Affinage

UBE3B

Ubiquitin-protein ligase E3B · UniProt Q7Z3V4

Length
1068 aa
Mass
123.1 kDa
Annotated
2026-06-10
19 papers in source corpus 11 papers cited in narrative 11 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

UBE3B is a mitochondrion-associated HECT-domain E3 ubiquitin ligase whose catalytic activity depends on its C-terminal HECT cysteine and is gated by an N-terminal IQ motif that binds calmodulin, with calcium-dependent dissociation relieving autoinhibition (PMID:28003368). Its activity is further controlled by self-ubiquitylation at K665, which drives oligomerization and inactivation (PMID:34599943). Through its ligase activity UBE3B shapes both metabolism and the neuronal synaptic proteome: it ubiquitylates the branched-chain ketoacid dehydrogenase kinase BCKDK and is required for normal nucleotide/TCA-cycle metabolism and mitochondrial respiration in muscle (PMID:30808755), and it ubiquitylates the calcineurin catalytic subunit Ppp3cc to restrain dendritic spine density, excitatory synapse number, and cortical circuit activity (PMID:32249816, PMID:41844341). UBE3B governs a broad synaptic ubiquitome and interacts with synaptic proteins including ATP1A1, DOCK7, NLGN2, and STX12 (PMID:41844341). In a cancer-relevant axis, UBE3B directly ubiquitylates MYC to promote its proteasomal turnover, an event antagonized by TRIB3 (PMID:33298911), yet it also stabilizes HIF-2α via K63-linked polyubiquitylation that blocks VHL-mediated degradation (PMID:37783786); reciprocally, VHL ubiquitylates UBE3B itself with K48 linkages at K286/K427 to target it for degradation (PMID:38914543). Loss of Ube3b in mice reduces viability, brain size, and cholesterol synthesis, consistent with UBE3B's developmental and metabolic roles (PMID:23200864). Biallelic UBE3B loss underlies Kaufman oculocerebrofacial syndrome, with the metabolic perturbations recapitulated in patient plasma (PMID:30808755).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Low

    Established UBE3B as a HECT-domain E3 ligase gene and raised the question of how functional protein levels are tuned, identifying an alternative splice form predicted to truncate before the HECT domain.

    Evidence cDNA cloning, RT-PCR, and bioinformatic splicing analysis

    PMID:12837265

    Open questions at the time
    • No functional assay confirming the truncated isoform is produced or regulatory
    • Catalytic activity not demonstrated
    • No substrate or pathway context
  2. 2012 Medium

    Connected UBE3B loss to a developmental and metabolic phenotype, showing the ligase is required for normal growth, brain size, and cholesterol synthesis in vivo.

    Evidence Ube3b knockout mouse phenotyping and C. elegans oxi-1 genetics under oxidative stress

    PMID:23200864

    Open questions at the time
    • No direct substrate identified
    • Mechanism linking ligase activity to cholesterol synthesis unresolved
    • Subcellular site of action not defined
  3. 2016 High

    Defined the biochemical core of UBE3B function: a catalytically active mitochondrion-associated HECT ligase whose activity is regulated by calcium/calmodulin binding through an N-terminal IQ motif.

    Evidence In vitro ubiquitylation with C1036A and HECT-deletion mutants, calmodulin Co-IP/pulldown, fractionation, and siRNA knockdown with mitochondrial readouts

    PMID:28003368

    Open questions at the time
    • Physiological substrates not yet identified
    • Structural basis of IQ-motif autoinhibition undefined
    • Link between calmodulin regulation and specific cellular outcomes unclear
  4. 2019 High

    Identified the first physiological substrate, BCKDK, placing UBE3B in control of branched-chain metabolism and mitochondrial respiration.

    Evidence Interactome MS screen, in vivo ubiquitylation assay, and KO mouse metabolomics with respiration assays

    PMID:30808755

    Open questions at the time
    • Ubiquitin linkage type and fate of ubiquitylated BCKDK not specified
    • How BCKDK turnover quantitatively explains metabolic phenotype unclear
  5. 2020 High

    Linked UBE3B to synaptic function by showing it ubiquitylates the calcineurin subunit Ppp3cc to restrain dendritic spine density, with overexpression epistasis confirming the axis.

    Evidence Ubiquitylation assay, Ube3b KO neurons, Ppp3cc overexpression epistasis, spine imaging, and electrophysiology

    PMID:32249816

    Open questions at the time
    • Ubiquitin linkage and whether Ppp3cc is degraded vs regulated not defined
    • Circuit-level consequences only partially mapped
  6. 2020 High

    Revealed an oncogenic relevance: UBE3B directly ubiquitylates MYC for degradation, and TRIB3 antagonizes this to stabilize MYC in lymphoma.

    Evidence Reciprocal Co-IP, ubiquitylation assays, TRIB3 deletion lymphoma model, and patient-derived xenograft

    PMID:33298911

    Open questions at the time
    • Conditions favoring MYC degradation vs stabilization across tissues unclear
    • Whether UBE3B-MYC axis operates in non-lymphoma contexts untested
  7. 2021 Medium

    Uncovered an intrinsic autoregulatory switch: self-ubiquitylation at K665 drives oligomerization and inactivation of UBE3B.

    Evidence Split-CAT bacterial selection assay, K665 mutagenesis, validation in yeast and mammalian cells

    PMID:34599943

    Open questions at the time
    • Structural basis of oligomerization not resolved
    • Physiological trigger for autoinactivation in vivo unknown
    • Single-lab assay system
  8. 2023 High

    Showed UBE3B can also stabilize a substrate: K63-linked polyubiquitylation of HIF-2α blocks VHL-mediated degradation and drives cancer growth and metastasis.

    Evidence Co-IP, K63-linkage-specific ubiquitylation assays, HIF-2α lysine mutagenesis, knockdown and xenograft

    PMID:37783786

    Open questions at the time
    • How linkage specificity (K63 vs K48) is determined per substrate unknown
    • Interplay with the UBE3B-MYC degradative axis unresolved
  9. 2024 High

    Placed UBE3B within a reciprocal regulatory loop with VHL, which ubiquitylates UBE3B (K48 at K286/K427) for proteasomal degradation, suppressing breast tumor growth.

    Evidence Co-IP, K48-linkage ubiquitylation assays, K286R/K427R mutagenesis, and xenograft models

    PMID:38914543

    Open questions at the time
    • PHD-independent recognition mechanism by VHL not structurally defined
    • Whether UBE3B-HIF-2α and VHL-UBE3B loops form a feedback circuit untested
  10. 2025 Medium

    Extended UBE3B's substrate repertoire to NCOA4, defining a Nrf2/UBE3B/NCOA4 axis that suppresses ferritinophagy and ferroptosis.

    Evidence Western blot, UBE3B overexpression/knockdown, Nrf2 knockdown rescue, and ferroptosis marker measurement in alveolar epithelial cells

    PMID:40671136

    Open questions at the time
    • Direct ubiquitylation assay detail limited
    • Ubiquitin linkage and NCOA4 fate not characterized
    • Single-lab, western-blot-based inference
  11. 2026 High

    Mapped UBE3B's neuronal role at proteome scale, identifying a synaptic ubiquitome and direct synaptic interactors controlling excitatory synapse density and circuit excitability.

    Evidence Quantitative proteomics/ubiquitome profiling, reciprocal Co-IP of ATP1A1/DOCK7/NLGN2/STX12, conditional CNS KO mouse, electrophysiology, and AMPA receptor surface assays

    PMID:41844341

    Open questions at the time
    • Which interactors are direct substrates vs adaptors not fully resolved
    • Causal substrate driving AMPA receptor and excitability phenotypes not pinpointed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBE3B selects between degradative (K48) and stabilizing (K63) ubiquitin linkages on different substrates, and how its calmodulin and self-ubiquitylation switches integrate to govern context-specific activity, remains unresolved.
  • No structural model coupling regulatory inputs to linkage specificity
  • Substrate-recognition determinants undefined
  • Tissue-specific substrate prioritization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 3 R-HSA-112316 Neuronal System 2 R-HSA-1430728 Metabolism 2
Partners
BCKDKCALM1HIF2AMYCNCOA4NLGN2PPP3CCVHL

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 UBE3B is a mitochondrion-associated HECT-domain E3 ubiquitin ligase; mutating the catalytic cysteine (C1036A) or deleting the HECT domain (aa 758–1068) abolishes ubiquitylation activity. UBE3B knockdown induces changes in mitochondrial morphology and physiology and a decrease in mitochondrial volume. UBE3B interacts with calmodulin via its N-terminal IQ motif (aa 29–58); deletion of the IQ motif increases in vitro ubiquitylation activity, and changes in calcium levels disrupt the calmodulin–UBE3B interaction. In vitro ubiquitylation assay, active-site mutagenesis (C1036A), domain deletion, Co-IP/pulldown for calmodulin binding, subcellular fractionation/imaging, siRNA knockdown with mitochondrial morphology readout The Journal of biological chemistry High 28003368
2019 UBE3B ubiquitinates branched-chain α-ketoacid dehydrogenase kinase (BCKDK) in vivo; BCKDK was identified as a UBE3B substrate through interactome profiling of 22 UBE3B interactors. Loss of Ube3b in mice perturbs nucleotide metabolism and the TCA cycle, and reduces substrate-induced mitochondrial respiration in skeletal muscle. Co-immunoprecipitation/mass spectrometry interactome screen, in vivo ubiquitylation assay, Ube3b knockout mouse metabolomics (plasma and cortex), mitochondrial respiration assay Proceedings of the National Academy of Sciences of the United States of America High 30808755
2020 Ube3b ubiquitinates Ppp3cc (the catalytic γ-subunit of calcineurin); overexpression of Ppp3cc phenocopies Ube3b loss with respect to increased dendritic spine density. Ube3b KO neurons exhibit increased dendritic spine density, aberrant spine morphology, altered synaptic physiology, and changes in hippocampal circuit activity. Ube3b regulates dendritic branching in a cell-autonomous manner. In vitro/in vivo ubiquitylation assay, Ube3b knockout mouse model, overexpression of Ppp3cc as epistasis test, dendritic spine imaging, electrophysiology Molecular psychiatry High 32249816
2020 TRIB3 interacts with MYC to suppress UBE3B-mediated MYC ubiquitination and proteasomal degradation, thereby stabilizing MYC and enhancing its transcriptional activity in lymphoma cells. UBE3B directly ubiquitinates MYC, and TRIB3 acts as a negative regulator of this UBE3B–MYC axis. Co-immunoprecipitation, in vitro/cellular ubiquitylation assay, TRIB3 deletion mouse model (MycEμ lymphoma), patient-derived xenograft, peptide disruption of TRIB3–MYC interaction Nature communications High 33298911
2021 UBE3B undergoes self-ubiquitylation at K665, which induces oligomerization and inactivation in mammalian cells (analogous to NEDD4 self-inactivation). This autoubiquitylation-dependent mechanism was demonstrated using a split-CAT bacterial reporter system and validated in yeast and mammalian cell models. Split-CAT genetic selection assay in E. coli, site-directed mutagenesis (K665), yeast and mammalian cell validation of oligomerization and inactivation Journal of molecular biology Medium 34599943
2023 UBE3B physically interacts with HIF-2α and promotes its K63-linked polyubiquitination at residues K394, K497, and K503, thereby inhibiting VHL E3 ligase complex-mediated HIF-2α degradation and stabilizing HIF-2α. K394/497/503R mutation of HIF-2α abolishes UBE3B-mediated cancer growth and metastasis. Co-immunoprecipitation, in vitro/cellular K63-linkage-specific ubiquitylation assay, site-directed mutagenesis of HIF-2α ubiquitination sites, UBE3B knockdown in vitro and xenograft in vivo Oncogene High 37783786
2024 VHL is an E3 ubiquitin ligase for UBE3B: VHL directly binds UBE3B and promotes its K48-linked polyubiquitination at K286 and K427 in a PHD-independent manner, leading to proteasomal degradation of UBE3B. K286/427R mutation of UBE3B abolishes the inhibitory effect of VHL on breast tumor growth and metastasis. Co-immunoprecipitation, in vitro/cellular ubiquitylation assay (K48-linkage specific), site-directed mutagenesis (K286R/K427R), in vivo xenograft models Cell death & disease High 38914543
2025 UBE3B ubiquitinates NCOA4 (nuclear receptor coactivator 4), suppressing NCOA4-mediated ferritinophagy and thereby reducing ferrous iron release and ferroptosis in alveolar epithelial cells. Nrf2 transcriptionally activates UBE3B expression, placing UBE3B in a Nrf2/UBE3B/NCOA4 regulatory axis. Western blot, overexpression/knockdown of UBE3B, Nrf2 knockdown rescue experiments, measurement of ferrous ion content and ferroptosis markers in alveolar epithelial cells Biology direct Medium 40671136
2026 UBE3B regulates the synaptic proteome: quantitative proteomics of neural stem cells identified 116 proteins with increased levels and reduced ubiquitination upon UBE3B loss. UBE3B interacts with synaptic proteins including ATP1A1, DOCK7, NLGN2, and STX12 (confirmed by Co-IP). Ube3b CNS-specific KO mice show reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Quantitative proteomics and ubiquitome profiling, Co-immunoprecipitation of synaptic interactors, Ube3b conditional CNS KO mouse, electrophysiology, AMPA receptor surface expression assay, dendritic morphology imaging Autism research : official journal of the International Society for Autism Research High 41844341
2003 UBE3B encodes a HECT-domain E3 ubiquitin ligase. Alternative splicing of exon 20 generates a transcript containing an in-frame stop codon that would truncate the protein before the HECT domain, predicting a non-functional variant lacking catalytic activity. This represents a potential mechanism for regulating intracellular levels of functional UBE3B. cDNA cloning, RT-PCR, bioinformatic analysis of alternative splicing Genomics Low 12837265
2012 Disruption of mouse Ube3b reduces viability, weight, and brain size, and causes downregulation of cholesterol synthesis. The C. elegans ortholog oxi-1 functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions, establishing UBE3B as a functional HECT E3 ligase with roles in neuronal development. Mouse Ube3b knockout model (viability, weight, brain size phenotyping), cholesterol synthesis assay, C. elegans oxi-1 genetic analysis under oxidative stress American journal of human genetics Medium 23200864

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. American journal of human genetics 83 23200864
2020 TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation. Nature communications 47 33298911
2013 Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. Journal of medical genetics 39 23687348
2016 UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase. The Journal of biological chemistry 36 28003368
2019 The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK. Proceedings of the National Academy of Sciences of the United States of America 29 30808755
2014 In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle. BMC genomics 29 25306138
2003 Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing. Genomics 24 12837265
2020 The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc. Molecular psychiatry 19 32249816
2023 UBE3B promotes breast cancer progression by antagonizing HIF-2α degradation. Oncogene 13 37783786
2015 Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B. American journal of medical genetics. Part A 13 25691420
2013 UBE3B and ZRANB1 polymorphisms and transcript abundance are associated with water holding capacity of porcine M. longissimus dorsi. Meat science 12 23743024
2024 VHL suppresses UBE3B-mediated breast tumor growth and metastasis. Cell death & disease 11 38914543
2025 Nrf2/UBE3B protects against acute lung injury by inhibiting ferritinophagy through the ubiquitination of NCOA4. Biology direct 5 40671136
2021 Split Chloramphenicol Acetyl-Transferase Assay Reveals Self-Ubiquitylation-Dependent Regulation of UBE3B. Journal of molecular biology 5 34599943
2025 Multiple association studies identify 3 novel candidate genes for teat number trait in Danish Landrace and Large White pigs: BRINP3, LIN52, and UBE3B. Journal of animal science 1 40305433
2024 Novel UBE3B mutations: report of eight patients with Kaufman oculocerebrofacial syndrome with additional clinical findings from a highly consanguineous population. Clinical dysmorphology 1 38410982
2023 The murine ortholog of Kaufman oculocerebrofacial syndrome gene Ube3b is crucial for the maintenance of the excitatory synapses in the young adult stage. Neuroscience letters 1 36623761
2026 The E3 Ubiquitin Ligase UBE3B Regulates Synaptic Development and Cortical Network Activity. Autism research : official journal of the International Society for Autism Research 0 41844341
2025 Kaufman oculocerebrofacial syndrome: case report of a UBE3B splice site variant and clinical overview of reported patients. Molecular cytogenetics 0 41318572

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