Affinage

UBR4

E3 ubiquitin-protein ligase UBR4 · UniProt Q5T4S7

Length
5183 aa
Mass
573.8 kDa
Annotated
2026-06-10
34 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBR4 is a large E3/E4 ubiquitin ligase of the N-degron (N-end rule) pathway that directs ubiquitin-proteasome and endolysosomal turnover of a broad set of substrates across development, proteostasis, and quality control (PMID:23431188, PMID:31365869). Its catalytic core comprises a hemiRING zinc finger and a UZI subdomain that specifically recruit and allosterically activate the cognate E2 enzymes UBE2A/UBE2B (RAD6), determining E2 selectivity (PMID:38182926, PMID:25582440). Substrate selection operates through a UBR box that recognizes type-1 (N-terminal Arg) and type-2 (aromatic) N-degrons via a distinct two-phenylalanine surface, with specialized recognition of MetAP2-generated position-3 Arg/Lys degrons [PMID:38030679, PMID:bio_10.1101_2024.10.03.616566]. UBR4 assembles with KCMF1 and calmodulin into a ~1.3 MDa ring with a central substrate arena; it functions predominantly as an E4 chain-elongating ligase that extends K48-linked chains on substrates already bearing priming mono-ubiquitin and an N-degron, with KCMF1 acting as a substrate filter — a logic that drives clearance of orphan subunits from the chaperonin, proteasome cap/core, and targeting complexes [PMID:40875847, PMID:bio_10.1101_2024.08.07.607117]. Through these activities UBR4 degrades diverse targets including the HAT1/RBBP4/RBBP7 complex to limit myofiber size (PMID:31365869), podocin multimers (PMID:26792178), MAPK (PMID:27552662), EZH2 (PMID:36906655), MLH1 (PMID:39032648), YAP (PMID:37644565), BIRC2 (PMID:38538582), and the stress kinase HRI (PMID:41548766), and is exploited by Dengue NS5 to degrade STAT2 (PMID:23555265). Independently of degradation, UBR4 governs endosomal/lysosomal trafficking via calmodulin-dependent recruitment to maturing endosomes, multivesicular body biogenesis, autophagic flux, mitophagy-linked mitochondrial quality control, and Golgi-derived neuropeptide secretion (PMID:23431188, PMID:30111582, PMID:30157281, PMID:35332162, PMID:40531870). UBR4 loss is embryonic lethal in mice with vascular, neural, and cardiovascular defects tied to surface-proteome turnover (PMID:23431188, PMID:30157281).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2013 High

    Established UBR4 as a bona fide N-recognin of the N-end rule pathway and tied it to autophagy and embryonic development, defining its core biological role.

    Evidence UBR knockout mouse with developmental phenotyping and LC3 lipidation/autophagic flux assays

    PMID:23431188

    Open questions at the time
    • Did not identify direct degradation substrates
    • Link between N-degron recognition and autophagy regulation left mechanistically unresolved
  2. 2013 High

    Showed UBR4 can be hijacked by a viral adaptor to degrade a host substrate, demonstrating substrate recruitment can occur via bridging proteins rather than intrinsic N-degron recognition alone.

    Evidence Reciprocal Co-IP, siRNA knockdown, proteasome inhibition, and viral replication assays with Dengue NS5/STAT2

    PMID:23555265

    Open questions at the time
    • Whether STAT2 carries an N-degron or is recruited solely via NS5 bridging not resolved
    • Direct ubiquitination of STAT2 by UBR4 not reconstituted
  3. 2015 High

    Defined the UBR4-KCMF1-RAD6 module architecture and connected it to endolysosomal compartments and X-linked intellectual disability through RAD6A mutations.

    Evidence AP-MS, NMR, in vitro interaction mapping, and colocalization microscopy

    PMID:25582440

    Open questions at the time
    • Substrates targeted by this complex at endosomes/lysosomes not identified
    • Catalytic logic of the assembly not yet defined
  4. 2016 High

    Identified specific physiological substrates and trafficking roles — podocin multimers and a MAPK degradation pathway — broadening UBR4 from a developmental factor to a substrate-specific ligase.

    Evidence AP-MS/ubiquitylomics with C. elegans validation (podocin); RNAi epistasis in Drosophila (MAPK/UBC6/UFD4/KCMF1)

    PMID:26792178 PMID:27552662

    Open questions at the time
    • Site-specific ubiquitination logic generalizability across substrates unknown
    • Mammalian conservation of the MAPK pathway not established
  5. 2018 Medium

    Mechanistically linked UBR4 to endosome biogenesis and surface-proteome turnover via calmodulin-dependent recruitment, explaining embryonic lethality through trafficking failure.

    Evidence Co-IP (calmodulin), fractionation, live imaging, KO mouse embryo proteomics and MVB assays

    PMID:30111582 PMID:30157281

    Open questions at the time
    • Whether endosomal roles require ligase activity or are scaffolding functions unclear
    • Direct surface-protein substrates not individually validated
  6. 2019 High

    Demonstrated that UBR4-mediated degradation of the HAT1/RBBP4/RBBP7 complex limits myofiber size, establishing a conserved proteostatic role in muscle.

    Evidence Drosophila RNAi screen, mouse KO, ubiquitination assays, mass spectrometry

    PMID:31365869

    Open questions at the time
    • How histone-binding complex turnover controls hypertrophy mechanistically unresolved
  7. 2021 High

    Revealed an antithetical role in which UBR4 boosts proteasome activity and protein quality control even as it restrains myofiber size, complicating its role in age-associated atrophy.

    Evidence Muscle-specific KO mouse, proteasome activity and in vivo force measurements

    PMID:33658508

    Open questions at the time
    • Molecular basis for UBR4 enhancement of proteasome activity not defined
  8. 2022 High

    Showed a degradation-independent trafficking function: UBR4 maintains Coronin 7 to drive Golgi-derived neuropeptide vesicle budding and circadian neuropeptide transport.

    Evidence Mouse KO, Drosophila RNAi, live imaging, Golgi export and neuropeptide trafficking assays

    PMID:35332162

    Open questions at the time
    • Whether Coronin 7 is a UBR4 ubiquitination substrate or stabilized by another route not resolved
  9. 2023 High

    Resolved the structural basis of UBR box N-degron recognition, showing a distinct two-phenylalanine mechanism for type-1 and type-2 residues.

    Evidence X-ray crystallography of the UBR box with binding assays

    PMID:38030679

    Open questions at the time
    • Structure does not connect N-degron binding to catalytic chain assembly
    • Second-ligand binding contribution to substrate selection in vivo unverified
  10. 2023 Medium

    Expanded the substrate repertoire to disease-relevant targets — EZH2 (with E2 UBE2L6) and YAP — and showed UBR4 itself is transcriptionally controlled by NF-kB.

    Evidence Co-IP, site-specific ubiquitination assays, fractionation, ChIP, animal studies

    PMID:36906655 PMID:37644565

    Open questions at the time
    • Whether these substrates are recognized via N-degron or other determinants unclear
    • Single-lab substrate assignments without structural validation
  11. 2024 High

    Defined the dedicated catalytic E3 module (hemiRING + UZI) and its E2 selectivity, providing the structural mechanism of UBE2A/UBE2B recruitment and activation.

    Evidence Crystal/cryo-EM of E2-E3 complex, in vitro ubiquitination, mutagenesis

    PMID:38182926

    Open questions at the time
    • How the catalytic module is positioned relative to substrates in the full assembly not resolved in this study
  12. 2024 High

    Established UBR4 as a convergence point acting downstream of a priming E3, recognizing both N-degron and pre-existing mono-ubiquitin to clear orphan complex subunits.

    Evidence Cellular epistasis and in vitro reconstitution (preprint)

    PMID:bio_10.1101_2024.08.07.607117

    Open questions at the time
    • Identity of all priming E3s unknown
    • Generality of the two-mark logic across substrates not exhaustively tested
  13. 2024 Medium

    Refined substrate-recognition specificity, showing UBR4 uniquely reads MetAP2-generated position-3 Arg/Lys N-degrons, distinguishing it from UBR1/UBR2.

    Evidence CRISPR KO of N-recognins, reporter assays, MetAP2 inhibition (preprint)

    PMID:bio_10.1101_2024.10.03.616566

    Open questions at the time
    • Endogenous substrates bearing this degron not enumerated
    • Preprint awaiting peer review
  14. 2024 Medium

    Added MLH1, procaspase-8, and BIRC2 as substrates whose stability is set by competing protective factors, linking UBR4 to mismatch repair, apoptosis, and cancer.

    Evidence Co-IP, domain mapping, ubiquitination assays, N-terminomics, KO/KD epistasis, drug-response assays

    PMID:38538582 PMID:39032648 PMID:39099191

    Open questions at the time
    • Whether UBR4 directly ubiquitinates each target or acts in larger complexes not fully resolved
    • Single-lab assignments per substrate
  15. 2025 High

    Provided the integrated structure of the ~1.3 MDa UBR4-KCMF1-CALM1 ring and defined UBR4's E4 chain-elongating function with KCMF1 as a substrate filter.

    Evidence Cryo-EM, in vitro reconstitution, epistasis

    PMID:40875847

    Open questions at the time
    • Dynamics of flexible catalytic units during processive chain elongation not captured
    • How the central arena selects among substrates structurally undefined
  16. 2025 Medium

    Connected UBR4 to mitochondrial quality control, showing its loss impairs mitophagy and drives senescence with tumor-suppressive consequences.

    Evidence CRISPR KO, senescence and mitophagy assays, xenografts, antioxidant rescue

    PMID:40531870

    Open questions at the time
    • Direct mitophagy substrate of UBR4 not identified
    • Relationship to its endolysosomal roles unclear
  17. 2026 Medium

    Extended UBR4's roles to stress-response and receptor turnover: degradation of HRI constrains the integrated stress response, EGFR routing to degradation, and a CaMKK2-scaffolded proteasome-targeting mechanism.

    Evidence Tissue-specific KO mouse (HRI/ISR/mitophagy), siRNA/Co-IP/MS (EGFR), Co-IP-MS and kinase assays (CaMKK2, preprint)

    PMID:41491123 PMID:41548766 PMID:42182340

    Open questions at the time
    • Whether HRI and EGFR are direct N-degron substrates not established
    • CaMKK2 scaffolding model from preprint awaiting peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBR4 partitions between proteasomal degradation, endolysosomal trafficking, autophagy/mitophagy, and degradation-independent scaffolding roles within a single megadalton assembly remains unresolved.
  • No unified model linking N-degron/E4 catalysis to non-degradative trafficking functions
  • Full endogenous substrate census incomplete
  • Tissue-specific cofactor configurations of the ring complex undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 4 GO:0031386 protein tag activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 3 R-HSA-9909396 Circadian clock 2
Partners
CALM1KCMF1PMS2RAD6STAT2UBE2AUBE2BUBE2L6
Complex memberships
UBR4-KCMF1-RAD6 moduleUBR4-KCMF1-calmodulin ring complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 UBR4 contains a distinct catalytic E3 module comprising a 'hemiRING' zinc finger, a helical-rich UBR zinc-finger interacting (UZI) subdomain, and an N-terminal affinity region that recruits cognate E2 conjugating enzymes UBE2A and UBE2B. The UZI subdomain allosterically activates the Ub-loaded E2 (E2~Ub). The hemiRING specifically recognizes UBE2A/UBE2B through determinants revealed by crystal structure of the E2-E3 complex. Crystal/cryo-EM structure of E2-E3 complex, in vitro ubiquitination assays, mutagenesis Nature structural & molecular biology High 38182926
2025 Cryo-EM analysis of UBR4 in complex with cofactors KCMF1 and 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 chain-elongating ligase, extending K48-linked ubiquitin chains on pre-ubiquitinated substrates. Efficient substrate targeting requires both preubiquitination and specific N-degrons, with KCMF1 acting as a substrate filter. Cryo-electron microscopy, in vitro ubiquitination reconstitution, epistasis analysis Science (New York, N.Y.) High 40875847
2024 The UBR4-KCMF1 ubiquitin ligase complex acts downstream of a priming E3 that mono-ubiquitinates orphan subunits; UBR4 then recognizes both the orphan protein and its mono-ubiquitin mark and builds K48-linked poly-ubiquitin chains for proteasomal degradation. This convergence point is required for efficient degradation of orphan subunits from the chaperonin, proteasome cap, proteasome core, and a protein targeting complex. Epistasis analysis in cells, in vitro reconstitution assays bioRxiv (preprint)preprint High bio_10.1101_2024.08.07.607117
2013 UBR4 (p600) recognizes N-degrons through its UBR box as an N-recognin of the N-end rule pathway, mediating ubiquitylation-dependent proteolysis. UBR4-deficient mice die during embryogenesis with impaired yolk sac vascular development. In the yolk sac endoderm, UBR4 regulates autophagic flux including LC3 lipidation/activation and autophagic double-membrane structure formation. Genetic knockout mouse model, autophagic flux assays, LC3 lipidation assays Proceedings of the National Academy of Sciences of the United States of America High 23431188
2013 Dengue virus NS5 protein bridges STAT2 and UBR4, recruiting UBR4 to promote proteasome-dependent STAT2 degradation. Processed (but not unprocessed) NS5 preferentially binds UBR4. UBR4 knockdown reduces DENV-mediated STAT2 degradation and impairs viral replication in IFN-I competent cells. Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assays, viral replication assays PLoS pathogens High 23555265
2023 Structural analysis of the UBR box of UBR4 reveals it recognizes type-2 N-terminal amino acids (containing aromatic rings) and type-1 N-terminal arginine through two phenylalanines on a hydrophobic surface, a distinct mechanism from other UBR box-containing proteins. The second ligand residue binding mechanism was also characterized. X-ray crystallography / structural analysis, binding assays Communications biology High 38030679
2019 Loss of UBR4 in Drosophila and mouse myofibers promotes hypertrophy via decreased ubiquitination and degradation of the HAT1/RBBP4/RBBP7 histone-binding complex. RNAi screening in Drosophila identified UBR4 as an N-end rule ubiquitin ligase that limits myofiber size. RNAi screening in Drosophila, mouse KO, ubiquitination assays, proteomics (mass spectrometry) Cell reports High 31365869
2021 UBR4 levels increase in skeletal muscle with aging and UBR4 increases proteasome proteolytic activity. Muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice but reduces specific force and accelerates protein quality control decline, demonstrating that UBR4 antithetically regulates myofiber size and muscle protein quality control. Muscle-specific KO mouse model, proteasome activity assays, in vivo muscle function measurements Nature communications High 33658508
2015 UBR4 associates with influenza A virus M2 protein (identified by affinity purification/mass spectrometry and Co-IP) and promotes apical transport of viral proteins; UBR4 knockdown impairs viral budding. Affinity purification-mass spectrometry, Co-immunoprecipitation, RNAi knockdown, viral protein localization assays Cell host & microbe Medium 26651948
2015 UBR4 forms a complex with KCMF1 and the E2 enzyme RAD6. NMR and in vitro interaction mapping showed KCMF1 C-terminus binds directly to RAD6, while KCMF1 N-terminal domains interact with UBR4. KCMF1 and RAD6 colocalize at late endosomes and lysosomes. RAD6A mutations (R7W, R11Q) found in X-linked intellectual disability specifically disrupt interaction with KCMF1 and UBR4. Affinity purification-mass spectrometry, NMR, in vivo and in vitro interaction mapping, co-localization microscopy Molecular & cellular proteomics : MCP High 25582440
2016 In Drosophila, POE/UBR4 acts as an E3 ubiquitin ligase together with E2 UBC6 and co-factor UFD4 to target MAPK for proteasomal degradation, opposing the deubiquitinase USP47. KCMF1 was identified as another key component modulating MAPK levels through this complex. Genetic interaction screening (RNAi-based epistasis) established the pathway order. RNAi-based genetic interaction screen (epistasis), Drosophila genetics, MAPK half-life measurements PLoS biology Medium 27552662
2018 UBR4 is recruited to maturing endosomes through interaction with Ca2+-bound calmodulin, and this endosomal recruitment is essential for biogenesis of early endosomes (EEs) and trafficking of endocytosed cargo. Loss of UBR4 disrupts endosome-lysosome pathway function in mouse embryos. Co-immunoprecipitation (calmodulin interaction), cellular fractionation, live-cell imaging, mouse embryo analysis, KO phenotyping Journal of cell science Medium 30111582
2018 UBR4-deficient mice die around E9.5-10.5 with defects in neurogenesis and cardiovascular development correlated with depletion of plasma membrane proteins and impaired multivesicular body (MVB) biogenesis, suggesting UBR4 governs proteome-wide turnover of cell surface proteins through the endosomal pathway. Conditional KO mouse model (UBR box deletion), proteomics of plasma membrane fractions, MVB biogenesis assays PloS one Medium 30157281
2016 The ubiquitin ligase UBR4 is a key component of the podocin interactome in podocytes and glomeruli (identified by purification and MS). UBR4 co-localizes with podocin and controls its ubiquitylation at K301 and a second lysine, regulating stability and disassembly of podocin/MEC-2 multimeric complexes. In C. elegans, Ubr4 degrades mislocalized MEC-2 multimers. Affinity purification-mass spectrometry, co-immunoprecipitation, ubiquitylomics, C. elegans genetics, molecular dynamics simulations Human molecular genetics High 26792178
2022 UBR4/POE ubiquitin ligase promotes neuropeptide trafficking in clock neurons by maintaining expression of Coronin 7, which is required for budding of Golgi-derived transport vesicles. Ubr4-deficient mice show resistance to jetlag; poe knockdown flies are prone to arrhythmicity due to reduced axonal trafficking of circadian neuropeptides. Mouse KO, Drosophila RNAi, live imaging, neuropeptide trafficking assays, Golgi export assays Nature communications High 35332162
2023 UBR4 ubiquitinates YAP at its substrate to promote YAP degradation and nuclear-cytoplasmic translocation, thereby reducing endometrial fibrosis. P65 (NF-κB) binds the UBR4 promoter to transcriptionally upregulate UBR4 expression in menstrual blood stromal cells. siRNA knockdown, ubiquitination assays, nuclear/cytoplasmic fractionation, chromatin immunoprecipitation (P65 on UBR4 promoter), co-immunoprecipitation Journal of nanobiotechnology Medium 37644565
2023 UBR4 (E3 ligase) cooperates with UBE2L6 (E2) to ubiquitinate EZH2 at K381, promoting its degradation. UHRF1-mediated CpG methylation downregulates UBE2L6 in low-pigmented melanoma cells, stabilizing EZH2. This UHRF1/UBE2L6/UBR4 axis controls EZH2 abundance and melanocytic differentiation states. Co-immunoprecipitation, mass spectrometry, ubiquitination assays, siRNA knockdown, animal studies Oncogene Medium 36906655
2024 UBR4 promotes proteasomal degradation of MLH1 through its ubiquitin ligase activity; the region of MLH1 encompassing amino acids 516-650 is crucial for UBR4-dependent degradation. PMS2 binding to this segment shields MLH1 from UBR4-mediated degradation. The deubiquitylase USP5 opposes UBR4 to stabilize MLH1. UBR4 or USP5 deficiency affects cellular response to 6-TG, linking them to mismatch repair. Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, domain-mapping (deletion constructs), 6-TG sensitivity assay The Journal of biological chemistry Medium 39032648
2024 NatB (N-terminal acetyltransferase B)-mediated N-terminal acetylation protects procaspase-8 from UBR4 (and UBR1) Arg/N-recognin-mediated degradation. In Naa20-/- MEFs lacking NatB catalytic activity, procaspase-8 is degraded via UBR4, reducing responsiveness to extrinsic apoptotic stimuli. UBR4 silencing in Naa20-/- cells partially restores procaspase-8 levels and apoptotic response. MEF KO (Naa20-/-), quantitative N-terminomics, label-free quantification, targeted proteomics, siRNA knockdown of UBR4, apoptosis assays Molecular and cellular biology Medium 39099191
2024 UBR4 exclusively (not UBR1 or UBR2) targets N-degrons bearing position-3 arginine or lysine residues after MetAP2-mediated co-translational cleavage of N-terminal methionine preceding second-position threonine or valines. This MetAP2-dependent Arg/N-degron pathway is a distinct substrate-recognition mechanism for UBR4. Reporter assays, CRISPR-Cas9 knockout of N-recognins (UBR1, UBR2, UBR4), MetAP2 inhibition bioRxiv (preprint)preprint Medium bio_10.1101_2024.10.03.616566
2024 NAP1L1 protects BIRC2 from UBR4-mediated ubiquitin-proteasome degradation. NAP1L1 knockdown promotes UBR4-dependent ubiquitination and degradation of BIRC2, inhibiting hepatocellular carcinoma cell proliferation and apoptotic escape. UBR4 was identified as the intermediate molecule linking NAP1L1 and BIRC2 by Co-IP and mass spectrometry. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, ubiquitination assays Cell death discovery Medium 38538582
2026 UBR4 promotes ubiquitination and proteasomal degradation of the kinase HRI, thereby constraining integrated stress response (ISR) overactivation and alleviating ISR-mediated inhibition of mitophagy in proximal tubular epithelial cells. Tubule-specific Ubr4 deficiency exacerbates cisplatin-induced kidney injury by allowing HRI-mediated ISR overactivation. Tubule-specific KO mouse model, ubiquitination assays, HRI protein stability assays, ISR pathway readouts, mitophagy assays Free radical biology & medicine Medium 41548766
2026 UBR4 mediates clathrin-dependent EGFR endocytosis and degradation in colorectal cancer cells. UBR4 knockdown promotes EGFR recycling rather than degradation, enhancing cell proliferation and reducing apoptosis in response to cetuximab. siRNA knockdown, co-immunoprecipitation, tandem mass spectrometry, immunofluorescence, cell viability and apoptosis assays Journal of gastroenterology Medium 41491123
2025 UBR4 knockout in A549 lung cancer cells induces cellular senescence with defective mitochondria caused by impaired mitophagy. Restoration of UBR4 or antioxidant treatment reverses the ΔUBR4 phenotypes, suggesting UBR4 regulates mitochondrial quality control to prevent senescence-associated tumor suppression. CRISPR KO, senescence assays, mitophagy flux assays, xenograft mouse models, antioxidant rescue experiments Proceedings of the National Academy of Sciences of the United States of America Medium 40531870
2016 In the murine SCN, UBR4 protein expression is time-of-day-dependent and light-inducible. UBR4 is localized exclusively to arginine vasopressin (AVP)-expressing neurons of the SCN shell, as determined by immunofluorescence microscopy. Photic stimulation in the early subjective night increases the number of UBR4-expressing SCN cells. Proteome-wide SCN screen, immunofluorescence microscopy, temporal expression profiling PloS one Medium 25084275
2022 UBR4 depletion reduces RVFV titers and viral RNA production, identifying UBR4 as a host factor required for Rift Valley fever virus replication. UBR4 was identified as a Gn glycoprotein-interacting protein by proteomics-based approach using V5-epitope tagged virus. Proteomics (affinity purification-mass spectrometry), siRNA knockdown, viral titer assays, viral RNA quantification Virology Medium 35032865
2026 CaMKK2 co-immunoprecipitates with UBR4 and the 19S proteasome regulatory particle (RP) in chondrocytes; CaMKK2 scaffolds UBR4 and 19S RP around polyubiquitinated proteins such as Sox9 for proteasomal degradation, independently of its kinase activity, while CaMKK2 kinase activity phosphorylates Psmc5 (19S ATPase) to enhance proteasome activity. Co-immunoprecipitation-mass spectrometry, kinase assays, phosphosite identification by mass spectrometry, proteasome activity assays, kinase-dead mutants bioRxiv (preprint)preprint Medium 42182340
2024 In IgG4-RD, a UBR4 variant prevents lysosomal degradation of the phosphatase CD45 in T cells, contributing to T cell hyperresponsiveness. This was established in patient-derived T cells carrying the specific UBR4 variant. Patient cell-based assays, CD45 protein stability measurements, lysosomal degradation assays The Journal of clinical investigation Low 38885295

Source papers

Stage 0 corpus · 34 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 715 26651948
2013 Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS pathogens 193 23555265
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
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
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 48 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 38 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
2024 UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nature structural & molecular biology 21 38182926
2023 P65 mediated UBR4 in exosomes derived from menstrual blood stromal cells to reduce endometrial fibrosis by regulating YAP Ubiquitination. Journal of nanobiotechnology 21 37644565
2023 UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. Oncogene 17 36906655
2022 UBR4/POE facilitates secretory trafficking to maintain circadian clock synchrony. Nature communications 17 35332162
2024 IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease. The Journal of clinical investigation 15 38885295
2023 Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates. Communications biology 15 38030679
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
2025 Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control. Science (New York, N.Y.) 9 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 8 39099191
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
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 6 38538582
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 5 40531870
2024 The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1. The Journal of biological chemistry 4 39032648
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
2023 UBR4 deficiency causes male sterility and testis abnormal in Drosophila. Frontiers in endocrinology 2 37529615
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
2026 A CAMKK2-UBR4-19S Proteasome Axis Regulates Chondrocyte Proteostasis and SOX9 Stability. bioRxiv : the preprint server for biology 0 42182340

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