pro-Leu-Pro (PPLP) motif of Vif and the C-terminal domain of EloB. Both interactions are required for formation of a functional CUL5-containing ligase complex. Purified protein binding assays, isothermal titration calorimetry, NMR spectroscopy, cell-based functional assays PLoS pathogens High 20532212
2014 Crystal structure of the Vif-CBF-β-CUL5-ELOB-ELOC pentameric complex revealed that Vif uses two domains to organize complex formation: an α/β domain binds CBF-β (competing with RUNX1), and an α-domain contacts both ELOC and CUL5 cooperatively, mimicking SOCS2 interactions. A unique zinc-finger motif of Vif stabilizes the α-domain conformation required for CUL5 interaction. X-ray crystallography (crystal structure), structural analysis Nature High 24402281
2013 Crystal structures of the ASB9-Elongin B/C ternary complex and the N-terminal domain of CUL5 reveal that ankyrin repeat SOCS-box proteins (ASBs) assemble with EloBC and CUL5 in a distinct architecture where the ankyrin domain is coaxial to the SOCS box-EloBC complex, positioning the substrate-binding site to face the E2-ubiquitin. The CUL5 structure showed a rigid-body rotation between Cullin repeats distinguishing it from other Cullins. X-ray crystallography, structural modeling of complete CUL5-based E3 ligase Journal of molecular biology High 23806657
2021 CUL5-RBX2-based E3 ligases partner with ARIH2 (RBR E3) for substrate ubiquitylation. CUL5-linked NEDD8 does not directly recruit ARIH2 (unlike CUL1-linked NEDD8 recruiting ARIH1); instead, NEDD8 allosterically rearranges CUL5 to expose cryptic ARIH2-binding sites, revealing a cullin-specific indirect allosteric activation mechanism. Cryo-EM structure, biochemical assembly assays, structural comparison with ARIH1-CUL1 complex Nature chemical biology High 34518685
2021 CUL5 neddylation allosterically exposes its ARIH2-binding site, promoting high-affinity ARIH2 binding, and simultaneously sequesters the NEDD8 E2 (UBE2F) binding site on RBX2. ASB9-CRL5 ubiquitylates its substrate CKB via the ASB9-CRL5-ARIH2-UBE2L3 complex; additional E2s (UBE2R1, UBE2D2) contribute to polyubiquitylation but do not alter ubiquitylation sites. In vitro ubiquitination assay, hydrogen-deuterium exchange mass spectrometry (HDX-MS), mass spectrometry analysis of ubiquitylation sites Molecular & cellular proteomics High 33268465
2019 CUL5, RNF7, and UBE2F form a CRL5 complex that proteasomally regulates levels of BH3-only pro-apoptotic proteins Bim and Noxa. Loss of CRL5 components re-sensitizes lung cancer cells to CDK9 and MCL1 inhibitors. Noxa accumulation upon CRL5 depletion is responsible for re-sensitization to CDK9 inhibitor. Genome-wide CRISPR screen (flow cytometry-based), genetic knockouts, protein level analysis eLife High 31294695
2019 CUL5-ASB11 is an E3 ubiquitin ligase that ubiquitinates BIK (pro-apoptotic BH3-only protein) for proteasomal degradation. During ER stress, XBP1s activates ASB11, promoting BIK ubiquitination and interaction with p97/VCP, enabling ER stress adaptation (cell survival). Genotoxic agents down-regulate the IRE1α-XBP1s-ASB11 axis, stabilizing BIK and promoting apoptosis. Co-immunoprecipitation, ubiquitination assay, knockdown/knockout experiments, cell death assays, IRE1α inhibitor treatment The Journal of cell biology High 31387940
2022 The Rab40b/CUL5 complex ubiquitylates the small GTPase Rap2. This ubiquitylation regulates Rap2 activation state and its recycling from the endolysosomal compartment to the lamellipodia of migrating breast cancer cells, controlling Rap2-dependent actin dynamics at the leading edge required for cell migration and invasion. Co-immunoprecipitation, ubiquitination assay, live-cell imaging, loss-of-function experiments, cell migration/invasion assays The Journal of cell biology High 35293963
2022 CUL5 determines CD4+ T cell fate between T helper and T regulatory cells by regulating IL-4 receptor signaling. Upon T cell activation, CUL5 forms a complex with CIS (SOCS-box protein) and phospho-Jak1 (pJak1). CUL5 deletion reduces ubiquitination and degradation of pJak1, elevating pJak1 and pSTAT6 levels and lowering the threshold for IL-4 receptor signaling, diverting cells from Treg to Th9 fate. Conditional knockout mice (Cul5 fl/fl x CD4-Cre), co-immunoprecipitation of CUL5-CIS-pJak1 complex, Western blot for pJak1/pSTAT6, T cell differentiation assays, in vivo asthma model Nature communications High 35589717
2024 CUL5 is a negative regulator of TCR and cytokine (IL-2) signaling in CD8+ T cells. CUL5 is upregulated by TCR stimulation and interacts with SOCS-box-containing protein PCMTD2 to inhibit signaling. CUL5 knockout enhances CD8+ T cell anti-tumor activity. Neddylation inhibition (MLN4924), which blocks CUL5 activation, similarly enhances CD8+ effector activities with CUL5 validated as a major target. CRISPR-based stepwise screening, CUL5 knockout in mouse CD8+ T cells, proteomics, co-immunoprecipitation (CUL5-PCMTD2), neddylation inhibitor (MLN4924), tumor growth assays Nature communications High 38242867
2020 The CUL5-type ubiquitin ligase KLHDC1 targets truncated SELENOS (a selenoprotein lacking selenocysteine due to failed UGA/Sec decoding) for proteasomal degradation. KLHDC1 knockdown in U2OS cells decreased ER stress-induced cell death and increased the population with lower ROS levels. Protein interaction assays, knockdown experiments, flow cytometry for ROS/cell death, proteasome inhibition assays iScience Medium 32200094
2021 CUL5-ASB6 complex acts as an E3 ubiquitin ligase mediating p62/SQSTM1 ubiquitination and proteasomal degradation. Depletion of CUL5 or ASB6 induced p62 accumulation; ASB6 overexpression promoted p62 ubiquitination and degradation, inhibited cell proliferation, and impaired autophagy. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown, overexpression, cell proliferation and autophagy assays Frontiers in cell and developmental biology Medium 34164402
2020 Gossypol inhibits CUL5 neddylation by directly binding to the SAG-CUL5 complex (with CUL5-H572 playing a key role in gossypol binding), blocking CUL5 E3 ligase activation and causing accumulation of NOXA (a CUL5 substrate) in cancer cells. AlphaScreen high-throughput in vitro neddylation assay, biochemical binding studies, compound library screen, cellular substrate accumulation assays Neoplasia Medium 32145688
2009 PKA-dependent phosphorylation of VACM-1/CUL5 at Ser730 controls its neddylation status. Mutation S730A increases NEDD8 modification of CUL5 and is associated with increased cellular growth. Induction of PKA activity with forskolin reduced NEDD8 modification of CUL5. PKC activity further promotes growth in S730A-CUL5 cells. Site-directed mutagenesis, Western blot with phospho-specific and NEDD8 antibodies, immunoprecipitation, cell growth assays, PKA/PKC agonists/inhibitors The Journal of biological chemistry Medium 19917606
2000 VACM-1/CUL5 expression inhibits basal and stimulated cAMP production in a PKA-dependent manner. Mutation at the PKA phosphorylation site (S730A) reverses the inhibitory effect on cAMP. VACM-1 expression also stimulates inositol 1,4,5-trisphosphate (IP3) production in response to AVP, establishing CUL5 as a regulator of cAMP and calcium signaling pathways. Stable cell line overexpression, cAMP assays, IP3 assays, PKA/PKC inhibitor treatments, site-directed mutagenesis American journal of physiology. Cell physiology Medium 10898738
2025 In hematopoietic stem cells, CUL5 forms a complex with LRRC41 (identified by reciprocal Co-IP), and CUL5 regulates STAT5 and LRRC41 protein levels during IL-3 stimulation. Mice lacking CUL5 in hematopoietic cells (Cul5Vav-Cre) accumulate LRRC41 and STAT5 during IL-3 stimulation, display myeloid/megakaryocyte-biased differentiation, increased HSC proliferation, and reduced CXCR4 surface expression. JAK1/2 inhibition (ruxolitinib) normalizes hematopoiesis. Conditional knockout mice (Cul5Vav-Cre), reciprocal co-immunoprecipitation (CUL5-LRRC41), whole-cell proteomics, cytokine stimulation assays, flow cytometry, ruxolitinib rescue The Journal of clinical investigation High 40569692
2016 A nuclear localization signal (NLS: 640PKLKRQ646) in VACM-1/CUL5 is required for its nuclear translocation and antiproliferative effect. Mutation of Lys642 and Lys644 to Gly significantly reduced nuclear localization and compromised the growth-inhibitory effect. The NLS also controls the proliferative phenotype and nuclear NEDD8 signal of the S730A-CUL5 mutant. Site-directed mutagenesis, immunocytochemistry, cell growth assays, Western blot for neddylation Cell and tissue research Medium 27834018
2012 VACM-1/CUL5 expression in vitro reduces aquaporin-1 (AQP1) protein levels (~6-fold) in COS-1 cells. In vivo, water deprivation increases CUL5 NEDD8 modification in vascular tissue, and AQP1 levels are inversely correlated with the ratio of neddylated to total VACM-1/CUL5, suggesting CUL5 regulates endothelial AQP1 concentration. Microarray, transfection with VACM-1 cDNA, Western blot, immunocytochemistry, in vivo water deprivation model Cell and tissue research Low 22581383
2012 VACM-1/CUL5 expression decreases AQP2 protein concentration in MDCK cells stably expressing AQP2 and in COS-1 cells co-transfected with AQP2 and VACM-1 cDNAs. In water-deprived rat kidneys, decreased CUL5 protein correlates with increased AQP2 levels in collecting duct. Overexpression/co-transfection, Western blot, immunocytochemistry, in vivo water deprivation Cellular physiology and biochemistry Low 23171819
2010 In Drosophila oogenesis, reduced CUL-5 activity causes aberrant follicle formation with excess germ cells, overproliferation of germ line cells, defective cyst encapsulation, and germ cell depletion. These phenotypes are enhanced by reduced activity of gustavus (a SOCS-box-containing substrate receptor of CUL5-based E3 ligases), establishing CUL5/Gus E3 complexes as required for germ cell proliferation, maintenance, and follicular morphogenesis. Drosophila genetics (cul-5 loss-of-function mutants, gustavus mutants, genetic epistasis), histology, immunofluorescence PloS one Medium 20140218
2010 In zebrafish, d-Asb11 requires its CUL5-box domain to function as part of a CUL5-based E3 ligase. Zebrafish mutants lacking the Asb11 Cul5-box fail to degrade the Notch ligand DeltaA, impair Notch target gene expression, and show defective cell fate specification in neurogenic regions, demonstrating that the CUL5-box is required for Notch signaling and neurogenesis in vivo. Zebrafish genetics (Cul5-box mutant), Notch reporter assays, immunostaining for DeltaA, RNA injection rescue experiments PloS one Medium 21124961
2025 ASB9-CRL5 ubiquitylates histones H3 and H4 (but not H2A or H2B) via K48 and K63 polyubiquitin chains, targeting free histones for degradation. Neddylated ASB9-CRL5 binds histones with highest affinity via electrostatic interactions. Histones in nucleosomes or bound to chaperone Asf1 are not ubiquitylated. This CUL5-mediated ubiquitylation does not require the RING-between-RING helper ligase ARIH2, representing the first example of ARIH2-independent CUL5-mediated ubiquitylation. In vitro ubiquitination reconstitution, mass spectrometry for ubiquitylation sites and chain types, binding experiments, neddylated vs. unneddylated complex comparison Molecular & cellular proteomics High 41260500
2025 The E3 ligase Cul5-Wsb2 uses BCL2 family proteins (Bcl-xl, Bcl-w, Bcl2 — but not Mcl1) as co-receptors to target Bim for ubiquitination and degradation. Wsb2 recognizes Bcl-xl through a conserved motif; disruption of this interaction prevents Wsb2 binding to the Bcl-xl/Bim dimer and blocks Bim degradation. Wsb2 contacts the Mcl1/Bim dimer through a separate Wsb2 interface. Co-immunoprecipitation, mutagenesis of Bcl-xl and Wsb2, ubiquitination assays, knockdown cell viability assays bioRxivpreprint Medium 40832228
2021 CUL5 interacts with NAMPT (Visfatin) as shown by co-immunoprecipitation, and CUL5 promotes NAMPT degradation. CUL5 overexpression in H2O2-stimulated human coronary artery endothelial cells reduces phosphorylation of p38 and Akt and decreases VEGF and MMP2 protein levels, inhibiting angiogenic functions. Co-immunoprecipitation, overexpression, Western blot for pAkt/p38/VEGF/MMP2, cell viability/migration/tube formation assays Journal of cardiovascular pharmacology Low 34596622
2026 CUL5 loss in bladder cancer cells reduces ubiquitination of PTBP1. Loss of PTBP1 ubiquitination alters alternative splicing of RUBCN pre-mRNA, increasing the RUBCN-S isoform, which inhibits autophagy and thereby prevents immune evasion from CD8+ T cell-mediated killing. Genome-wide CRISPR-Cas9 screen under CD8+ T cell pressure, ubiquitination assay, alternative splicing analysis, in vivo xenograft with anti-PD-1 combination PLoS biology Medium 41662369
2026 CUL5 neddylation at Lys724 is critical for its antiproliferative effect; K724R mutation converts CUL5 from a growth inhibitor to a growth promoter in endothelial and cancer cells. Multi-site neddylation (at K724, K727, K728) contributes to CUL5's regulatory effects. In T47D cells, MAPK phosphorylation and ERα expression are directly correlated with CUL5 neddylation status. Site-directed mutagenesis of neddylation sites, cell proliferation assays, Western blot, MLN4924 neddylation inhibitor, immunoprecipitation Cellular physiology and biochemistry Medium 41797611

Source papers

Stage 0 corpus · 68 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.) 1008 14564014
2004 VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes & development 411 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 269 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 178 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 168 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 138 11384984
2005 Regulation of Apobec3F and human immunodeficiency virus type 1 Vif by Vif-Cul5-ElonB/C E3 ubiquitin ligase. Journal of virology 134 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 69 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) 60 17449237
2021 CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Nature chemical biology 58 34518685
2013 Downregulation of miR-7 upregulates Cullin 5 (CUL5) to facilitate G1/S transition in human hepatocellular carcinoma cells. IUBMB life 51 24339204
1997 Identification and analysis of expression of human VACM-1, a cullin gene family member located on chromosome 11q22-23. Genome research 50 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 46 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 39 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
2019 The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells. eLife 31 31294695
2020 Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes. Neoplasia (New York, N.Y.) 30 32145688
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 30 12917106
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 24 30521783
2022 Ubiquitylation by Rab40b/Cul5 regulates Rap2 localization and activity during cell migration. The Journal of cell biology 23 35293963
2021 The Mechanism of NEDD8 Activation of CUL5 Ubiquitin E3 Ligases. Molecular & cellular proteomics : MCP 23 33268465
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
2022 The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation. Nature communications 21 35589717
2019 BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress. The Journal of cell biology 21 31387940
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 20 17950367
2024 The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells. Nature communications 19 38242867
2020 Cul5-type Ubiquitin Ligase KLHDC1 Contributes to the Elimination of Truncated SELENOS Produced by Failed UGA/Sec Decoding. iScience 19 32200094
2009 Granulocytic differentiation of HL-60 promyelocytic leukemia cells is associated with increased expression of Cul5. In vitro cellular & developmental biology. Animal 18 19118439
2009 Phosphorylation of VACM-1/Cul5 by protein kinase A regulates its neddylation and antiproliferative effect. The Journal of biological chemistry 17 19917606
2016 Nuclear localization signal sequence is required for VACM-1/CUL5-dependent regulation of cellular growth. Cell and tissue research 16 27834018
2010 Resveratrol enhances anti-proliferative effect of VACM-1/cul5 in T47D cancer cells. Cell biology and toxicology 16 20949323
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
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
2021 CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy. Frontiers in cell and developmental biology 14 34164402
2010 Reduced cul-5 activity causes aberrant follicular morphogenesis and germ cell loss in Drosophila oogenesis. PloS one 14 20140218
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 12 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 10 33099949
2021 CUL5-Mediated Visfatin (NAMPT) Degradation Blocks Endothelial Proliferation and Angiogenesis via the MAPK/PI3K-AKT Signaling. Journal of cardiovascular pharmacology 9 34596622
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 8 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 8 23171819
2011 Mutational analysis of VACM-1/cul5 exons in cancer cell lines. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 8 21635549
2022 Cul5 mediates taurine-stimulated mTOR mRNA expression and proliferation of mouse mammary epithelial cells. Amino acids 7 36449095
2018 CUL5 is required for thalidomide-dependent inhibition of cellular proliferation. PloS one 7 29746508
2014 New insights into the mechanism for VACM-1/cul5 expression in vascular tissue in vivo. International review of cell and molecular biology 6 25376490
2025 The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice. The Journal of clinical investigation 5 40569692
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
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
2026 CUL5 E3 ubiquitin ligase regulates the evasion of bladder cancer cells to CD8+ T cell-mediated killing by inhibiting autophagy. PLoS biology 1 41662369
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 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
2026 Cul5: immune cell function and therapeutic potential. Frontiers in immunology 0 42064089
2026 CUL5-mediated ubiquitination in cancer cell therapy: context-dependent roles, molecular networks, and emerging therapeutic avenues. Frontiers in medicine 0 42078440
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

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