Affinage

UBE4A

Ubiquitin conjugation factor E4 A · UniProt Q14139

Length
1066 aa
Mass
122.6 kDa
Annotated
2026-06-10
15 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBE4A is a ubiquitin chain-elongating E3/E4 ligase that amplifies and diversifies polyubiquitin signals on diverse substrates to control protein degradation, DNA repair, and signal transduction (PMID:29499138, PMID:37084817). In the DNA damage response, it is recruited to double-strand break sites downstream of primary DDR E3 ligases, where it enhances and sustains K48- and K63-linked ubiquitin chains required for RAP80 and BRCA1 complex assembly, end resection, and the channeling of repair toward homologous recombination (PMID:29499138). As a chain elongator it extends polyubiquitin on retrotranslocated NRF1 in the cytosol to prime it for DDI2-mediated cleavage and activation, driving proteasomal subunit gene transcription; a ligase-dead mutant acts as a dominant negative and recombinant UBE4A ubiquitinates NRF1 in vitro (PMID:37084817). UBE4A directs both degradative and non-degradative ubiquitination of specific targets: it catalyzes K6-linked ubiquitination of Viperin following HAT1-mediated acetylation priming, leading to Viperin turnover (PMID:31812350), and K63-linked ubiquitination of Akt and its activator APPL1 to enable insulin-induced Akt activation (PMID:37429524). It additionally targets ILEI/FAM3C (PMID:27862841), PCBP1 (PMID:28963376), BMP7 (PMID:30663414), and STAT1 (PMID:42058507) for proteasomal degradation. In vivo, UBE4A loss produces metabolic phenotypes including obesity, insulin resistance, and hepatic steatosis (PMID:37429524), and biallelic loss-of-function variants cause a syndromic neurodevelopmental disorder with intellectual disability, developmental delay, hypotonia, and seizures (PMID:33420346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2016 Medium

    Established UBE4A as a degradative E3 ligase with an identified substrate, defining its capacity to drive proteasomal turnover and influence cancer cell behavior.

    Evidence Mass spectrometry of substrate immunoprecipitates, Co-IP, polyubiquitination and migration/invasion assays in prostate cancer cells

    PMID:27862841

    Open questions at the time
    • No in vitro reconstitution with recombinant UBE4A
    • Chain linkage type on ILEI not defined
    • Recruitment/specificity determinants unknown
  2. 2017 Medium

    Extended the degradative substrate repertoire to PCBP1, reinforcing that UBE4A polyubiquitination targets proteins for proteasomal destruction in a second cancer context.

    Evidence Mass spectrometry of PCBP1 immunoprecipitates, RNAi, overexpression, Co-IP with polyubiquitination assay in thyroid carcinoma cells

    PMID:28963376

    Open questions at the time
    • No in vitro reconstitution
    • Linkage specificity unresolved
    • Physiological relevance beyond cancer cells unclear
  3. 2018 High

    Defined a non-degradative role for UBE4A as a chain elongator in DNA repair, showing it sustains ubiquitin signaling needed to enforce homologous recombination over alternative end-joining.

    Evidence Epistasis, immunofluorescence at DSB sites, ubiquitin chain-linkage analysis, cell-based DSB repair assays

    PMID:29499138

    Open questions at the time
    • Direct substrate of UBE4A at DSBs not identified
    • Which primary E3 recruits UBE4A not pinned down
    • Structural basis of chain elongation unknown
  4. 2019 High

    Revealed acetylation-primed substrate recruitment and an unusual K6 chain output, showing UBE4A degrades the antiviral effector Viperin only after HAT1-mediated acetylation creates a docking signal.

    Evidence Reciprocal Co-IP, modification-site mutagenesis, ubiquitin linkage assays, interfering peptides, in vivo viral challenge

    PMID:31812350

    Open questions at the time
    • How acetylation generates the UBE4A binding interface structurally unresolved
    • Broader scope of K6-chain substrates unknown
  5. 2019 Medium

    Added BMP7 as a substrate under diabetic-nephropathy conditions, linking UBE4A-driven degradation to a disease-relevant cellular stress.

    Evidence Mass spectrometry, Co-IP, RNAi, overexpression, MG-132 treatment in renal NRK-52E cells

    PMID:30663414

    Open questions at the time
    • No in vitro reconstitution
    • Whether glucose regulates UBE4A activity or recruitment unknown
  6. 2021 Medium

    Connected UBE4A enzymatic function to human disease, establishing that biallelic loss-of-function causes a syndromic neurodevelopmental disorder.

    Evidence Exome sequencing, patient RNA/protein quantification, patient-specific knock-in mouse with neurobehavioral phenotyping

    PMID:33420346

    Open questions at the time
    • Causal substrate(s) underlying neurological phenotype not identified
    • Single-study genetic association
  7. 2022 Medium

    Placed UBE4A within an upstream regulatory circuit, showing its mRNA is stabilized by PTBP3 and that it contributes to p53 turnover to support colorectal cancer proliferation.

    Evidence RNAi, rescue, 3' UTR mRNA stability assay, p53 Western blot, in vitro and xenograft proliferation assays

    PMID:35136024

    Open questions at the time
    • Direct UBE4A-mediated p53 ubiquitination not demonstrated in vitro
    • Chain linkage on p53 undefined
  8. 2023 High

    Defined UBE4A as a chain-length-extending E4 priming NRF1 for DDI2 cleavage, mechanistically linking it to proteasome bounce-back gene expression with recombinant-protein validation.

    Evidence In vitro ubiquitination with recombinant UBE4A, ligase-dead dominant-negative mutant, knockout/depletion, NRF1 cleavage Western blots, RT-qPCR of proteasomal genes

    PMID:37084817

    Open questions at the time
    • Initiating E3 that primes NRF1 before UBE4A elongation not defined
    • Chain linkage type on NRF1 not specified
  9. 2023 High

    Demonstrated a K63-linked, non-degradative signaling role in metabolism, showing UBE4A ubiquitinates Akt and APPL1 to enable insulin signaling and prevent metabolic disease in mice.

    Evidence In vitro K63-ubiquitination with recombinant Ube4A, Co-IP, whole-body knockout mouse metabolic phenotyping, lipidomics, RNA-seq, proteomics

    PMID:37429524

    Open questions at the time
    • How UBE4A is recruited to the Akt/APPL1 complex unknown
    • Whether insulin regulates UBE4A activity not established
  10. 2026 Medium

    Showed UBE4A is co-opted by Viperin to degrade STAT1 and dampen type-I interferon signaling, defining a viral-relevant immune-suppressive axis.

    Evidence Co-IP, ubiquitination assays, RNAi, overexpression, interfering peptide (VS-IP1), STAT1 Western blots

    PMID:42058507

    Open questions at the time
    • No in vitro reconstitution stated
    • Single publication, single lab
    • STAT1 chain linkage type undefined
  11. 2026 Low

    Implicated UBE4A in intestinal homeostasis, showing its deficiency dysregulates colonic lipid metabolism and antimicrobial defense and worsens experimental colitis.

    Evidence Global Ube4A knockout mice, DSS colitis model, RNA-seq, immunofluorescence, flow cytometry, histology (preprint)

    PMID:41502940

    Open questions at the time
    • Preprint, not peer-reviewed
    • No colonic substrate identified
    • Mechanism linking UBE4A to lipid/inflammatory genes unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBE4A achieves substrate selectivity and chain-linkage choice across its diverse degradative and signaling targets, and which primary E3 ligases recruit it in each pathway, remain unresolved.
  • No unifying structural model for substrate/priming-E3 recognition
  • Determinants of K6 vs K48 vs K63 output unknown
  • Tissue-specific substrate hierarchy uncharacterized

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 4
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1 R-HSA-73894 DNA Repair 1
Partners
AKT1APPL1BMP7ILEINRF1PCBP1STAT1VIPERIN

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 UBE4A is recruited to sites of DNA double-strand breaks (DSBs) in a manner dependent on primary E3 ligases in the DDR, where it promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains. This activity is required for timely recruitment of RAP80 and BRCA1, proper organization of their associated protein complexes at DSB sites, optimal end resection, and suppression of alternative end-joining in favor of homologous recombination repair. Epistasis, loss-of-function experiments, immunofluorescence at DSB sites, ubiquitin chain-linkage analysis, cell-based DSB repair assays Molecular cell High 29499138
2019 UBE4A promotes K6-linked polyubiquitination at Lys206 of Viperin, leading to Viperin protein degradation in epithelial cells. This is contingent on prior HAT1-mediated Lys197-acetylation of Viperin, which recruits UBE4A. Interfering peptides blocking UBE4A-Viperin interaction restore Viperin protein levels and enhance antiviral defense. Co-immunoprecipitation, site-directed mutagenesis of ubiquitination/acetylation sites, ubiquitin linkage assays, RNAi knockdown, interfering peptide design, in vivo viral challenge Molecular cell High 31812350
2016 UBE4A directly interacts with and polyubiquitinates ILEI (FAM3C protein), targeting it for proteasomal degradation. RNAi silencing of UBE4A stabilizes ILEI, and overexpression of UBE4A reduces ILEI levels, cell migration, and invasion in prostate cancer cells. Mass spectrometry of FLAG-ILEI immunoprecipitates, co-immunoprecipitation of endogenous proteins, polyubiquitination assay, RNAi knockdown, overexpression, migration/invasion assays IUBMB life Medium 27862841
2017 UBE4A is the E3 ubiquitin ligase responsible for polyubiquitination and proteasomal degradation of PCBP1 in thyroid carcinoma cells. RNAi-mediated knockdown of UBE4A stabilizes PCBP1 protein, and overexpression of UBE4A increases PCBP1 polyubiquitination. Mass spectrometry of PCBP1 immunoprecipitates, RNAi silencing, overexpression, co-immunoprecipitation with polyubiquitination assay Bioscience reports Medium 28963376
2019 UBE4A is the E3 ubiquitin ligase responsible for polyubiquitination and proteasomal degradation of BMP7 in renal (NRK-52E) cells under high-glucose conditions mimicking diabetic nephropathy. Knockdown of UBE4A stabilizes BMP7, and co-immunoprecipitation confirms direct UBE4A-BMP7 interaction. Mass spectrometry, co-immunoprecipitation, RNAi silencing, overexpression, Western blot, MG-132 proteasome inhibitor treatment Archives of physiology and biochemistry Medium 30663414
2023 UBE4A catalyzes ubiquitination of retrotranslocated NRF1 at the cytosol, extending polyubiquitin chain length to prime NRF1 for DDI2-mediated endoproteolytic cleavage and activation. UBE4A depletion reduces ubiquitin modification on NRF1, shortens polyubiquitin chains, decreases NRF1 cleavage efficiency, and impairs transcription of proteasomal subunit genes. A ligase-dead UBE4A mutant acts as a dominant negative. Recombinant UBE4A promotes NRF1 ubiquitination in vitro. In vitro ubiquitination assay with recombinant UBE4A, co-immunoprecipitation, UBE4A knockout/depletion, ligase-dead mutant (dominant negative), Western blot for NRF1 cleavage products, RT-qPCR for proteasomal genes Biochimica et biophysica acta. Gene regulatory mechanisms High 37084817
2023 Ube4A interacts with the Akt activator APPL1 and directly K63-ubiquitinates Akt in vitro. In whole-body Ube4A knockout mice, K63-linked ubiquitination of both Akt and APPL1 is impaired, resulting in defective insulin-induced Akt activation in liver and adipose tissue, and exacerbated obesity, insulin resistance, and hepatic steatosis on high-fat diet. In vitro K63-ubiquitination assay with recombinant Ube4A, Ube4A knockout mouse model, co-immunoprecipitation (APPL1 interaction), insulin signaling assays (pAkt), metabolic phenotyping, lipidomics, RNA-seq, proteomics Molecular metabolism High 37429524
2026 Viperin recruits UBE4A to promote STAT1 ubiquitination and degradation, thereby attenuating type-I IFN (IFN-I) antiviral immune signaling. IFN-I first upregulates ITCH to degrade UBR5, after which Viperin-UBE4A cooperate to degrade STAT1. A multifunctional interfering peptide (VS-IP1) blocks Viperin-mediated STAT1 degradation and enhances IFN-I signaling. Co-immunoprecipitation, ubiquitination assays, RNAi/knockdown, overexpression, interfering peptide experiments, Western blot for STAT1 levels Cell insight Medium 42058507
2022 PTBP3 binds the 3' UTR of UBE4A mRNA to prevent its degradation, thereby maintaining UBE4A protein levels. UBE4A in turn participates in p53 degradation; PTBP3 knockdown reduces UBE4A expression and elevates p53 levels, and UBE4A overexpression rescues the proliferative defect caused by PTBP3 knockdown in colorectal cancer cells. RNAi knockdown, overexpression rescue, mRNA stability assay (3' UTR binding), Western blot for p53, cell proliferation assays in vitro and in vivo (xenograft) Cell death & disease Medium 35136024
2021 Biallelic loss-of-function variants in UBE4A in humans cause reduced UBE4A RNA and protein levels and are associated with syndromic intellectual disability, global developmental delay, hypotonia, and seizures. Mice engineered with patient-specific Ube4a loss-of-function variants exhibit muscular and neurological/behavioral abnormalities, establishing that UBE4A enzymatic activity is required for normal neurological development. Exome sequencing, clinical sample protein/RNA quantification, patient-specific knock-in mouse model with neurological/behavioral phenotyping Genetics in medicine Medium 33420346
2026 Ube4A deficiency in mice disrupts colon homeostasis and exacerbates DSS-induced experimental colitis. Transcriptomic profiling of UKO mouse colons revealed baseline dysregulation of lipid transport/storage and antimicrobial defense pathways, enhanced inflammatory signaling, increased mast cell activation, and elevated matrix metalloproteinase expression upon DSS treatment, indicating Ube4A is a regulator of colonic epithelial lipid metabolism and inflammatory responses. Global Ube4A knockout mouse model, DSS-induced colitis model, transcriptomic (RNA-seq) analysis, immunofluorescence, flow cytometry, histology bioRxivpreprint Low 41502940

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense. Molecular cell 62 31812350
2018 The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. Molecular cell 48 29499138
2008 Autoantibodies against ubiquitination factor E4A (UBE4A) are associated with severity of Crohn's disease. Inflammatory bowel diseases 35 18069675
2006 The two human homologues of yeast UFD2 ubiquitination factor, UBE4A and UBE4B, are located in common neuroblastoma deletion regions and are subject to mutations in tumours. European journal of cancer (Oxford, England : 1990) 23 16386891
2022 PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability. Cell death & disease 22 35136024
2004 Expression analysis of the gene encoding for the U-box-type ubiquitin ligase UBE4A in human tissues. Gene 22 15019985
2016 The ubiquitin ligase UBE4A inhibits prostate cancer progression by targeting interleukin-like EMT inducer (ILEI). IUBMB life 19 27862841
2007 [Differential expression of USP2, USP14 and UBE4A between ovarian serous cystadenocarcinoma and adjacent normal tissues]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 16 17553343
2017 Poly r(C) binding protein (PCBP) 1 expression is regulated by the E3 ligase UBE4A in thyroid carcinoma. Bioscience reports 14 28963376
2019 Bone morphogenetic protein (BMP) 7 expression is regulated by the E3 ligase UBE4A in diabetic nephropathy. Archives of physiology and biochemistry 12 30663414
2023 UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage. Biochimica et biophysica acta. Gene regulatory mechanisms 9 37084817
2023 Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo. Molecular metabolism 9 37429524
2021 Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genetics in medicine : official journal of the American College of Medical Genetics 6 33420346
2026 Loss of E3 ligase Ube4A Disrupts Colon Homeostasis and Accelerates Experimental Colitis via Altered Lipid Handling. bioRxiv : the preprint server for biology 0 41502940
2026 Viperin weakens IFN-I-induced immune activity by facilitating STAT1 degradation through E3 ligase UBE4A. Cell insight 0 42058507

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