Affinage

UBR1

E3 ubiquitin-protein ligase UBR1 · UniProt Q8IWV7

Length
1749 aa
Mass
200.2 kDa
Annotated
2026-04-28
62 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBR1 is a RING-type E3 ubiquitin ligase that operates through multiple substrate-recognition modes to control protein homeostasis, signaling, and development. Its UBR box (type-1 site) and N domain (type-2 site) bind destabilizing N-terminal basic and hydrophobic residues, respectively, while allosteric activation by amino acids or dipeptides at these sites stimulates ubiquitylation of internal-degron substrates such as CUP9 and the lipid droplet protein Plin2, thereby coupling amino acid sensing to proteolysis (PMID:18566452, PMID:37057345). Beyond canonical N-degron recognition, UBR1 functions as a chaperone-dependent protein quality control ligase—requiring Hsp70 ATPase cycling, co-chaperones Sis1 and Sse1—to ubiquitylate misfolded cytoplasmic, ERAD, and endosomal substrates, and its specificity is further reprogrammed under stress by the SHRED pathway effector Roq1, which engages both type-1 and hydrophobic binding sites to redirect UBR1 toward misfolded proteins (PMID:32966159, PMID:29861160, PMID:39920309). Loss-of-function mutations in human UBR1 cause Johanson-Blizzard syndrome, characterized by exocrine pancreatic destruction and developmental defects (PMID:16311597).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Establishing that mammalian UBR1 is a functionally conserved N-end rule E3 ligase with tissue-specific physiological roles resolved whether the yeast pathway operated in mammals and revealed organismal consequences of its loss.

    Evidence UBR1−/− mouse construction; heterologous complementation of yeast ubr1Δ; tissue-specific phenotyping

    PMID:11689692

    Open questions at the time
    • Mechanism of tissue-specific compensation by UBR1-like proteins not defined
    • Substrates responsible for muscle and adipose phenotypes not identified
  2. 2005 High

    Identification of UBR1 loss-of-function mutations as the cause of Johanson-Blizzard syndrome established a direct disease link and revealed that UBR1-mediated proteolysis is essential for pancreatic acinar cell survival.

    Evidence Genetic mapping in JBS families; mutation identification; Ubr1−/− mouse pancreatic functional assays

    PMID:16311597

    Open questions at the time
    • Specific UBR1 substrates whose accumulation causes acinar cell destruction remain unknown
    • Whether JBS phenotypes beyond pancreas involve distinct substrates is unresolved
  3. 2006 High

    Demonstrating that UBR1 ubiquitylates c-Fos in the cytoplasm and that ERK5 phosphorylation of c-Fos disrupts this interaction established UBR1 as a signal-regulated E3 for a key transcription factor, broadening its repertoire beyond N-degron substrates.

    Evidence Co-IP; ubiquitylation assay; c-Fos phosphosite mutagenesis; siRNA knockdown in mammalian cells

    PMID:17018293

    Open questions at the time
    • Whether c-Fos is recognized through an N-degron or internal degron is unresolved
    • Contribution of UBR1-c-Fos axis to JBS phenotypes not tested
  4. 2006 High

    UBR1/UBR2 double knockout causing midgestational lethality with neurogenesis and cardiovascular defects revealed essential, partially redundant developmental roles and implicated altered cyclin D and Notch1 expression as downstream consequences.

    Evidence UBR1−/−UBR2−/− double-knockout mouse embryos; histology; immunofluorescence; Western blot

    PMID:16606826

    Open questions at the time
    • Whether cyclins and Notch1 are direct UBR1/UBR2 substrates or indirect targets is unknown
    • Individual contributions of UBR1 versus UBR2 in each tissue not dissected
  5. 2008 High

    Biochemical dissection of three distinct substrate-binding sites within UBR1's first ~700 residues—type-1, type-2, and an internal-degron site—with allosteric cross-talk between them defined the molecular logic of multi-modal substrate recognition.

    Evidence Separation-of-function mutations; fluorescence polarization and SPR binding assays; reconstituted in vitro ubiquitylation

    PMID:18566452

    Open questions at the time
    • Structural basis for allosteric coupling between type-1/2 and internal-degron sites not visualized
    • Full inventory of internal-degron substrates beyond CUP9 not established
  6. 2008 High

    Discovery that UBR1 phosphorylation at Ser300 by Yck1/Yck2, priming sequential GSK3-family Mck1 phosphorylations, regulates CUP9-dependent peptide import established post-translational tuning of UBR1 activity.

    Evidence In vivo phosphosite mapping; kinase-deletion mutants; site-directed mutagenesis; peptide import assays in yeast

    PMID:19033468

    Open questions at the time
    • Whether phosphorylation alters UBR1 substrate selectivity beyond CUP9 pathway is untested
    • Mammalian equivalent phosphoregulation not identified
  7. 2008 High

    Establishing UBR1 as a cytoplasmic protein quality control E3 ligase for misfolded proteins—independent of its N-end rule function—revealed a second major arm of UBR1 biology parallel to nuclear San1.

    Evidence ubr1Δ yeast; in vivo degradation assays of misfolded reporter proteins

    PMID:19041308 PMID:20080635

    Open questions at the time
    • How UBR1 distinguishes misfolded from native conformers at a structural level remains unknown
  8. 2010 High

    In vitro reconstitution showing UBR1 directly binds denatured (but not native) substrates and that Hsp70 stimulates their polyubiquitylation clarified that chaperone and ligase cooperate directly rather than acting in separate steps.

    Evidence Purified component ubiquitylation assay with denatured luciferase; Co-IP; chaperone mutant suppression genetics

    PMID:20462952

    Open questions at the time
    • Whether Hsp70 delivers substrate to UBR1 or activates UBR1 conformationally is unresolved
  9. 2010 High

    Discovery that UBR1 and the HECT E3 Ufd4 form a heterodimeric complex with enhanced polyubiquitin chain processivity established a paradigm for E3-E3 cooperation and expanded UBR1's reach to UFD substrates.

    Evidence Co-immunoprecipitation; in vitro ubiquitylation assays; genetic epistasis in yeast

    PMID:21076411

    Open questions at the time
    • Structural basis of Ubr1-Ufd4 interaction undefined
    • In vivo significance of enhanced processivity for specific substrates not determined
  10. 2013 Medium

    Identifying Type II Hsp40 Sis1 as a required co-chaperone that sequentially cooperates with Hsp70 to deliver misfolded substrates to UBR1 specified the chaperone relay pathway upstream of ubiquitylation.

    Evidence Genetic deletion; fluorescence microscopy of misfolded GFP reporter puncta; degradation assays in yeast

    PMID:23341891

    Open questions at the time
    • Direct physical interaction between Sis1 and Ubr1 not demonstrated
    • Whether other Hsp40 family members substitute in mammalian cells is untested
  11. 2013 Medium

    Demonstrating UBR1 participation in ERAD of polytopic membrane proteins Ste6* and human CFTR, particularly when canonical ER ligases are absent, extended UBR1's QC role to retrotranslocated ER substrates.

    Evidence Genetic epistasis with hrd1Δ/doa10Δ; in vivo degradation assays; Co-IP in yeast

    PMID:23988329

    Open questions at the time
    • How UBR1 is recruited to retrotranslocated substrates at the ER membrane is unclear
    • Quantitative contribution relative to canonical ERAD ligases in wild-type cells is unknown
  12. 2018 High

    Discovery of the SHRED pathway—stress-induced Roq1 cleavage by Ynm3 generating a fragment that reprograms UBR1 substrate specificity—revealed a regulated mechanism to redirect UBR1 from N-degron substrates toward misfolded proteins during stress.

    Evidence Genetic epistasis; Co-IP; in vivo degradation assays; transcriptional profiling in yeast

    PMID:29861160

    Open questions at the time
    • Mammalian equivalent of SHRED pathway not identified
    • Full repertoire of SHRED-redirected substrates uncharacterized
  13. 2020 High

    A bead-based reconstitution with immobilized misfolded substrate proved that Hsp70 ATPase cycling (not simply substrate holding) is directly required for UBR1-mediated ubiquitylation, resolving whether chaperone enzymatic activity was essential.

    Evidence Bead-immobilized substrate assay eliminating substrate conformation changes; Hsp70 ATPase mutants; nucleotide exchange factor requirement

    PMID:32966159

    Open questions at the time
    • Whether Hsp70 transfers substrate to UBR1 or acts as a co-factor during catalysis is still ambiguous
    • Structural view of Hsp70-UBR1-substrate ternary complex lacking
  14. 2021 High

    Cryo-EM structures of yeast UBR1 with its E2 Ubc2, ubiquitin, and N-degron peptides visualized the Ubc2-binding region and acceptor-ubiquitin-binding loop, explaining how UBR1 mediates both initiation and K48-linked chain elongation at a structural level.

    Evidence Cryo-EM with chemically synthesized reaction intermediate mimics; active-site mutagenesis validation

    PMID:34789879

    Open questions at the time
    • Structure of full-length UBR1 with misfolded substrate or Roq1 not obtained
    • Structural basis of allosteric activation by dipeptides/amino acids not visualized
  15. 2023 High

    Reconstitution of amino acid-dependent UBR1 activation of Plin2 ubiquitylation established UBR1 as a bona fide amino acid sensor whose ligand-induced conformational change relieves autoinhibition, linking N-degron pockets to metabolic regulation of lipid droplets.

    Evidence Cell-free ubiquitylation with purified proteins; binding-pocket mutagenesis; Drosophila genetics

    PMID:37057345

    Open questions at the time
    • Structural basis of autoinhibition and its relief by amino acids not visualized
    • Whether other metabolic substrates are similarly regulated is unknown
  16. 2025 High

    Dissection of Roq1's heterobivalent binding to UBR1—N-terminal arginine engaging the type-1 site as a pseudosubstrate and a hydrophobic motif independently accelerating misfolded protein ubiquitylation—defined the molecular logic of SHRED-mediated reprogramming.

    Evidence Roq1 motif mutagenesis; in vitro ubiquitylation assays; Co-IP; yeast genetic assays

    PMID:39920309

    Open questions at the time
    • Whether the hydrophobic motif contacts a defined surface on UBR1 distinct from the type-2 site is unresolved
    • In vivo stoichiometry and dynamics of Roq1-UBR1 complex formation during stress not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis of UBR1 autoinhibition and its allosteric relief by amino acids; how Hsp70 physically engages UBR1 during substrate handoff; identification of mammalian SHRED-equivalent pathways; and the specific substrates whose accumulation drives JBS pancreatic pathology.
  • No structure of full-length UBR1 in autoinhibited versus activated state
  • Hsp70-UBR1-substrate ternary complex not structurally resolved
  • Mammalian Roq1 ortholog or functional analog not identified
  • JBS-causative substrate(s) in acinar cells remain unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016874 ligase activity 6 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005829 cytosol 5 GO:0005634 nucleus 1 GO:0005768 endosome 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-1643685 Disease 1 R-HSA-9612973 Autophagy 1
Partners
CFOSRECQL4ROQ1SIS1SSA1UBE2AUFD4YAP1
Complex memberships
RECQL4-UBR1 complexUbr1-Ufd4 heterodimeric E3 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cryo-EM structures of yeast Ubr1 in complex with Ubc2 (E2), ubiquitin, and N-degron peptides revealed key structural elements for ubiquitination: a Ubc2-binding region and an acceptor ubiquitin-binding loop on Ubr1 mediate both initiation (first ubiquitin transfer) and elongation (polyubiquitin chain extension) steps, with chemical mimics of reaction intermediates used to trap each state. Cryo-EM structure determination with chemically synthesized reaction intermediate mimics; active-site mutagenesis validation Nature High 34789879
2008 UBR1 (yeast) contains three distinct substrate-binding sites within its first ~700 residues: a type-1 site (UBR motif) for basic N-terminal residues (Arg, Lys, His), a type-2 site for bulky hydrophobic N-terminal residues (Trp, Phe, Tyr, Leu, Ile), and a third internal degron-binding site targeting CUP9. Binding affinity (Kd ~1 µM) was measured by fluorescence polarization and surface plasmon resonance; type-1/2 site occupancy by cognate dipeptides allosterically stimulates CUP9 ubiquitylation, reconstituted in a fully defined in vitro system. Genetic screen for separation-of-function mutations; fluorescence polarization; surface plasmon resonance; in vitro ubiquitylation reconstitution The Journal of biological chemistry High 18566452
2010 The RING-type Ubr1 E3 and the HECT-type Ufd4 E3 physically interact and form a functional complex. Ubr1 alone can polyubiquitylate N-end rule substrates, but the Ubr1-Ufd4 complex is more processive, producing longer polyubiquitin chains; conversely, Ubr1 enhances Ufd4-mediated ubiquitylation of UFD substrates. Ubr1 was also shown to recognize the N-terminal ubiquitin moiety of UFD substrates. Co-immunoprecipitation; in vitro ubiquitylation assays; genetic epistasis Nature cell biology High 21076411
2009 Yeast Ubr1 mediates chaperone-dependent ubiquitination of misfolded cytoplasmic proteins as a protein quality control E3 ligase, a function distinct from its N-end rule role. This activity is parallel to nuclear San1-mediated QC; Ubr1 requires chaperones and protects cells from proteotoxic stress. Genetic epistasis (ubr1Δ, san1Δ single and double mutants); biochemical ubiquitination assays; phenotypic analysis under proteotoxic stress Proceedings of the National Academy of Sciences of the United States of America High 20080635
2008 Yeast Ubr1 is the E3 ubiquitin ligase responsible for proteasomal degradation of misfolded cytoplasmic proteins, functioning independently of its classical N-end rule substrate-recognition activity. Genetic deletion (ubr1Δ); in vivo degradation assays of misfolded reporter proteins FEBS letters High 19041308
2010 Yeast Ubr1 directly binds denatured (but not native) luciferase in a purified system and catalyzes its ubiquitylation; Hsp70 stimulates polyubiquitylation of the denatured substrate. Loss of Ubr1 (and Ubr2) suppresses growth arrest caused by chaperone mutation, indicating partitioning of foldable conformers toward the proteasome. In vitro ubiquitylation assay with purified components; Co-IP; genetic epistasis (chaperone mutant suppression) Molecular biology of the cell High 20462952
2020 HSP70 ATPase activity is directly required for Ubr1-mediated ubiquitination of misfolded cytoplasmic proteins. Using a bead-based in vitro assay with covalently immobilized misfolded substrate, only Hsp70 (with its ATPase cycle, nucleotide exchange factor Sse1, and J-proteins) was required alongside Ubr1 for ubiquitination, demonstrating direct chaperone involvement rather than indirect effects on substrate conformation. Bead-based in vitro ubiquitination assay; ATPase mutants; genetic analysis of Hsp70 co-chaperones Molecular biology of the cell High 32966159
2013 The Type II Hsp40 Sis1 cooperates sequentially with Hsp70 to deliver misfolded cytosolic proteins to Ubr1 for proteasomal degradation. Compromise of Sis1 or Ubr1 leads to accumulation of misfolded reporter in Triton X-100-soluble puncta; Ubr1 mediates degradation of substrate released from these cytosolic protein handling centers. Genetic deletion; fluorescence microscopy; degradation assays of misfolded GFP reporter PloS one Medium 23341891
2013 Yeast Ubr1 participates in ERAD of polytopic membrane proteins Ste6* and human CFTR, functioning together with Hsp70 chaperone Ssa1 and AAA-ATPase Cdc48 to direct retrotranslocated substrates to the proteasome, particularly under stress conditions or absence of canonical ER ligases Hrd1 and Doa10. Genetic epistasis (ubr1Δ, hrd1Δ, doa10Δ); in vivo degradation assays; Co-IP Proceedings of the National Academy of Sciences of the United States of America Medium 23988329
2006 UBR1 E3 ligase ubiquitylates c-Fos in the cytoplasm to promote its degradation. UBR1 expression is induced by STAT3, and UBR1 physically interacts with c-Fos. ERK5 disrupts UBR1-c-Fos interaction by phosphorylating Ser32 of c-Fos, and inhibits nuclear export of c-Fos by phosphorylating Thr232 in its NES, thereby spatiotemporally controlling c-Fos/AP-1 activity and cell growth. Co-immunoprecipitation; ubiquitylation assay; siRNA knockdown; site-directed mutagenesis; cell proliferation assay Molecular cell High 17018293
2005 UBR1 is an E3 ubiquitin ligase of the N-end rule pathway essential for exocrine pancreatic function; loss-of-function mutations cause Johanson-Blizzard syndrome with destructive pancreatitis. In Ubr1−/− mice, impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury confirm a physiological role for UBR1-mediated proteolysis in acinar cell homeostasis. Ubr1−/− mouse model; functional pancreatic assays (stimulus-secretion coupling); genetic mapping; mutation identification in patients Nature genetics High 16311597
2001 Mouse UBR1 (200 kDa) can rescue the N-end rule pathway in ubr1Δ S. cerevisiae in the presence of cognate mouse E2, confirming functional conservation. UBR1−/− mice have reduced skeletal muscle and adipose tissue mass, and skeletal muscle of UBR1−/− mice lacks the N-end rule pathway and shows abnormal regulation of fatty acid synthase upon starvation, whereas fibroblasts retain N-end rule activity due to UBR1-like proteins. Heterologous complementation in yeast; UBR1−/− mouse construction; Western blot; N-end rule substrate stability assays Molecular and cellular biology High 11689692
2004 RECQL4 (mutated in Rothmund-Thomson/RAPADILINO syndromes) forms a stable complex with UBR1 and UBR2 in HeLa cells. The isolated RECQL4-UBR1/2 complex has DNA-stimulated ATPase activity. RECQL4 in this complex is not ubiquitylated and is a long-lived protein, indicating a non-degradative role for UBR1 in this interaction. Co-immunoprecipitation; ATPase activity assay; in vivo ubiquitylation assay; pulse-chase stability assay Human molecular genetics Medium 15757315
2006 UBR1−/−UBR2−/− double-knockout mouse embryos die at midgestation with defects in neurogenesis (reduced neural progenitor proliferation, precocious migration/differentiation) and cardiovascular development, with altered expression of D-type cyclins and Notch1, demonstrating non-redundant, tissue-specific roles of UBR1 and UBR2 beyond N-degron recognition. Double-knockout mouse construction; histology; immunofluorescence; Western blot for cell-cycle regulators Proceedings of the National Academy of Sciences of the United States of America High 16606826
2008 Yeast Ubr1 is phosphorylated in vivo at multiple sites. Casein kinases Yck1/Yck2 phosphorylate Ubr1 on Ser300, priming sequential phosphorylations by Mck1 (GSK3-family) at Ser296, Ser292, Thr288, and Tyr277. Phosphorylation at Ser300 plays a major role in controlling Cup9-dependent regulation of peptide import via the N-end rule pathway. In vivo phosphorylation mapping; kinase-deletion mutants; site-directed mutagenesis; peptide import assays Proceedings of the National Academy of Sciences of the United States of America High 19033468
2010 CDK1/2-mediated phosphorylation of the E2 enzyme Ubc2/Rad6 at Ser120 regulates its activity with the N-end rule E3α/UBR1 ligase. Ubc2bS120D is 20-fold less active with UBR1 in vitro (8-fold increase in Km, 2.5-fold decrease in Vmax for initiation), while S120A shows defects in chain elongation, revealing that E2 phosphorylation differentially tunes UBR1-mediated ubiquitin conjugation steps. In vitro E3α/UBR1-catalyzed conjugation kinetics; E2 phosphomutants; cell-based N-end rule degradation assay The Journal of biological chemistry Medium 21041297
2018 The SHRED cascade reprograms Ubr1 substrate specificity: various stresses induce Roq1, which is cleaved by the HtrA protease Ynm3; cleaved Roq1 interacts with Ubr1 and transforms its substrate specificity to accelerate proteasomal degradation of both misfolded proteins and native ER membrane proteins, expanding Ubr1's QC repertoire during stress. Genetic epistasis; Co-immunoprecipitation; in vivo degradation assays; transcriptional profiling Molecular cell High 29861160
2025 Roq1 controls Ubr1 reprogramming through two cooperating multifunctional motifs: its N-terminal arginine (engaging Ubr1's type-1 substrate-binding site as a pseudosubstrate) regulates ubiquitination of N-degron substrates and folded proteins, while a short hydrophobic motif accelerates ubiquitination of misfolded proteins. These constitute a heterobivalent binding mechanism to reprogram Ubr1. Mutagenesis of Roq1 motifs; in vitro ubiquitination assays; Co-immunoprecipitation; yeast genetic assays The EMBO journal High 39920309
2010 UBR1 and UBR2 bind leucine directly via leucine-immobilized affinity beads and function as negative regulators of the leucine-mTOR signaling pathway. Overexpression reduces mTOR-dependent S6K1 phosphorylation; knockdown increases S6K1 phosphorylation in amino acid-starved cells. Leucine binding to the substrate-recognition domain of UBR2 inhibits N-end rule substrate degradation in vitro. Leucine-affinity pulldown; overexpression and siRNA knockdown; in vitro ubiquitination assay; S6K1 phosphorylation assay Genes to cells Medium 20298436
2023 UBR1 acts as an amino acid sensor that targets the lipid droplet protein Plin2 for ubiquitin-proteasome degradation in an amino acid-dependent manner. Amino acid binding to Ubr1's two canonical substrate-binding pockets (for basic and hydrophobic amino acids) allosterically activates Ubr1 by relieving auto-inhibition, enabling Plin2 ubiquitination; loss of amino acid sensing by Ubr1 leads to Plin2 accumulation and steatosis. Reconstituted in cell-free in vitro systems. Cell-free in vitro ubiquitination assay; amino acid-binding assay with purified proteins; pulldown; immunoprecipitation in mammalian cells; Drosophila genetics Journal of cachexia, sarcopenia and muscle High 37057345
2011 UBR1 is required for efficient degradation of Hsp90 client protein kinases (Akt, Cdk4) upon Hsp90 inhibition by geldanamycin. Ubr1−/− cells show accelerated recovery of client levels after drug treatment. UBR1 is itself an Hsp90 client (levels fall upon geldanamycin treatment). UBR1 functionally overlaps with CHIP E3 ligase in protein kinase quality control. Ubr1−/− mouse embryonic fibroblasts; Western blot of kinase client stability; geldanamycin treatment; siRNA knockdown Experimental cell research Medium 21983172
2013 UBR1 deletion specifically impairs degradation of glucocorticoid receptor and androgen receptor (but not estrogen receptor α) when their misfolding is promoted by Hsp90 inhibition, demonstrating substrate specificity among Hsp90 client nuclear receptors. UBR1-null cells; Western blot of receptor stability; Hsp90 inhibitor treatment FEBS open bio Medium 24251101
2019 Ubr1 preferentially targets mistranslocated secretory and mitochondrial proteins in the cytosol by recognizing P2-position residues that encode cellular location signals naturally embedded in most proteins. Systematic mutagenesis of single residues at the P2 position of misfolded proteins and bioinformatic analysis of the yeast proteome established this mechanism. Systematic P2-position mutagenesis; in vivo degradation assays in ubr1Δ yeast; bioinformatic proteome analysis Journal of cell science Medium 30940687
2024 UBR1 directly interacts with ACE2 and promotes its ubiquitination and degradation in a sex-specific manner (regulated by testosterone but not estradiol) in hypertensive male mice. In vivo UBR1 knockdown restores ACE2 levels and transiently reduces blood pressure via intracerebroventricular delivery. UBR1 and Nedd4-2 synergistically ubiquitinate ACE2. Proteomics; Co-immunoprecipitation; siRNA in vivo knockdown; blood pressure measurement; cell treatment with sex hormones Hypertension Medium 39601126
2022 UBR1 functions as a protein quality control E3 ubiquitin ligase at endosomes, promoting ESCRT-dependent lysosomal degradation of mutant MLC1 and selective endosomal autophagy (endophagy) of ubiquitinated and arginylated cargoes via SQSTM1/p62 during endosomal stress or cytosolic Ca2+ assault. Loss of UBR1 or arginylation elicits endosomal compartment stress. Co-immunoprecipitation; ubiquitination assay; fluorescence microscopy; genetic knockdown; autophagy flux assay Cellular and molecular life sciences Medium 35233680
2024 UBR1 directly interacts with YAP and promotes its monoubiquitylation, which competitively suppresses polyubiquitylation and extends YAP protein half-life, thereby stabilizing YAP and promoting anaplastic thyroid carcinoma cell proliferation and migration. Co-immunoprecipitation; ubiquitylation assay; siRNA knockdown; half-life measurement; xenograft tumor model Scientific reports Medium 39174635
2018 C. elegans UBR-1 regulates glutamate metabolism in premotor interneurons of the reversal motor circuit: ubr-1 loss elevates glutamate levels, causing synchronized A-class motor neuron activation and motor deficit. This deficit is rescued by removing GOT-1 (aspartate-to-glutamate transaminase), placing UBR-1 upstream of GOT-1 in a glutamate homeostasis pathway. C. elegans genetics; calcium imaging; metabolite measurement; epistasis (ubr-1;got-1 double mutant) PLoS genetics Medium 29649217
2011 Fission yeast Ubr1 ubiquitin ligase degrades the active, nuclear form of the Pap1 bZIP transcription factor to downregulate oxidative stress response. Ubr1 is enriched in the nucleus where Pap1 is preferentially degraded; inactive (DNA-binding-defective) Pap1 is stabilized, indicating Ubr1 targets the DNA-bound active conformation. Genetic deletion (ubr1Δ); protein stability assays; subcellular fractionation/localization; mutagenesis of Pap1 DNA-binding domain Molecular microbiology Medium 21410566
2006 Loss of Ubr1 in mice promotes chromosome missegregation (anaphase bridges, lagging chromosomes, hypodiploid karyotypes) in B lymphocytes and fibroblasts, demonstrating a role for UBR1 in chromosome stability. This cooperates with TLX1/HOX11 overexpression to accelerate B-cell lymphomagenesis. Ubr1−/− mouse; micronucleus assay; karyotyping; siRNA knockdown; mitotic figure analysis Oncogene Medium 16862188

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1. Proceedings of the National Academy of Sciences of the United States of America 229 20080635
2005 Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nature genetics 194 16311597
2008 Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS letters 132 19041308
2010 Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Molecular biology of the cell 121 20462952
2001 Construction and analysis of mouse strains lacking the ubiquitin ligase UBR1 (E3alpha) of the N-end rule pathway. Molecular and cellular biology 120 11689692
2010 The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nature cell biology 117 21076411
2021 Structural insights into Ubr1-mediated N-degron polyubiquitination. Nature 96 34789879
2008 Substrate-binding sites of UBR1, the ubiquitin ligase of the N-end rule pathway. The Journal of biological chemistry 94 18566452
2006 Spatiotemporal regulation of c-Fos by ERK5 and the E3 ubiquitin ligase UBR1, and its biological role. Molecular cell 93 17018293
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
2014 Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation. Proceedings of the National Academy of Sciences of the United States of America 83 24449897
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
2013 The Type II Hsp40 Sis1 cooperates with Hsp70 and the E3 ligase Ubr1 to promote degradation of terminally misfolded cytosolic protein. PloS one 66 23341891
2013 Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation. Proceedings of the National Academy of Sciences of the United States of America 46 23988329
2011 Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. PloS one 43 21931868
2012 The yeast ubr1 ubiquitin ligase participates in a prominent pathway that targets cytosolic thermosensitive mutants for degradation. G3 (Bethesda, Md.) 35 22670231
2008 Regulation of peptide import through phosphorylation of Ubr1, the ubiquitin ligase of the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America 33 19033468
2018 SHRED Is a Regulatory Cascade that Reprograms Ubr1 Substrate Specificity for Enhanced Protein Quality Control during Stress. Molecular cell 31 29861160
2014 Mutations in the human UBR1 gene and the associated phenotypic spectrum. Human mutation 31 24599544
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
2020 Circ-UBR1 facilitates proliferation, metastasis, and inhibits apoptosis in breast cancer by regulating the miR-1299/CCND1 axis. Life sciences 23 33259864
2011 Fission yeast Ubr1 ubiquitin ligase influences the oxidative stress response via degradation of active Pap1 bZIP transcription factor in the nucleus. Molecular microbiology 23 21410566
2011 UBR1 promotes protein kinase quality control and sensitizes cells to Hsp90 inhibition. Experimental cell research 23 21983172
2018 HSV-1-encoded microRNA miR-H1 targets Ubr1 to promote accumulation of neurodegeneration-associated protein. Virus genes 22 29541932
2008 Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. World journal of gastroenterology 20 19058315
2010 Ser(120) of Ubc2/Rad6 regulates ubiquitin-dependent N-end rule targeting by E3{alpha}/Ubr1. The Journal of biological chemistry 17 21041297
2023 Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle. Journal of cachexia, sarcopenia and muscle 15 37057345
2008 Johanson-Blizzard syndrome caused by identical UBR1 mutations in two unrelated girls, one with a cardiomyopathy. American journal of medical genetics. Part A 14 19006206
2020 Direct involvement of Hsp70 ATP hydrolysis in Ubr1-dependent quality control. Molecular biology of the cell 13 32966159
2021 Circular RNA UBR1 promotes the proliferation, migration, and invasion but represses apoptosis of lung cancer cells via modulating microRNA-545-5p/SSFA2 axis. Bioengineered 12 34787049
2010 Novel UBR1 gene mutation in a patient with typical phenotype of Johanson-Blizzard syndrome. European journal of pediatrics 11 20556423
2006 Loss of Ubr1 promotes aneuploidy and accelerates B-cell lymphomagenesis in TLX1/HOX11-transgenic mice. Oncogene 11 16862188
2021 Ubr1-mediated ubiquitylation orchestrates asexual development, polar growth, and virulence-related cellular events in Beauveria bassiana. Applied microbiology and biotechnology 10 33686455
2019 The N-end rule pathway and Ubr1 enforce protein compartmentalization via P2-encoded cellular location signals. Journal of cell science 10 30940687
2022 Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress. Cellular and molecular life sciences : CMLS 9 35233680
2020 Loss of protein quality control gene UBR1 sensitizes Saccharomyces cerevisiae to the aminoglycoside hygromycin B. Fine focus 9 33554225
2015 Two novel UBR1 gene mutations ın a patient with Johanson Blizzard Syndrome: A mild phenotype without mental retardation. Gene 9 26149651
2013 Specificity in the actions of the UBR1 ubiquitin ligase in the degradation of nuclear receptors. FEBS open bio 9 24251101
2017 Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis. Molecular genetics & genomic medicine 8 29178640
2002 Behavioral characterization of mice lacking the ubiquitin ligase UBR1 of the N-end rule pathway. Genes, brain, and behavior 8 12882367
2020 Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 7 31980351
2015 Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung. Cancer research 7 26183928
2012 Essential role of Ubr11, but not Ubr1, as an N-end rule ubiquitin ligase in Schizosaccharomyces pombe. Yeast (Chichester, England) 7 23348717
2024 UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension. Hypertension (Dallas, Tex. : 1979) 6 39601126
2023 Upregulation of UBR1 m6A Methylation by METTL14 Inhibits Autophagy in Spinal Cord Injury. eNeuro 6 37094938
2018 The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans. PLoS genetics 6 29649217
2023 N-recognins UBR1 and UBR2 as central ER stress sensors in mammals. Molecules and cells 5 38376480
2020 Johanson-Blizzard's Syndrome with a Novel UBR1 Mutation. Journal of pediatric genetics 4 35769968
2025 The UBR Domain of Plant Ubr1 Homolog PRT6 Accommodates Basic and Hydrophobic Amino Termini for Substrate Recognition. Journal of molecular biology 3 39799992
2024 Johanson-Blizzard syndrome caused by novel UBR1 mutation in four Saudi patients. JPGN reports 3 38756130
2024 UBR1 promotes anaplastic thyroid carcinoma progression via stabilizing YAP through monoubiquitylation. Scientific reports 3 39174635
2016 Variants in the UBR1 gene are not associated with chronic pancreatitis in Japan. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2 27397733
2025 Glutamate metabolism disruption in Johanson-Blizzard syndrome: Insights from C. elegans ubr-1 model. Journal of biosciences 1 39912399
2025 Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs. The EMBO journal 1 39920309
2018 From Precise Slicing to General SHREDding: The Ubiquitin Ligase Ubr1 Roqs as a Multipurpose Protein Terminator. Molecular cell 1 29932909
2014 Case report. Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation. Genetics and molecular research : GMR 1 25036160
2025 Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 0 39925176
2025 UBR-1 enzyme network regulates glutamate homeostasis to affect organismal behavior and developmental viability. bioRxiv : the preprint server for biology 0 40766417
2024 UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension. medRxiv : the preprint server for health sciences 0 38826318
2024 Establishment of a human induced pluripotent stem cell line (SDQLCHi079-A) from a patient with Johanson-Blizzard syndrome carrying heterozygous mutation in UBR1 gene. Stem cell research 0 39053320
2022 [Analysis of a child with Johanson-Blizzard syndrome due to novel compound heterozygous variants of UBR1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 36453963
2022 Reprogramming endo-lysosomal proteostasis disease stress by UBR1- and arginylation-driven endophagy and autophagy protein quality control. Autophagy reports 0 40396008