Affinage

UBR4

E3 ubiquitin-protein ligase UBR4 · UniProt Q5T4S7

Length
5183 aa
Mass
573.8 kDa
Annotated
2026-04-28
43 papers in source corpus 28 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBR4 is a giant (~570 kDa) E3/E4 ubiquitin ligase of the N-degron pathway that functions as a central hub for protein quality control, endosomal trafficking, and signal-dependent proteolysis across diverse cell types. Its UBR box recognizes type-1 and type-2 N-degrons through a structurally distinct hydrophobic surface (PMID:38030679), while a hemiRING catalytic module recruits UBE2A/UBE2B E2 enzymes (PMID:38182926); UBR4 assembles with KCMF1 and calmodulin into a 1.3-MDa ring complex that acts as an E4 ligase extending K48-linked polyubiquitin chains on pre-ubiquitinated and orphan protein substrates (PMID:40875847). UBR4 is essential for embryonic development—knockout causes lethality with defective vascular angiogenesis, neurogenesis, and cardiovascular morphogenesis—and regulates autophagy, multivesicular body biogenesis, Golgi vesicle budding (via Coronin 7), cell surface protein turnover through the endosome–lysosome pathway, and myofiber size homeostasis (PMID:23431188, PMID:30157281, PMID:35332162, PMID:31365869). Identified substrates include the HAT1/RBBP4/RBBP7 complex, EZH2, MLH1, HRI kinase, procaspase-8, MAPK (Drosophila), and podocin, and UBR4 is co-opted by dengue virus NS5, influenza M2, and HPV E7 to redirect its ubiquitin ligase activity toward host immune and signaling proteins (PMID:36906655, PMID:39032648, PMID:41548766, PMID:39099191, PMID:27552662, PMID:23555265, PMID:16061792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 High

    Discovery of UBR4/p600 as an HPV E7-binding protein that promotes anchorage-independent growth established UBR4 as a previously uncharacterized giant protein exploited by viral oncoproteins for cellular transformation.

    Evidence Tandem affinity purification/MS identification of p600 as E7 partner; RNAi knockdown reduced soft agar colony formation in HPV-positive and -negative cells; BPV E7 mutagenesis confirmed binding-transformation correlation

    PMID:16061792 PMID:16081543

    Open questions at the time
    • Ubiquitin ligase activity of UBR4 not yet recognized
    • Mechanism by which E7–p600 interaction drives anchorage independence unknown
  2. 2005 High

    Demonstration that p600 localizes to both nucleus (with retinoblastoma protein as a chromatin scaffold) and cytoplasm (with clathrin in cytoskeletal meshwork) revealed dual compartment functions and linked UBR4 to integrin-mediated membrane ruffling and anoikis resistance.

    Evidence Co-IP with pRB and clathrin; RNAi abolished membrane ruffles and sensitized cells to anoikis

    PMID:16214886

    Open questions at the time
    • Enzymatic activity not yet established
    • How clathrin association relates to ubiquitin ligase function unknown
  3. 2013 High

    Identification of UBR4 as an N-recognin of the N-end rule pathway, combined with the finding that UBR4-null mice die at E9.5–10.5 with vascular and autophagic defects, established UBR4 as an essential E3 ligase linking N-degron recognition to autophagy regulation and embryonic development.

    Evidence UBR4 knockout mouse; UBR box–N-degron recognition; LC3 lipidation and autophagosome formation assays; electron microscopy of autophagic vacuole accumulation

    PMID:23431188

    Open questions at the time
    • Specific autophagy substrates of UBR4 not identified
    • Catalytic mechanism (E2 partner, chain type) unknown
  4. 2013 High

    Two parallel discoveries—UBR4 mediating DENV NS5-directed STAT2 degradation for immune evasion, and UBR4 binding calmodulin/CaMKIIα to regulate ER Ca²⁺ homeostasis and neuronal survival—expanded UBR4's roles to antiviral immunity and calcium signaling.

    Evidence DENV: Co-IP of NS5–UBR4–STAT2 ternary complex, proteasome inhibition rescue, IFN-competent replication assays; Neurons: calmodulin interaction by NMR, live Ca²⁺ imaging, ER fragmentation upon UBR4 loss

    PMID:23555265 PMID:23861403

    Open questions at the time
    • Whether UBR4 directly ubiquitinates STAT2 or serves as scaffold unclear
    • Structural basis of calmodulin–UBR4 atypical interaction unresolved
  5. 2014 High

    UBR4 was placed in the mitotic spindle orientation machinery through its interaction with Ndel1, with UBR4 loss causing microcephaly-like phenotypes in developing cortex by randomizing spindle angle and shifting progenitor pools.

    Evidence Knockout mouse brain analysis, in utero electroporation, Co-IP with Ndel1, spindle angle quantification

    PMID:24812355

    Open questions at the time
    • Whether UBR4 ubiquitinates Ndel1 or acts as a scaffold in this context is unknown
    • Relationship between spindle orientation role and N-degron recognition not tested
  6. 2015 High

    The identification of KCMF1 as a bridging factor that recruits RAD6 (UBE2A/UBE2B) to UBR4 defined the E2–E3 complex architecture and linked it to late endosome/lysosome dynamics; disease-associated RAD6A mutations specifically disrupting this complex connected UBR4 to X-linked intellectual disability pathology.

    Evidence AP-MS and NMR mapping of RAD6–KCMF1–UBR4 ternary complex; co-localization at late endosomes; RAD6A XLID patient mutation analysis

    PMID:25582440

    Open questions at the time
    • Chain linkage type not determined
    • Endosomal substrates of the ternary complex not identified
  7. 2016 High

    In Drosophila, genetic epistasis revealed that UBR4/POE with KCMF1 and E2 UBC6 degrades MAPK via the N-end rule, opposed by deubiquitinase USP47, placing UBR4 as a direct regulator of RAS-MAPK signaling output.

    Evidence RNAi screen, MAPK half-life measurements, epistasis with USP47 in Drosophila

    PMID:27552662

    Open questions at the time
    • Whether MAPK is a direct UBR4 substrate or requires adaptor-mediated recognition unknown
    • Conservation of this regulation in mammals not confirmed
  8. 2016 High

    UBR4 was found to ubiquitinate podocin at conserved lysine residues, with cross-species validation in C. elegans showing degradation of mislocalized MEC-2 multimers, establishing UBR4 as a quality control E3 for misfolded/mislocalized membrane protein complexes.

    Evidence Ubiquitylomics MS, Co-IP, C. elegans genetics, molecular dynamics

    PMID:26792178

    Open questions at the time
    • Whether N-degron recognition is involved in podocin targeting not addressed
    • Kidney disease phenotype in UBR4 mutants not characterized
  9. 2018 High

    Two studies resolved UBR4's endosomal roles: calmodulin-dependent recruitment of UBR4 to maturing endosomes is essential for early endosome biogenesis and cargo trafficking, while UBR4-deficient mice show impaired MVB generation and global loss of cell surface protein turnover via the endosome–lysosome pathway.

    Evidence Calmodulin Co-IP, subcellular fractionation, live imaging, UBR4 KO mouse embryo analysis, cell surface proteomics, MVB electron microscopy

    PMID:30111582 PMID:30157281

    Open questions at the time
    • Specific endosomal substrates ubiquitinated by UBR4 not identified
    • How calmodulin-dependent endosomal recruitment interfaces with N-degron recognition unknown
  10. 2019 High

    Identification of the HAT1/RBBP4/RBBP7 histone-binding complex as a direct UBR4 substrate in myofibers, whose stabilization upon UBR4 loss drives hypertrophy, revealed UBR4 as a negative regulator of muscle fiber size through chromatin-modifier turnover.

    Evidence RNAi screen in Drosophila flight muscle, mouse myofiber-specific KO, MS-based substrate identification, ubiquitination assays

    PMID:31365869

    Open questions at the time
    • How HAT1 complex accumulation mechanistically causes hypertrophy is not determined
    • Whether N-degron signals are present on HAT1 complex subunits not tested
  11. 2021 High

    UBR4 was shown to increase with aging in skeletal muscle; its loss rescues age-related atrophy but compromises force and protein quality, revealing UBR4 as a regulator of the trade-off between myofiber size and proteostasis through modulation of proteasome activity.

    Evidence Muscle-specific UBR4 KO in aging mice, proteasome activity assays, force measurements, Drosophila lifespan analysis

    PMID:33658508

    Open questions at the time
    • Mechanism by which UBR4 enhances proteasome activity is unknown
    • Whether UBR4 directly ubiquitinates proteasome components in muscle not tested
  12. 2022 High

    UBR4 was found to regulate circadian pacemaker function by maintaining Coronin 7 expression, which is required for Golgi vesicle budding and axonal trafficking of circadian neuropeptides, adding Golgi-to-plasma-membrane vesicle transport to UBR4's trafficking repertoire.

    Evidence Ubr4 KO mice and Drosophila poe knockdown, circadian behavioral assays, neuropeptide imaging, Coronin 7 expression analysis

    PMID:35332162

    Open questions at the time
    • Whether UBR4 directly ubiquitinates a negative regulator of Coronin 7 or acts transcriptionally not resolved
    • The downstream circadian clock targets of neuropeptide loss not identified
  13. 2023 High

    Crystal structures of the UBR4 UBR box revealed a unique N-degron recognition mechanism using two surface phenylalanines to accommodate type-1 (Arg) and type-2 (aromatic) N-terminal residues, structurally explaining UBR4's broader substrate selectivity compared to other N-recognins.

    Evidence X-ray crystallography of UBR box–N-degron peptide complexes, mutagenesis validation

    PMID:38030679

    Open questions at the time
    • Full-length structural context of UBR box relative to catalytic domain not available at this point
    • Quantitative binding affinities for different N-degrons not comprehensively measured
  14. 2024 High

    Multiple substrate-specific studies identified EZH2 (K381 ubiquitination via UBE2L6), MLH1 (degradation opposed by USP5 and shielded by PMS2), HRI kinase (degradation constraining ISR and promoting mitophagy), and procaspase-8 (degraded when N-terminally deacetylated) as direct UBR4 substrates, greatly expanding the catalog of regulated targets.

    Evidence Site-directed mutagenesis of EZH2 K381 and MLH1 region 516–650; ubiquitination assays; NatB-KO MEFs with UBR4 siRNA rescue for procaspase-8; tubule-specific Ubr4 KO mice for HRI/cisplatin AKI model

    PMID:36906655 PMID:39032648 PMID:39099191 PMID:41548766

    Open questions at the time
    • Whether these substrates are recognized via N-degrons or alternative mechanisms is not uniformly resolved
    • Structural basis for E2 selectivity (UBE2L6 for EZH2 vs UBE2A/B for N-degron substrates) not explained
  15. 2024 High

    The hemiRING structure of UBR4 in complex with UBE2A/UBE2B was solved, revealing the catalytic mechanism: a hemiRING zinc finger recruits E2, while the UZI subdomain allosterically activates ubiquitin-loaded E2, establishing UBE2A/UBE2B as the cognate E2 pair for UBR4's core catalytic activity.

    Evidence Cryo-EM and crystal structures of E2–hemiRING complex, in vitro ubiquitination reconstitution, allosteric activation measurements

    PMID:38182926

    Open questions at the time
    • How E2 specificity is switched for non-canonical E2s like UBE2L6 is unresolved
    • Full integration of hemiRING into the ring complex architecture not yet visualized
  16. 2025 High

    The cryo-EM structure of the complete 1.3-MDa UBR4–KCMF1–calmodulin ring revealed a central substrate-binding arena with flexibly attached catalytic units; reconstitution demonstrated that UBR4 acts as an E4 ligase extending K48-linked chains on pre-ubiquitinated substrates, with KCMF1 serving as a substrate filter requiring both prior ubiquitination and N-degron signals for efficient targeting.

    Evidence Cryo-EM structure, in vitro ubiquitination reconstitution with pre-ubiquitinated substrates, substrate binding assays

    PMID:40875847

    Open questions at the time
    • How different substrate classes (N-degron vs. orphan proteins) are triaged within the ring is unclear
    • In vivo validation of dual-signal requirement not yet performed
    • Conformational dynamics during catalytic cycle not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how UBR4 coordinates its E3 versus E4 activities in vivo, how its multiple trafficking roles (endosome, MVB, Golgi) are spatiotemporally regulated, and whether its disease associations (IgG4-RD, neurological disorders, cancer drug resistance) reflect unified or distinct substrate degradation pathways.
  • No in vivo reconstitution distinguishing E3 from E4 mode in a physiological context
  • Structural basis for calmodulin-dependent endosomal recruitment versus substrate recognition not determined
  • Comprehensive substrate catalog across tissues is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0008092 cytoskeletal protein binding 2 GO:0016874 ligase activity 2
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
CALM1CAMK2ACLTCKCMF1NDEL1UBE2AUBE2BUBE2L6
Complex memberships
RAD6–KCMF1–UBR4 E2–E3 complexUBR4–KCMF1–calmodulin ring complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 UBR4/p600 was identified as a binding partner of HPV-16 E7 oncoprotein via tandem affinity purification and mass spectrometry; this association is independent of pocket proteins (pRB, p107, p130) and is mediated through the N-terminal E7 domain. Depletion of p600 by RNAi substantially decreased anchorage-independent growth in HPV-positive and -negative human cancer cells. Tandem affinity purification, mass spectrometry, RNA interference, anchorage-independent growth assay Proceedings of the National Academy of Sciences of the United States of America High 16061792
2005 BPV-1 E7 oncoprotein binds p600/UBR4; this interaction correlates with anchorage independence and transformation, and E7 mutants impaired in p600 binding are transformation-defective, establishing p600 as a functional target of E7 in cellular transformation. Tandem affinity purification, mutagenesis, transformation assays, RNAi knockdown Proceedings of the National Academy of Sciences of the United States of America High 16081543
2005 p600/UBR4 associates with retinoblastoma protein in the nucleus (acting as a chromatin scaffold) and with clathrin in the cytoplasm (forming a meshwork structure contributing to cytoskeletal organization and membrane morphogenesis). Knockdown of p600 abrogates integrin-mediated ruffled membrane formation, prevents activation of integrin-mediated survival pathways, and sensitizes cells to anoikis. Co-immunoprecipitation, RNAi knockdown, live-cell imaging, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 16214886
2013 DENV NS5 protein bridges STAT2 and UBR4; UBR4 preferentially binds proteolytically processed NS5, promotes proteasome-dependent STAT2 degradation, and is necessary for efficient viral replication in IFN-I competent cells, thereby mediating immune evasion. Co-immunoprecipitation, siRNA knockdown, proteasome inhibition assays, viral replication assays PLoS pathogens High 23555265
2013 UBR4 is an N-recognin of the N-end rule pathway that recognizes destabilizing N-terminal residues through its UBR box. UBR4 deficiency in mice causes embryonic lethality with impaired yolk sac vascular angiogenesis and accumulation of autophagic vacuoles. UBR4 regulates autophagy including LC3 synthesis, lipidation/activation, and autophagic double membrane formation, and undergoes starvation-induced association with autophagic cargoes. Knockout mouse model, electron microscopy, LC3 lipidation assays, immunofluorescence, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America High 23431188
2013 p600/UBR4 associates with the calmodulin·CaMKIIα complex downstream of NMDA receptors. A direct and atypical p600/calmodulin interaction is required for neuronal survival; p600 depletion leads to glutamate-induced ER fragmentation and ER Ca2+ release via IP3 receptors, demonstrating a role in Ca2+ homeostasis and signaling. Co-immunoprecipitation, siRNA knockdown, live calcium imaging, immunofluorescence, NMR (calmodulin interaction) The Journal of biological chemistry High 23861403
2015 UBR4 associates with the influenza A virus M2 protein and promotes apical transport of viral proteins, as established by integrative OMICs meta-analysis followed by functional validation. Protein interaction datasets (affinity purification-MS), RNAi functional validation, viral protein localization assays Cell host & microbe Medium 26651948
2015 KCMF1 directly binds RAD6 (E2 enzyme) through its C-terminus and binds UBR4 through its N-terminal domains, forming a RAD6-KCMF1-UBR4 E2-E3 complex. KCMF1 and RAD6 colocalize at late endosomes and lysosomes. Disruption of KCMF1 or RAD6 causes defects in late endosome vesicle dynamics. RAD6A XLID patient mutations (R7W, R11Q) specifically disrupt interaction with KCMF1 and UBR4. Affinity purification-MS, NMR interaction mapping, in vitro and in vivo interaction assays, co-localization imaging Molecular & cellular proteomics High 25582440
2016 UBR4/Ubr4 is a key component of the podocin interactome in podocytes and glomeruli; it colocalizes with podocin and regulates its stability via ubiquitylation at two conserved lysine residues (K301 and one other). In C. elegans, Ubr4 degrades mislocalized MEC-2 multimers. Ubiquitylation at K301 may affect stability and disassembly of the multimeric complex. Co-immunoprecipitation, ubiquitylomics mass spectrometry, molecular dynamics simulations, C. elegans genetics Human molecular genetics High 26792178
2016 In Drosophila, the deubiquitinase USP47 counteracts proteasome-mediated MAPK degradation by opposing the E3 ligase POE/UBR4 and E2 UBC6; KCMF1 is identified as another component of the UBR4-associated degradation module controlling MAPK levels, placing UBR4 in the N-end rule pathway that governs RAS-MAPK signaling output. RNAi-based genetic interaction screen, epistasis analysis, MAPK half-life assays in Drosophila PLoS biology High 27552662
2018 UBR4 is recruited to maturing endosomes through an interaction with Ca2+-bound calmodulin. Endosomal recruitment of UBR4 is essential for the biogenesis of early endosomes, trafficking of endocytosed protein cargos, and degradation of extracellular cargos by endosomal hydrolases. Co-immunoprecipitation with calmodulin, subcellular fractionation, immunofluorescence, live imaging, UBR4 KO mouse embryos Journal of cell science High 30111582
2018 UBR4-deficient mice (UBR box deletion) die at E9.5-10.5 with defects in neurogenesis and cardiovascular development correlated with inability to maintain cell integrity and adhesion. UBR4 is required for multivesicular body (MVB) generation, which mediates proteome-wide turnover of cell surface proteins via the endosome-lysosome pathway. UBR box knockout mouse, embryo analysis, MVB electron microscopy, cell surface proteomics PloS one High 30157281
2019 Loss of UBR4 (N-end rule ubiquitin ligase) promotes myofiber hypertrophy in Drosophila and mice via decreased ubiquitination and degradation of the HAT1/RBBP4/RBBP7 histone-binding complex, identifying this complex as a direct substrate set of UBR4 in myofibers. RNAi screen in Drosophila, mouse myofiber-specific KO, ubiquitination assays, mass spectrometry substrate identification Cell reports High 31365869
2021 UBR4 levels increase in skeletal muscle with aging; muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice but reduces muscle-specific force and accelerates protein quality decline. UBR4 increases the proteolytic activity of the proteasome, placing it as an antagonistic regulator of myofiber size versus protein quality control. Muscle-specific UBR4 KO mice, aging cohorts, proteasome activity assays, muscle force measurements, Drosophila lifespan analysis Nature communications High 33658508
2022 UBR4/POE ubiquitin ligase strengthens the circadian pacemaker by facilitating neuropeptide trafficking in clock neurons. Mechanistically, Ubr4 ablation impairs export of secreted proteins from the Golgi by reducing expression of Coronin 7 (required for budding of Golgi-derived transport vesicles), resulting in reduced axonal trafficking of circadian neuropeptides. Ubr4 knockout mice and poe knockdown Drosophila, behavioral circadian assays, neuropeptide trafficking imaging, Coronin 7 expression analysis Nature communications High 35332162
2023 The UBR box of UBR4 has a distinct recognition mechanism for N-degrons: it recognizes type-2 N-terminal amino acids containing an aromatic ring and type-1 N-terminal arginine through two phenylalanines on its hydrophobic surface, differing from other UBR boxes in the N-degron binding sites. Crystal structure of UBR box-N-degron complex, structural analysis, mutagenesis Communications biology High 38030679
2023 UBR4 ubiquitinates EZH2 at K381 in cooperation with the E2-conjugating enzyme UBE2L6, promoting EZH2 degradation. This pathway is regulated by UHRF1-mediated CpG methylation that suppresses UBE2L6 expression in low-pigmented melanoma cells. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, animal xenograft studies, site-directed mutagenesis of EZH2 K381 Oncogene High 36906655
2024 UBR4 contains a catalytic E3 module consisting of a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal region serving as affinity factor for E2 enzymes. The structure of the UBR4 hemiRING in complex with UBE2A/UBE2B reveals specificity determinants; the UZI subdomain allosterically and modestly activates Ub-loaded E2 (E2~Ub). UBE2A and UBE2B are the cognate E2s for UBR4. Cryo-EM/crystal structure of E2-E3 complex, in vitro ubiquitination assays, mutagenesis, allosteric activation assays Nature structural & molecular biology High 38182926
2024 NatB-mediated N-terminal acetylation protects procaspase-8 from UBR4 (and UBR1) Arg/N-recognin-mediated degradation. In NatB-deficient MEFs, procaspase-8 is degraded by UBR4, reducing responsiveness to extrinsic apoptotic stimuli; UBR4 silencing in Naa20-/- MEFs partially reverses this phenotype. NatB knockout MEFs, quantitative N-terminomics, label-free proteomics, targeted proteomics, UBR4 siRNA knockdown, apoptosis assays Molecular and cellular biology High 39099191
2024 UBR4 ubiquitinates and promotes degradation of MLH1 (DNA mismatch repair protein); the deubiquitylase USP5 opposes this activity. The region aa 516-650 of MLH1 is crucial for its degradation. PMS2 binding to this region shields MLH1 from UBR4-mediated degradation. UBR4 or USP5 deficiency affects cellular response to the nucleotide analog 6-TG. Co-immunoprecipitation, ubiquitination assays, deletion mutagenesis of MLH1, siRNA knockdown, 6-TG sensitivity assays The Journal of biological chemistry High 39032648
2024 A UBR4 variant in familial IgG4-RD prevents lysosomal degradation of the phosphatase CD45, leading to elevated CD45 levels that lower the threshold for T cell activation in a FYN-dependent positive regulatory loop. Functional variant analysis in patient T cells, CD45 protein stability assays, T cell activation assays The Journal of clinical investigation Medium 38885295
2025 Cryo-EM structure of UBR4 in complex with KCMF1 and calmodulin (CALM1) reveals a 1.3-megadalton ring structure with a central substrate-binding arena and flexibly attached catalytic units. UBR4 acts as an E4 ubiquitin ligase that extends K48-linked ubiquitin chains on pre-ubiquitinated substrates. Efficient substrate targeting requires both preubiquitination and specific N-degrons, with KCMF1 acting as a key substrate filter. Cryo-electron microscopy, in vitro ubiquitination reconstitution, substrate binding assays Science High 40875847
2025 UBR4 promotes ubiquitination and proteasomal degradation of the kinase HRI, thereby constraining integrated stress response (ISR) overactivation and relieving ISR-mediated inhibition of mitophagy. Tubule-specific Ubr4 deficiency in mice exacerbates cisplatin-induced AKI, while UBR4 enhancement or ISR inhibition mitigates nephrotoxicity. Tubule-specific KO mice, ubiquitination assays, HRI protein stability assays, mitophagy assays, cisplatin AKI model Free radical biology & medicine High 41548766
2026 UBR4 mediates clathrin-dependent EGFR degradation after cetuximab treatment; UBR4 knockdown promotes EGFR recycling rather than degradation, enhances cell proliferation, and reduces apoptosis in response to cetuximab, identifying UBR4 as a critical mediator of EGFR endocytic fate. siRNA knockdown, co-immunoprecipitation, tandem mass spectrometry, immunofluorescence, cell viability and apoptosis assays Journal of gastroenterology Medium 41491123
2014 p600/UBR4 interacts directly with Ndel1 and regulates spindle orientation in apical neural progenitors. Loss of p600 randomizes spindle orientation, decreases Pax6-positive progenitors, increases Tbr2-positive basal progenitors, and impairs neuron production, resulting in microcephaly. Knockout mice, in utero electroporation, Co-immunoprecipitation with Ndel1, immunofluorescence, spindle angle quantification Biology open High 24812355
2014 p600/UBR4 stabilizes microtubules to prevent CaMKIIα aggregation during neuronal depolarization; during photoconductive stimulation, p600 loss leads to interrupted CaMKIIα translocation to microtubules and instead sustained self-aggregation preventable by paclitaxel. This is mechanistically distinct from the calmodulin-dependent mode during glutamate treatment. Photoconductive stimulation, live imaging of single neurons, siRNA knockdown, paclitaxel pharmacological rescue Cellular & molecular biology letters Medium 25034033
2022 UBR4 interacts with Rift Valley fever virus Gn glycoprotein; UBR4 depletion significantly decreases RVFV titers and viral RNA production, identifying UBR4 as a host factor required for RVFV production. Proteomics-based Gn interactome (V5-tagged virus + AP-MS), siRNA knockdown, viral titer assays, viral RNA quantification Virology Medium 35032865
2024 The UBR4-KCMF1 complex acts as an E4 ubiquitin ligase that functions downstream of priming E3 ligases to extend K48-linked polyubiquitin chains on mono-ubiquitinated orphan subunits from the chaperonin, proteasome cap, proteasome core, and protein targeting complexes, representing a convergence point for multiple orphan protein quality control pathways. Epistasis analysis in cells, in vitro reconstitution of ubiquitin chain extension, identification of orphan substrates by proteomics bioRxivpreprint High
2024 UBR4 specifically recognizes and degrades peptides bearing position 3 arginine or lysine N-termini via a MetAP2-dependent Arg/N-degron pathway. MetAP2 co-translationally cleaves the N-terminal methionine preceding second-position threonine/valine to expose these degrons. CRISPR knockout shows this pathway is exclusively mediated by UBR4 and not UBR1 or UBR2. Reporter assays, CRISPR-Cas9 KO of N-recognins, MetAP2 inhibition, bioinformatic substrate identification bioRxivpreprint Medium
2024 BIRC6 mono-ubiquitinates TRIM52, with subsequent K48-linked polyubiquitin chain extension by UBR4/KCMF1, leading to rapid proteasomal degradation of TRIM52. Genetic and proteomic analyses, ubiquitination assays, epistasis experiments bioRxivpreprint Medium
2024 NAP1L1 modulates UBR4-mediated ubiquitination of BIRC2; knockdown of NAP1L1 promotes UBR4-dependent ubiquitin-mediated degradation of BIRC2, inhibiting proliferation and apoptotic escape of HCC cells. Co-IP and mass spectrometry identified UBR4 as an intermediate molecule associating NAP1L1 with BIRC2. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, ubiquitination assays Cell death discovery Medium 38538582

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Meta- and Orthogonal Integration of Influenza "OMICs" Data Defines a Role for UBR4 in Virus Budding. Cell host & microbe 712 26651948
2013 Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS pathogens 189 23555265
2005 Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. Proceedings of the National Academy of Sciences of the United States of America 149 16061792
2013 UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy. Proceedings of the National Academy of Sciences of the United States of America 75 23431188
2005 Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding. Proceedings of the National Academy of Sciences of the United States of America 70 16081543
2013 A novel locus for episodic ataxia:UBR4 the likely candidate. European journal of human genetics : EJHG 67 23982692
2019 A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice. Cell reports 65 31365869
2005 p600, a unique protein required for membrane morphogenesis and cell survival. Proceedings of the National Academy of Sciences of the United States of America 60 16214886
2021 Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging. Nature communications 58 33658508
2016 The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes. Human molecular genetics 47 26792178
2015 KCMF1 (potassium channel modulatory factor 1) Links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and lysosome-mediated degradation. Molecular & cellular proteomics : MCP 37 25582440
2016 The Deubiquitinase USP47 Stabilizes MAPK by Counteracting the Function of the N-end Rule ligase POE/UBR4 in Drosophila. PLoS biology 36 27552662
2018 The N-recognin UBR4 of the N-end rule pathway is required for neurogenesis and homeostasis of cell surface proteins. PloS one 31 30157281
2014 p600/UBR4 in the central nervous system. Cellular and molecular life sciences : CMLS 28 25424645
2023 P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination. Journal of nanobiotechnology 19 37644565
2013 A Ca2+-dependent mechanism of neuronal survival mediated by the microtubule-associated protein p600. The Journal of biological chemistry 19 23861403
2024 UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nature structural & molecular biology 17 38182926
2023 UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. Oncogene 16 36906655
2022 UBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony. Nature communications 16 35332162
2023 Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates. Communications biology 15 38030679
2024 IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease. The Journal of clinical investigation 13 38885295
2018 The N-recognin UBR4 of the N-end rule pathway is targeted to and required for the biogenesis of the early endosome. Journal of cell science 13 30111582
2021 Blocking circ_UBR4 suppressed proliferation, migration, and cell cycle progression of human vascular smooth muscle cells in atherosclerosis. Open life sciences 12 33981849
2013 p600 Plays Essential Roles in Fetal Development. PloS one 12 23824717
2010 Bovine papillomavirus E7 oncoprotein binds to p600 in naturally occurring equine sarcoids. The Journal of general virology 11 20965990
2014 p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex. Biology open 10 24812355
2014 Time-of-day- and light-dependent expression of ubiquitin protein ligase E3 component N-recognin 4 (UBR4) in the suprachiasmatic nucleus circadian clock. PloS one 8 25084275
2011 Inhibition of p600 expression suppresses both invasiveness and anoikis resistance of gastric cancer. Annals of surgical oncology 8 21347795
2025 Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control. Science (New York, N.Y.) 7 40875847
2024 NatB Protects Procaspase-8 from UBR4-Mediated Degradation and Is Required for Full Induction of the Extrinsic Apoptosis Pathway. Molecular and cellular biology 7 39099191
2021 Circ_UBR4 Knockdown Alleviates Oxidized Low-Density Lipoprotein-Provoked Growth and Migration of Human Vascular Smooth Muscle Cells by Acting on the miR-637/FOXO4 Pathway. Journal of cardiovascular pharmacology 7 34225339
2019 Aberrant UBR4 expressions in Hirschsprung disease patients. BMC pediatrics 7 31830949
2024 NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression. Cell death discovery 5 38538582
2020 Semantic P600-but not N400-effects index crosslinguistic variability in speakers' expectancies for expression of motion. Neuropsychologia 5 33007360
2025 Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 4 40531870
2023 Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis. Open medicine (Warsaw, Poland) 4 37693837
2022 Rift Valley fever virus Gn V5-epitope tagged virus enables identification of UBR4 as a Gn interacting protein that facilitates Rift Valley fever virus production. Virology 4 35032865
2024 The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1. The Journal of biological chemistry 3 39032648
2023 UBR4 deficiency causes male sterility and testis abnormal in Drosophila. Frontiers in endocrinology 2 37529615
2014 p600 stabilizes microtubules to prevent the aggregation of CaMKIIα during photoconductive stimulation. Cellular & molecular biology letters 2 25034033
2025 The interaction of UBR4, LRP1, and OPHN1 in refractory epilepsy: Drosophila model to investigate the oligogenic effect on epilepsy. Neurobiology of disease 1 40374006
2026 UBR4 enhances efficacy of anti-EGFR antibody by facilitating clathrin-dependent EGFR endocytosis in colorectal cancer. Journal of gastroenterology 0 41491123
2026 UBR4 attenuates cisplatin-induced acute kidney injury by regulating the HRI-ISR axis. Free radical biology & medicine 0 41548766