Affinage

UBR3

E3 ubiquitin-protein ligase UBR3 · UniProt Q6ZT12

Length
1888 aa
Mass
212.4 kDa
Annotated
2026-06-10
10 papers in source corpus 9 papers cited in narrative 10 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

UBR3 is a RING- and UBR-box-containing E3 ubiquitin ligase that controls the abundance of diverse substrates by targeting them for ubiquitin-dependent degradation, thereby shaping DNA repair, developmental signaling, cardiac excitability, and apoptosis (PMID:21933813, PMID:27195754, PMID:26059563). Although it possesses the UBR-box shared with the N-recognins UBR1 and UBR2 and binds the same E2 enzymes HR6A/HR6B, UBR3 does not recognize canonical N-end rule substrates (PMID:17462990). Its catalytic activity polyubiquitylates the DNA-repair enzyme APE1 to set its steady-state level, with loss of UBR3 causing APE1 accumulation and genomic instability (PMID:21933813). UBR3 also positively regulates Hedgehog signaling by polyubiquitylating and degrading the kinesin Cos2/Kif7 (PMID:27195754), and post-translationally lowers cardiac ion channel levels by targeting Nav1.5 and the Cav1.2 L-type Ca2+ channel for proteasomal degradation, thereby tuning action potential amplitude and Ca2+-induced Ca2+ release (PMID:26059563, PMID:32988261). In nucleus pulposus cells it ubiquitylates DUSP1 to sustain p38 MAPK activation and drive inflammation and apoptosis (PMID:35332432). Independently of its RING/E3 activity, the UBR-box domain binds the caspase-cleaved neo-epitope of DIAP1 to promote caspase ubiquitination and anti-apoptotic signaling (PMID:25146930), and UBR3 negatively regulates mono-ubiquitination of non-muscle Myosin II, linking it to the Myosin VIIa-based Usher syndrome machinery during auditory and sensory organ development (PMID:27331610). Knockout mice die during embryogenesis or perinatally and display sensory-system expression and defects, consistent with broad developmental requirements (PMID:17462990).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    Established that UBR3 belongs to the UBR-box/RING N-recognin family yet is mechanistically distinct, answering whether it acts via the same E2 partners and substrate logic as UBR1/UBR2.

    Evidence Cloning, E2-E3 binding assays with HR6A/HR6B, and N-end rule substrate recognition assays

    PMID:17462990

    Open questions at the time
    • Did not identify any bona fide substrate
    • Left the functional role of the UBR-box undefined given absence of N-end rule recognition
  2. 2007 Medium

    Defined the in vivo requirement for UBR3 by showing embryonic/perinatal lethality and sensory-system expression, framing it as a developmentally essential ligase.

    Evidence Ubr3 knockout mouse strains, LacZ reporter expression, and behavioral phenotyping

    PMID:17462990

    Open questions at the time
    • Did not connect phenotypes to specific molecular substrates
    • Background-dependent severity not mechanistically explained
  3. 2011 High

    Identified the first direct UBR3 substrate, APE1, explaining how the ligase couples ubiquitin-dependent turnover to DNA repair capacity and genome stability.

    Evidence In vitro ubiquitylation assays, protein purification, and Ubr3 knockout MEFs scored for genomic instability

    PMID:21933813

    Open questions at the time
    • Did not map which E2 drives APE1 ubiquitylation in cells
    • Did not establish whether APE1 misregulation underlies the organismal phenotypes
  4. 2014 High

    Revealed a RING-independent, UBR-box-mediated function in apoptosis control, showing UBR3 can act as an adaptor rather than a catalytic ligase.

    Evidence Co-IP of the UBR-box with cleaved DIAP1, RING-domain mutant analysis, and genetic epistasis with dronc and p35 in Drosophila

    PMID:25146930

    Open questions at the time
    • Mammalian counterpart of the DIAP1 interaction not demonstrated
    • How UBR-box recognizes the cleaved neo-epitope structurally unresolved
  5. 2016 High

    Linked UBR3 to two developmental axes — positive regulation of Hedgehog signaling via degradation of Cos2/Kif7, and negative regulation of Myosin II mono-ubiquitination connecting it to Usher syndrome proteins.

    Evidence Drosophila genetic screens, in vitro/cell ubiquitination assays, zebrafish and mouse loss-of-function, reciprocal Co-IP and cross-species cochlea/RPE validation

    PMID:27195754 PMID:27331610

    Open questions at the time
    • Did not resolve how a single ligase produces both poly- and mono-ubiquitination outcomes on different substrates
    • Direct mammalian Kif7 ubiquitylation in vivo not fully dissected
  6. 2015 Medium

    Extended UBR3 substrate control to cardiac electrophysiology by showing post-translational, proteasome-dependent regulation of the Nav1.5 sodium channel.

    Evidence siRNA knockdown in neonatal rat ventricular myocytes and HEK293T cells, proteasome inhibition, ubiquitylation assay, and electrophysiology

    PMID:26059563

    Open questions at the time
    • Direct ligase-substrate contact not shown by reconstitution
    • Physiological consequence at the whole-heart level untested
  7. 2020 Medium

    Showed a second cardiac substrate, Cav1.2, establishing UBR3 as a regulator of Ca2+-induced Ca2+ release with selectivity over other handling proteins.

    Evidence siRNA knockdown, cycloheximide chase, electrophysiology and Ca2+ imaging in neonatal rat ventricular myocytes

    PMID:32988261

    Open questions at the time
    • Direct ubiquitylation of Cav1.2 by purified UBR3 not reconstituted
    • In vivo cardiac relevance not addressed
  8. 2022 Medium

    Connected UBR3 to inflammatory signaling by showing ubiquitylation of the phosphatase DUSP1 sustains p38 MAPK activity and drives apoptosis/inflammation.

    Evidence Co-IP, knockdown/overexpression in nucleus pulposus cells, ubiquitination assay, and DUSP1 rescue

    PMID:35332432

    Open questions at the time
    • Ubiquitin linkage type and whether DUSP1 is degraded vs inactivated not fully defined
    • Generality beyond nucleus pulposus cells untested
  9. 2019 Medium

    Placed UBR3 in an ancient developmental patterning module with Mlpt micropeptides and Shavenbaby, broadening its role beyond degradative ubiquitination.

    Evidence Genetic interaction and loss/restoration-of-function studies in Drosophila and Tribolium

    PMID:30896406

    Open questions at the time
    • Biochemical nature of the Ubr3-Mlpt-Svb complex not defined
    • Whether catalytic activity is required within this module unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how UBR3 achieves substrate selectivity across such diverse targets and how its catalytic (RING) versus adaptor (UBR-box) modes are partitioned in mammalian tissues.
  • No structural basis for substrate recognition reported
  • Degron/recognition determinants on substrates unmapped
  • Tissue-specific cofactors directing different substrates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CAV1.2DIAP1DUSP1HR6AHR6BKIF7NAV1.5
Complex memberships
Ubr3-Mlpt-Shavenbaby developmental module

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 UBR3 is an E3 ubiquitin ligase that polyubiquitylates APE1 (Ref-1) at multiple lysine residues clustered on the N-terminal tail, controlling steady-state cellular levels of APE1; knockout of Ubr3 in mouse embryonic fibroblasts leads to up-regulation of APE1 protein and subsequent genomic instability. In vitro ubiquitylation assay, protein purification, Ubr3 knockout mouse embryonic fibroblasts with genomic instability readout Nucleic acids research High 21933813
2007 UBR3 contains RING and UBR box domains similar to UBR1 and UBR2; E2 enzymes HR6A and HR6B, which bind UBR1 and UBR2, also physically interact with UBR3. However, unlike UBR1 and UBR2, UBR3 does not recognize N-end rule substrates. Binding assay (E2-E3 interaction), cloning and biochemical characterization, N-end rule substrate recognition assay The Journal of biological chemistry Medium 17462990
2007 UBR3 knockout mice (129SvImJ background) die during embryogenesis; C57BL/6 background Ubr3-/- mice show neonatal lethality, suckling impairment, and adult female-specific behavioral anosmia. LacZ reporter reveals UBR3 expression in olfactory pathway cells and cells of touch, vision, hearing, and taste systems. Ubr3 gene knockout mouse strains, LacZ reporter expression, behavioral phenotyping The Journal of biological chemistry Medium 17462990
2016 Drosophila Ubr3 (ortholog of mammalian UBR3) negatively regulates mono-ubiquitination of non-muscle Myosin II; mono-ubiquitinated Myosin II physically interacts with Myosin VIIa (responsible for Usher syndrome type IB). Ubr3 interacts genetically and physically with three Usher syndrome proteins, and the Myosin VIIa–Myosin IIa interaction is conserved in the mammalian cochlea and human retinal pigment epithelium cells. Forward genetic screen in Drosophila, Co-immunoprecipitation, ubiquitination assay, genetic epistasis, mammalian cochlea and human cell validation eLife High 27331610
2016 Drosophila Ubr3 (ortholog of mammalian UBR3) is a positive regulator of Hedgehog (Hh) signaling and promotes poly-ubiquitination and degradation of Cos2 (a central Hh signaling component). Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2; loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. Genetic screen in Drosophila, in vitro/cell-based ubiquitination assay, zebrafish loss-of-function, cultured cell knockdown, protein level measurement PLoS genetics High 27195754
2014 Drosophila Ubr3 (ortholog of mammalian UBR3) physically interacts via its UBR-box domain with the neo-epitope of DIAP1 exposed after caspase-mediated cleavage, promoting recruitment and ubiquitination of substrate caspases by DIAP1 and thus positively regulating DIAP1 activity. This function is independent of the RING domain (E3 ligase activity). Loss of ubr3 causes caspase-dependent apoptosis, suppressible by loss of Dronc or ectopic p35 expression. Co-immunoprecipitation (UBR-box domain interaction), RING-domain mutant analysis, genetic epistasis (dronc loss-of-function, p35 overexpression), apoptosis assays in Drosophila eye and wing discs Cell death and differentiation High 25146930
2019 Ubr3 (Drosophila/insect ortholog of mammalian UBR3) forms a molecular complex with Mlpt micropeptides and transcription factor Shavenbaby (Svb) that constitutes an ancient developmental module for embryo patterning; this complex is required for early insect embryo segmentation. Genetic interaction studies, loss-of-function analysis in Drosophila and Tribolium, restoration-of-function epistasis experiments eLife Medium 30896406
2015 UBR3 (and UBR6) regulate cardiac Nav1.5 channel protein levels via the ubiquitin-proteasome pathway; knockdown of UBR3 increases Nav1.5 protein and ubiquitylation, enhances Nav1.5 channel opening, and increases action potential amplitude. The effect is abolished by proteasome inhibition and is post-translational (not transcriptional). siRNA knockdown in neonatal rat ventricular myocytes and HEK293T cells, proteasome inhibitor experiments, ubiquitylation assay, electrophysiological recordings Journal of cellular and molecular medicine Medium 26059563
2020 UBR3 (and UBR6) modulate cardiac Ca2+-induced Ca2+ release (CICR) by targeting Cav1.2 (L-type Ca2+ channel alpha1C subunit) for proteasomal degradation; knockdown of UBR3 increases Cav1.2 protein levels and enhances Cav1.2 channel current and SR Ca2+ release amplitude without affecting RyR2, SERCA2a, or PLB levels. siRNA knockdown in neonatal rat ventricular myocytes, protein level measurement, cycloheximide chase, electrophysiological recordings, Ca2+ imaging Channels (Austin, Tex.) Medium 32988261
2022 UBR3 promotes ubiquitination of DUSP1 in nucleus pulposus cells; this leads to reduced DUSP1 activity, sustained p38 MAPK activation, and enhanced inflammation and apoptosis. Co-immunoprecipitation confirmed the UBR3–DUSP1 physical interaction; overexpression of DUSP1 reversed the pro-apoptotic/pro-inflammatory effects of UBR3 overexpression. Co-immunoprecipitation, siRNA knockdown and overexpression in nucleus pulposus cells, ubiquitination assay, rescue by DUSP1 overexpression, p38 phosphorylation readout Human cell Medium 35332432

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Ubiquitin ligase UBR3 regulates cellular levels of the essential DNA repair protein APE1 and is required for genome stability. Nucleic acids research 55 21933813
2007 Biochemical and genetic studies of UBR3, a ubiquitin ligase with a function in olfactory and other sensory systems. The Journal of biological chemistry 45 17462990
2016 The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals. eLife 25 27331610
2019 The mlpt/Ubr3/Svb module comprises an ancient developmental switch for embryonic patterning. eLife 21 30896406
2014 Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. Cell death and differentiation 20 25146930
2016 Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination. PLoS genetics 17 27195754
2015 Cardiac Nav 1.5 is modulated by ubiquitin protein ligase E3 component n-recognin UBR3 and 6. Journal of cellular and molecular medicine 15 26059563
2022 UBR3 promotes inflammation and apoptosis via DUSP1/p38 pathway in the nucleus pulposus cells of patients with intervertebral disc degeneration. Human cell 12 35332432
2020 Modulation of Ca2+-induced Ca2+ release by ubiquitin protein ligase E3 component n-recognin UBR3 and 6 in cardiac myocytes. Channels (Austin, Tex.) 8 32988261
2020 Breakpoint Mapping of Symptomatic Balanced Translocations Links the EPHA6, KLF13 and UBR3 Genes to Novel Disease Phenotype. Journal of clinical medicine 6 32344861

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