Affinage

UBR2

E3 ubiquitin-protein ligase UBR2 · UniProt Q8IWV8

Length
1755 aa
Mass
200.5 kDa
Annotated
2026-04-28
25 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBR2 is a RING-type E3 ubiquitin ligase of the N-degron (N-end rule) pathway that functions in protein quality control, chromatin regulation, innate immune signaling, and meiotic chromosome dynamics. As an N-recognin, UBR2 recognizes destabilizing N-terminal residues on substrates for polyubiquitination and proteasomal degradation, mediating cytosolic quality control of misfolded proteins and degradation of cleaved NLRP1B to activate the inflammasome following anthrax lethal toxin exposure (PMID:20462952, PMID:31268597). UBR2 also acts as a scaffold E3 ligase that promotes HR6B-dependent monoubiquitylation of histones H2A and H2B, a function allosterically activated by N-degron dipeptides and essential for meiotic sex chromosome silencing, DNA double-strand break repair, and chromosome stability (PMID:20080676, PMID:22616001, PMID:16488448). UBR2 additionally catalyzes K63-linked ubiquitination of the kinase Lck to promote TCR signaling (PMID:38225265), stabilizes Tex19.1 protein non-degradatively during spermatogenesis (PMID:21103378), and is transcriptionally upregulated in cachectic muscle via the p38β–C/EBPβ axis (PMID:23568773).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Establishing UBR2 as an N-end rule E3 ligase essential for male meiosis answered whether a second mammalian N-recognin existed and had non-redundant physiological roles.

    Evidence UBR2 knockout mice showing spermatocyte arrest and female embryonic lethality, combined with N-degron substrate-binding assays

    PMID:14585983

    Open questions at the time
    • Molecular substrates of UBR2 in meiosis unknown
    • Basis of female-specific embryonic lethality unresolved
    • Mechanism of meiotic arrest not defined
  2. 2004 High

    Identification of UBR2's first physiological substrate (yeast Rpn4) and its partnership with Rad6 established that Ubr2 mediates proteasomal degradation of a transcription factor through internal-lysine ubiquitination.

    Evidence In vitro and in vivo ubiquitination assays in yeast with Ubr2/Rad6 targeting Rpn4

    PMID:15504724

    Open questions at the time
    • Whether mammalian UBR2 degrades transcription factors analogously was unknown
    • Structural basis of Ubr2-Rad6 interaction not defined
  3. 2004 High

    Discovery that UBR2 forms a stable complex with the RECQL4 helicase without targeting it for degradation revealed a non-degradative physical interaction, raising the question of whether UBR2 has scaffold functions.

    Evidence Reciprocal co-immunoprecipitation from HeLa cells, pulse-chase showing RECQL4 stability, ATPase assays

    PMID:15317757

    Open questions at the time
    • Functional consequence of UBR2-RECQL4 interaction for DNA repair undefined
    • Whether UBR2 ubiquitinates other complex members unknown
  4. 2006 High

    Demonstration that UBR2-deficient somatic cells exhibit chromosomal instability and impaired homologous recombination repair established UBR2 as a genome stability factor beyond its meiotic role.

    Evidence UBR2 KO MEFs with elevated chromosomal aberrations, mitomycin C hypersensitivity, impaired HR reporter assay, normal NHEJ

    PMID:16488448

    Open questions at the time
    • Direct HR substrate of UBR2 ubiquitination unknown
    • Whether HR defect is secondary to chromatin modification unresolved
  5. 2006 High

    UBR1/UBR2 double knockout revealed functional divergence and synergistic requirements in neurogenesis and cardiovascular development, showing that these two N-recognins are not fully redundant.

    Evidence Double KO mouse midgestation lethality with altered D-type cyclin and Notch1 expression in neural progenitors

    PMID:16606826

    Open questions at the time
    • Whether developmental phenotypes reflect direct ubiquitination of Notch/cyclin substrates unknown
    • Individual contributions of UBR1 vs UBR2 to each tissue phenotype not delineated
  6. 2010 High

    Three contemporaneous discoveries expanded UBR2's mechanism: it ubiquitinates histone H2A via HR6B to silence sex chromosomes during meiosis, it participates in cytosolic misfolded protein quality control, and it binds leucine to negatively regulate mTOR signaling.

    Evidence Chromatin localization and ubiquitination assays in UBR2 KO spermatocytes [PMID:20080676]; reconstituted ubiquitination of denatured luciferase plus genetic suppression of chaperone mutants in yeast [PMID:20462952]; leucine affinity pulldown and S6K1 phosphorylation assays [PMID:20298436]

    PMID:20080676 PMID:20298436 PMID:20462952

    Open questions at the time
    • Whether leucine-mTOR regulation is direct or via substrate competition unresolved
    • Identity of misfolded protein substrates in mammalian cells unknown
    • How allosteric dipeptide activation of histone ubiquitylation is structurally achieved unclear
  7. 2010 Medium

    Finding that UBR2 stabilizes Tex19.1 protein without degrading it established a non-canonical, non-degradative function of this E3 ligase in spermatogenesis.

    Evidence Co-IP of UBR2-Tex19.1 complex in testes; Tex19.1 protein absent in Ubr2 KO despite normal mRNA

    PMID:21103378

    Open questions at the time
    • Mechanism by which UBR2 binding prevents Tex19.1 degradation unknown
    • Whether UBR2 shields Tex19.1 from another E3 ligase not tested
  8. 2012 High

    Biochemical characterization of UBR2 as a scaffold E3 promoting HR6B-dependent mono- and polyubiquitylation of H2A/H2B, allosterically activated by N-degron dipeptides, unified its chromatin and N-end rule functions.

    Evidence In vitro histone ubiquitylation assays with allosteric dipeptide activation, UBR2 KO spermatocyte DSB repair analysis

    PMID:22616001

    Open questions at the time
    • Structural basis for allosteric activation not determined
    • Whether scaffold mechanism applies to non-histone chromatin substrates unknown
  9. 2013 High

    Two parallel advances linked UBR2 to kinetochore quality control in yeast (via Dsn1 ubiquitylation with Mub1) and to transcriptional upregulation in cancer cachexia through the p38β–C/EBPβ axis.

    Evidence Kinetochore particle purification and Dsn1 ubiquitylation/genetic rescue in yeast [PMID:23408894]; p38β/C/EBPβ KO mice with tumor cachexia model and UBR2 promoter reporter [PMID:23568773]

    PMID:23408894 PMID:23568773

    Open questions at the time
    • Whether mammalian UBR2 regulates kinetochore proteins unknown
    • Downstream UBR2 substrates mediating muscle wasting not identified
  10. 2019 High

    Genome-wide screens identified UBR2 as essential for NLRP1B inflammasome activation by anthrax lethal toxin, revealing that N-degron recognition of cleaved NLRP1B triggers its degradation and liberates the CARD domain to activate caspase-1.

    Evidence Two independent genome-wide screens (siRNA and CRISPR), ubiquitination assays identifying UBE2O as E2 partner

    PMID:31268597

    Open questions at the time
    • Whether UBR2 activates other inflammasome sensors via N-degron recognition unknown
    • Structural basis of NLRP1B neo-N-terminus recognition not resolved
  11. 2023 Medium

    Discovery that UBR2 is itself regulated by K48-linked polyubiquitination and proteasomal turnover under basal conditions, with stabilization under ER stress conferring cytoprotection, established UBR2 as an ER stress-responsive factor.

    Evidence K48-linkage-specific ubiquitination assays, UBR1/UBR2 double KO cells hypersensitive to ER stress-induced apoptosis

    PMID:38376480

    Open questions at the time
    • The E3 ligase responsible for UBR2 degradation under basal conditions was not identified in this study
    • Cytoprotective substrates of UBR2 during ER stress unknown
    • Single-lab finding awaiting independent confirmation
  12. 2024 High

    Identification of UBR2 as a K63-linked ubiquitin ligase for Lck at defined residues, regulated by DUSP22-mediated dephosphorylation and SCF-dependent degradation, placed UBR2 in TCR signaling and inflammatory cytokine production.

    Evidence K63-specific ubiquitination assays, Lck mutagenesis, DUSP22/UBR2 double KO epistasis, scRNA-seq in T cells

    PMID:38225265

    Open questions at the time
    • Whether UBR2 K63-ubiquitination of Lck involves N-degron recognition unknown
    • Upstream signals activating UBR2 phosphorylation in T cells not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • No structural model of mammalian UBR2 exists, the full repertoire of physiological substrates across tissues remains undefined, and how its N-degron recognition, scaffold E3, and K63-ligase activities are coordinately regulated is unknown.
  • No crystal or cryo-EM structure of mammalian UBR2
  • Systematic substrate identification across cell types not performed
  • Regulatory post-translational modifications beyond DUSP22-mediated dephosphorylation not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 6 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 GO:0005634 nucleus 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
CEBPBDUSP22HR6BLCKNLRP1RECQL4TEX19UBE2O
Complex memberships
Mub1-Ubr2 (yeast kinetochore QC complex)RECQL4-UBR2UBR2-HR6B (E3-E2 complex)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 UBR2 is an E3 ubiquitin ligase of the N-end rule pathway with substrate-binding properties highly similar to UBR1, recognizing proteins with destabilizing N-terminal residues (N-degrons). UBR2 knockout mice show spermatocyte apoptosis with arrest between leptotene/zygotene and pachytene, absence of intact synaptonemal complexes, and female embryonic lethality, establishing UBR2 as required for male meiosis and spermatogenesis. UBR2 knockout mouse construction, substrate-binding assays, histological analysis, genetic background manipulation Molecular and cellular biology High 14585983
2004 UBR2 forms a stable complex with RECQL4 (mutated in Rothmund-Thomson and RAPADILINO syndromes) as isolated from HeLa cells. The RECQL4-UBR1/UBR2 complex has DNA-stimulated ATPase activity. Despite its association with ubiquitin ligases, RECQL4 is not ubiquitylated in vivo and is a long-lived protein. Co-immunoprecipitation with anti-RECQL4 antibodies, ATPase and helicase assays, in vivo ubiquitylation assays, pulse-chase Human molecular genetics High 15317757
2004 Yeast Ubr2 ubiquitin ligase, partnering with the E2 enzyme Rad6, directly ubiquitinates the transcriptional activator Rpn4 (on internal lysines) to mediate its proteasomal degradation. Rad6 directly interacts with Ubr2 and is required for this ubiquitin-dependent degradation pathway. In vivo and in vitro ubiquitination assays, genetic deletion analysis, synthetic growth defect assays The Journal of biological chemistry High 15504724
2006 UBR2 is required for chromosome stability and homologous recombination repair. UBR2-deficient mouse fibroblasts show elevated chromosomal bridges, micronuclei, spontaneous chromosomal gaps (fragile sites replicated late in S phase), hypersensitivity to mitomycin C, and significantly impaired homologous recombination repair of double-strand breaks, while non-homologous end joining was normal. UBR2 knockout mouse embryonic fibroblasts, metaphase spreads, DSB repair reporter assay, mitomycin C sensitivity assay, NHEJ assay Mutation research High 16488448
2006 UBR1 and UBR2 double knockout embryos die at midgestation with defects in neurogenesis and cardiovascular development, including reduced proliferation and precocious migration/differentiation of neural progenitor cells, with altered expression of D-type cyclins and Notch1. UBR1 and UBR2 have divergent functions despite similar N-degron recognition. Double knockout mouse construction, histological and immunohistochemical analysis, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 16606826
2010 UBR2 localizes to meiotic chromatin (including unsynapsed axial elements) and mediates transcriptional silencing via ubiquitination of histone H2A. UBR2 interacts with the E2 enzyme HR6B and substrate H2A, promotes HR6B-H2A interaction and ubiquitin transfer, and UBR2-deficient spermatocytes fail to ubiquitinate H2A and fail to silence X- and Y-chromosome-linked genes. Chromatin immunolocalization, co-immunoprecipitation, ubiquitination assays, analysis of gene silencing in UBR2-/- spermatocytes Proceedings of the National Academy of Sciences of the United States of America High 20080676
2010 Yeast Ubr1 and Ubr2 E3 ligases promote degradation of unfolded/misfolded cytosolic proteins as a quality control pathway. Ubr1 catalyzes ubiquitinylation of denatured (but not native) luciferase in a purified system by direct interaction; Hsp70 stimulates polyubiquitinylation. Loss of Ubr1 and Ubr2 suppresses growth arrest from chaperone mutations. In vitro ubiquitination reconstitution with purified components, genetic suppressor analysis, protein folding assays Molecular biology of the cell High 20462952
2010 UBR2 (and UBR1) bind leucine directly via their substrate-recognition domain. UBR1/UBR2 overexpression reduces mTOR-dependent S6K1 phosphorylation, while their knockdown increases S6K1 phosphorylation in amino acid-starved cells. Leucine binding inhibits degradation of N-end rule substrates in vitro, identifying UBR1/UBR2 as negative regulators of the leucine-mTOR signaling pathway. Leucine-immobilized affinity bead pulldown, overexpression/knockdown S6K1 phosphorylation assay, in vitro N-end rule substrate degradation assay Genes to cells Medium 20298436
2010 UBR2 (Ubr2) forms a stable protein complex with Tex19.1 in mouse testes. Binding of Ubr2 to Tex19.1 metabolically stabilizes Tex19.1 protein during spermatogenesis (Tex19.1 mRNA is transcribed but protein is absent in Ubr2-deficient germ cells), revealing a non-canonical, non-degradative function of Ubr2 outside the N-end rule pathway. Co-immunoprecipitation, Western blotting in Ubr2-/- testes, genetic phenotype comparison PloS one Medium 21103378
2012 UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent monoubiquitylation and polyubiquitylation of histone H2A and H2B (but not H3 or H4), via a mechanism distinct from typical polyubiquitylation. UBR2's E3 activity in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. UBR2-deficient spermatocytes show impaired DSB repair and pachytene arrest; UBR2-deficient somatic cells show chromosomal instability and hypersensitivity to DNA damage. Chromatin fractionation, histone ubiquitylation assays, allosteric activation by dipeptide assay, DSB repair assays in KO cells, chromosome stability assays PloS one High 22616001
2013 Tumor-induced up-regulation of UBR2 in skeletal muscle is mediated by the p38β MAPK isoform, which phosphorylates C/EBPβ at Thr-188, enabling C/EBPβ binding to a functional cis-element in the UBR2 promoter. Genetic gain and loss of function of p38β, and genetic ablation of C/EBPβ, confirmed this signaling pathway is necessary and sufficient for UBR2 up-regulation in cachectic muscle. Pharmacological inhibition of p38α/β, p38β gain/loss-of-function in C2C12 myotubes, luciferase reporter assay, C/EBPβ KO mice with tumor model FASEB journal High 23568773
2013 The yeast Mub1/Ubr2 ubiquitin ligase complex associates with kinetochore particles via the CENP-C (Mif2) protein and regulates levels of the outer kinetochore protein Dsn1 via ubiquitylation, functioning as part of a quality control system monitoring kinetochore integrity. Kinetochore particle purification, co-immunoprecipitation, ubiquitylation assays, genetic deletion rescue of Dsn1 mutant PLoS genetics High 23408894
2019 UBR2 is required for NLRP1B inflammasome activation by anthrax lethal toxin (LT). LT cleaves NLRP1B after Lys44, exposing an N-terminal leucine; UBR2 recognizes this neo-N-terminus and mediates ubiquitination and degradation of cleaved NLRP1B in partnership with E2 enzyme UBE2O. This degradation triggers release of the noncovalently bound CARD domain, enabling downstream caspase-1 activation. UBR2 also mediates ubiquitination of constitutively autocleavage-generated NLRP1B fragments. Genome-wide siRNA screen, CRISPR-Cas9 knockout screen, dual-fluorescence reporter for ASC speck formation and pyroptosis, ubiquitination assays The EMBO journal High 31268597
2020 UBR2 protects cells from caspase-independent cell death (CICD) via the MAPK/Erk pathway. Genome-wide siRNA screening identified UBR2 as a regulator of CICD; UBR2 downregulation sensitized cells to CICD while overexpression was protective, and this protection required MAPK/Erk signaling. Genome-wide siRNA lethality screen, UBR2 knockdown/overexpression, MAPK/Erk pathway inhibition Cell death & disease Medium 33288741
2023 UBR1 and UBR2 function as ER stress sensors in mammalian cells. Under normal conditions, UBR1 and UBR2 are polyubiquitinated via Lys48-linked chains and degraded by the 26S proteasome. Under ER stress, UBR1 and UBR2 are stabilized and cells lacking both are hypersensitive to ER stress-induced apoptosis, indicating these cytoplasmic E3 ligases have anti-ER stress activities. ER stress induction, polyubiquitination assays (K48-linkage), double KO cells, apoptosis assays under ER stress Molecules and cells Medium 38376480
2024 DUSP22 dephosphorylates UBR2 at specific serine residues, leading to ubiquitin-mediated UBR2 degradation (via SCF E3 ligase complex through K48-linked ubiquitination at multiple lysines). UBR2 in turn induces K63-linked ubiquitination of Lck at Lys99 and Lys276, promoting Lck Tyr394 phosphorylation and activation downstream of TCR signaling. UBR2-mediated Lck activation promotes proinflammatory cytokine expression, and UBR2 genomic deletion attenuates inflammatory phenotypes caused by DUSP22 knockout. Dephosphorylation assays, ubiquitination assays (K48/K63-specific), site-directed mutagenesis of Lck ubiquitination sites, CRISPR KO, single-cell RNA sequencing, T cell activation assays Nature communications High 38225265

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Female lethality and apoptosis of spermatocytes in mice lacking the UBR2 ubiquitin ligase of the N-end rule pathway. Molecular and cellular biology 130 14585983
2010 Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Molecular biology of the cell 121 20462952
2004 RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Human molecular genetics 89 15317757
2019 The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin. The EMBO journal 84 31268597
2017 UBR2 Enriched in p53 Deficient Mouse Bone Marrow Mesenchymal Stem Cell-Exosome Promoted Gastric Cancer Progression via Wnt/β-Catenin Pathway. Stem cells (Dayton, Ohio) 81 28895255
2006 Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America 78 16606826
2004 Rpn4 is a physiological substrate of the Ubr2 ubiquitin ligase. The Journal of biological chemistry 75 15504724
2010 UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 74 20080676
2013 Signaling mechanism of tumor cell-induced up-regulation of E3 ubiquitin ligase UBR2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38 23568773
2012 UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells. PloS one 32 22616001
2010 The ubiquitin ligase Ubr2, a recognition E3 component of the N-end rule pathway, stabilizes Tex19.1 during spermatogenesis. PloS one 32 21103378
2010 Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine-mTOR signaling pathway. Genes to cells : devoted to molecular & cellular mechanisms 31 20298436
2013 The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein. PLoS genetics 24 23408894
2006 Loss of Ubr2, an E3 ubiquitin ligase, leads to chromosome fragility and impaired homologous recombinational repair. Mutation research 21 16488448
2024 The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling. Nature communications 18 38225265
2014 The Ubr2 Gene is Expressed in Skeletal Muscle Atrophying as a Result of Hind Limb Suspension, but not Merg1a Expression Alone. European journal of translational myology 16 26913136
2020 The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway. Cell death & disease 12 33288741
2016 Synergistic Control of Kinetochore Protein Levels by Psh1 and Ubr2. PLoS genetics 7 26891228
2011 Single nucleotide polymorphism in the UBR2 gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest. Journal of assisted reproduction and genetics 7 21573678
2023 N-recognins UBR1 and UBR2 as central ER stress sensors in mammals. Molecules and cells 5 38376480
2017 Defects in methylation of arginine 37 on CENP-A/Cse4 are compensated by the ubiquitin ligase complex Ubr2/Mub1. FEMS yeast research 4 28158539
2016 Association of single nucleotide polymorphisms in UBR2 gene with idiopathic aspermia or oligospermia in Sichuan, China. Andrologia 2 26940145
2025 Saccharomyces cerevisiae Mub1, a substrate adaptor of E3 ubiquitin ligase Ubr2, modulates sensitivity to cell wall stressors through multiple transcription factors. The FEBS journal 1 40165610
2025 Upregulation of E3 ligase UBR2 in acetaldehyde-treated C2C12 myotubes and its potential involvement in fast-twitch muscle atrophy in alcohol-fed rats. Alcohol, clinical & experimental research 1 40511880
2025 The role of UBR2 in triple-negative breast cancer and its implications for immune checkpoint blockade therapy. Discover oncology 0 40676335