Affinage

UBE2L6

Ubiquitin/ISG15-conjugating enzyme E2 L6 · UniProt O14933

Length
153 aa
Mass
17.8 kDa
Annotated
2026-06-10
19 papers in source corpus 15 papers cited in narrative 15 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

UBE2L6 (UbcH8) is a dual-specificity E2 conjugating enzyme that bridges activating E1 and substrate-targeting E3 enzymes to drive both ISG15 conjugation (ISGylation) and canonical K48-linked ubiquitination, thereby controlling protein stability across innate immune signaling, lipid metabolism, and cell differentiation (PMID:31820845, PMID:36906655). In the ISGylation cascade it operates as the E2 between E1 (UBA7) and E3 (HERC5), and its catalytic activity is required for ATRA-induced ISG15 conjugation and leukemic neutrophil differentiation (PMID:31820845). Structurally, UBA7 binds UBE2L6 with specificity distinct from its paralog UBE2L3 through a disulfide-linked complex whose activation depends on the catalytic cysteine capping loop and catalytic-cysteine thiolate state [PMID:bio_10.1101_2024.11.07.622398], and UBE2L6 itself populates a concentration-dependent monomer-dimer equilibrium via a backside interface that modulates its E1 and E3 contacts (PMID:39346869). As a ubiquitin-conjugating enzyme it cooperates with the E3 ligase UBR4 to ubiquitinate EZH2 at K381 and target it for degradation (PMID:36906655), promotes K48-linked ubiquitination of the innate sensors RIG-I and MDA5 to dampen type I interferon responses (PMID:40611336), and ubiquitinates the lipase ATGL to restrain lipolysis (PMID:33712284). Beyond degradative targeting, UBE2L6 promotes ISGylation and activation of STAT1 to drive M1 macrophage polarization (PMID:37820603), and is exploited by viruses such as Senecavirus A, whose RNA-dependent RNA polymerase it ubiquitinates at K169/K321 (requiring cysteine 86) to stabilize the polymerase and enhance replication (PMID:33104725). Through its control of ATGL stability it also acts as a positive regulator of adipogenic differentiation (PMID:23557705). Lower-confidence reports extend its substrate range to FoxO3a, Mcl-1, and FLT3-ITD.

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Low

    Established the gene's identity and locus, framing UBE2L6 as a UBE2L3 paralog with conserved genomic architecture before any enzymatic function was assigned.

    Evidence Genomic cloning, sequence analysis, and chromosomal mapping to 11q12

    PMID:10894956

    Open questions at the time
    • No functional experiment; redundancy with UBE2L3 inferred from sequence, not tested
    • No substrate or pathway assignment
  2. 2013 Medium

    Defined a physiological role in metabolism by showing a loss-of-function Ube2l6 allele prolongs ATGL half-life and represses adipogenesis, establishing UBE2L6 as a positive regulator of adipogenic differentiation.

    Evidence Congenic mouse strain plus siRNA knockdown in 3T3-L1 adipocytes with ATGL half-life and adipogenesis assays

    PMID:23557705

    Open questions at the time
    • Direct ubiquitination of ATGL by UBE2L6 not biochemically reconstituted here
    • E3 partner for ATGL not identified
  3. 2017 Medium

    Linked UBE2L6 to autophagy regulation, showing it acts with ISG15 to restrain basal autophagic flux.

    Evidence siRNA knockdown with LC3II western blotting and Cyto-ID staining in esophageal cancer cells

    PMID:28186990

    Open questions at the time
    • Molecular target of ISGylation/ubiquitination controlling autophagy not defined
    • Mechanism linking ISG15 conjugation to flux unresolved
  4. 2020 Medium

    Cemented UBE2L6 as the catalytic E2 of the ISGylation cascade between UBA7 and HERC5 and tied this activity to a defined differentiation phenotype.

    Evidence shRNA knockdown in NB4 APL cells with ISG15-conjugate western blots and ATRA differentiation assays

    PMID:31820845

    Open questions at the time
    • Specific ISGylation substrates driving differentiation not enumerated
    • Distinction between ISGylation and ubiquitination contributions not separated
  5. 2020 High

    Provided the first residue-level demonstration that UBE2L6 directly ubiquitinates a substrate, showing it modifies the Senecavirus A 3D polymerase at K169/K321 via catalytic Cys86 to stabilize it and promote viral replication.

    Evidence Co-IP, ubiquitination assay, enzyme and substrate mutagenesis, and recombinant virus rescue

    PMID:33104725

    Open questions at the time
    • E3 ligase cooperating with UBE2L6 on the polymerase not identified
    • Ubiquitin linkage type not specified
  6. 2020 Low

    Tested UBE2L6 in drug resistance, indicating it influences cisplatin resistance through transcriptional control of ABCB6.

    Evidence siRNA knockdown, expression profiling, and ABCB6 promoter reporter assay

    PMID:32329696

    Open questions at the time
    • Transcriptional effect not connected to E2 enzymatic activity
    • Single method, single lab; mechanism indirect
  7. 2021 Low

    Extended the substrate repertoire toward leukemia survival proteins by linking UBE2L6 to proteasomal degradation of Mcl-1 in FLT3-ITD AML.

    Evidence shRNA knockdown with Mcl-1 western blotting and proteasome inhibitor rescue

    PMID:34594375

    Open questions at the time
    • No direct ubiquitination biochemistry shown
    • Single lab, protein-level readout only
  8. 2023 High

    Identified a specific E2-E3 pairing and ubiquitination site by showing UBE2L6 cooperates with UBR4 to ubiquitinate EZH2 at K381 for degradation, with epigenetic silencing of UBE2L6 stabilizing EZH2 in melanoma.

    Evidence Biochemical ubiquitination assays, K381 mutagenesis, siRNA, proteasome inhibition, and animal studies

    PMID:36906655

    Open questions at the time
    • Ubiquitin linkage type on EZH2 not specified
    • Generality beyond melanoma context untested
  9. 2023 Medium

    Demonstrated a signaling-activation role distinct from degradation, showing UBE2L6 ISGylates and activates STAT1 to promote M1 macrophage polarization in adipose tissue.

    Evidence Adipose-specific Ube2l6 knockout mice, Co-IP with STAT1, flow cytometry, and expression analyses

    PMID:37820603

    Open questions at the time
    • STAT1 ISGylation site not mapped
    • E3 ligase for STAT1 ISGylation not identified
  10. 2024 Medium

    Resolved the structural basis for E1-E2 selectivity, showing UBA7 binds UBE2L6 (not UBE2L3) through a disulfide complex governed by the catalytic cysteine capping loop and thiolate state.

    Evidence Cryo-EM of the UBA7•UBE2L6 complex with biochemical reconstitution and mutagenesis (preprint)

    PMID:bio_10.1101_2024.11.07.622398

    Open questions at the time
    • Preprint, single lab, not peer-reviewed
    • Structure of E2-E3 (HERC5) transfer step not resolved
  11. 2024 Medium

    Revealed an intrinsic regulatory feature, a concentration-dependent monomer-dimer equilibrium with a backside interface that reshapes E1 and E3 contact surfaces.

    Evidence SAXS and NMR spectroscopy with GST-fusion dimer dissociation

    PMID:39346869

    Open questions at the time
    • Functional consequence of dimerization in cells untested
    • Physiological concentrations relative to equilibrium unknown
  12. 2024 Low

    Placed UBE2L6 downstream of p53 in a senescence circuit, indicating p53-induced UBE2L6 promotes FoxO3a degradation in diabetic retinopathy.

    Evidence p53 inhibition, siRNA, ubiquitination assay, and scRNA-seq/bulk RNA-seq in db/db mice

    PMID:38437929

    Open questions at the time
    • Direct ubiquitination of FoxO3a by UBE2L6 not fully reconstituted
    • Largely expression- and knockdown-based
  13. 2025 Medium

    Defined a viral-hijack mechanism in which PRRSV upregulates UBE2L6 to drive K48-linked degradation of RIG-I and MDA5, suppressing type I IFN, while UBE2L6 stabilizes viral NSP5.

    Evidence Co-IP, knockdown/overexpression, and K48 linkage-specific ubiquitination assays

    PMID:40611336

    Open questions at the time
    • E3 ligase mediating RIG-I/MDA5 degradation not pinpointed
    • Direct versus NSP5-bridged ubiquitination contributions not separated
  14. 2025 Low

    Reinforced a therapeutic angle in AML by showing UBE2L6 mediates FLT3-ITD degradation, sensitizing cells to decursin-induced apoptosis.

    Evidence shRNA knockdown, western blotting, viability assays, and patient-derived mouse model

    PMID:40176110

    Open questions at the time
    • No direct ubiquitination biochemistry on FLT3-ITD
    • Single lab; degradation readout only

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBE2L6 partitions between ISG15- and ubiquitin-conjugation, selects among its many reported substrates, and which E3 ligases pair with it in each context remain unresolved.
  • Determinants of ISG15 versus ubiquitin charging in cells unknown
  • E3 partners for most substrates (ATGL, STAT1, RIG-I/MDA5, FLT3-ITD) unidentified
  • Structure of the productive E2-E3 transfer complex not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 2 GO:0031386 protein tag activity 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 1
Partners
HERC5STAT1UBA7UBR4

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 Cryo-EM structure of the UBA7•UBE2L6 disulfide complex reveals three factors governing complex formation: (1) strong binding affinity and specificity of UBA7 for UBE2L6 (distinct from UBE2L3); (2) conformational differences in the catalytic cysteine capping loop (CCL); and (3) increased thiolate/thiol ratios at catalytic cysteines. Modification of any of these factors impacts complex activation and ISG15 transfer cascade. Cryo-EM structure determination, biochemical reconstitution, mutagenesis bioRxiv (preprint)preprint Medium bio_10.1101_2024.11.07.622398
2024 UBE2L6/UbcH8 exists in a concentration-dependent monomer-dimer equilibrium in solution, with a backside dimerization interface identified by NMR. Dimer formation induces conformational dynamics at E1 and E3 interfaces. SAXS and NMR spectroscopy; GST-fusion construct used to dissociate dimer ACS omega Medium 39346869
2020 UBE2L6 is the E2 enzyme in the ISGylation cascade, functioning between E1 (UBA7) and E3 (HERC5). UBE2L6 depletion in NB4 APL cells attenuated ATRA-induced ISG15 conjugation and impeded ATRA-induced neutrophil differentiation, demonstrating a catalytic role in ISGylation that is functionally required for leukemic differentiation. shRNA-mediated UBE2L6 knockdown, Western blotting for ISG15 conjugates, differentiation assays Molecular oncology Medium 31820845
2017 UBE2L6 and ISG15 act as inhibitors of basal autophagic flux in esophageal cancer cells; siRNA depletion of UBE2L6 or ISG15 enhanced endogenous autophagy as measured by LC3II accumulation and Cyto-ID staining. siRNA knockdown, LC3II western blotting, Cyto-ID autophagy staining Oncotarget Medium 28186990
2023 In high-pigmented melanoma cells, UBE2L6 (E2 conjugating enzyme) cooperates with UBR4 (E3 ligase) to ubiquitinate EZH2 at lysine 381, promoting EZH2 protein degradation. UHRF1-mediated CpG methylation downregulates UBE2L6 in low-pigmented melanoma cells, thereby stabilizing EZH2. Biochemical ubiquitination assays, siRNA knockdown, site-directed mutagenesis (K381), animal studies, proteasome inhibitor treatment Oncogene High 36906655
2020 UBE2L6 promotes ubiquitination of adipocyte triglyceride lipase (ATGL), reducing ATGL protein stability and lipolysis. Adipose-specific Ube2l6 knockout mice on a high-fat diet showed enhanced ATGL protein expression and increased ATGL-mediated lipolysis compared to controls. Adipose-specific knockout mouse model, Western blotting, lipolysis assays Journal of pharmacological sciences Medium 33712284
2013 A hypomorphic loss-of-function allele of Ube2l6 (nonsynonymous SNP abolishing protein expression) in BALB/c mice prolongs ATGL half-life in adipose tissue and represses adipogenesis. Ube2l6 knockdown in 3T3-L1 adipocytes recapitulated repressed adipogenesis, indicating Ube2l6 promotes adipogenic differentiation. Congenic mouse strain generation, Ube2l6 siRNA knockdown in 3T3-L1 cells, adipogenesis assays, ATGL half-life measurement Diabetes Medium 23557705
2023 UBE2L6 promotes ISGylation of STAT1, leading to STAT1 activation and M1 macrophage polarization. Ube2l6 adipose-specific knockout mice showed reduced M1 macrophage polarization on high-fat diet, and co-immunoprecipitation confirmed UBE2L6 interaction with STAT1. Adipose-specific Ube2l6 knockout mice, Co-IP, flow cytometry, RT-qPCR, Western blotting, ELISA Obesity facts Medium 37820603
2020 UBE2L6 interacts with and ubiquitinates the Senecavirus A RNA-dependent RNA polymerase (3D protein) at lysines 169 and 321, inhibiting 3D degradation and promoting viral replication. This ubiquitination requires cysteine 86 in UBE2L6. Recombinant viruses with K169R and K321R mutations in 3D showed significantly decreased replication. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis, recombinant virus rescue PLoS pathogens High 33104725
2025 PRRSV infection upregulates UBE2L6, which promotes K48-linked ubiquitination and proteasomal degradation of RIG-I and MDA5 (in cooperation with viral NSP5), thereby inhibiting type I IFN production and ISGylation. UBE2L6 also interacts with and stabilizes PRRSV NSP5. Knockdown of UBE2L6 reduced viral replication. Co-immunoprecipitation, knockdown/overexpression, Western blotting, ubiquitination assay with K48 linkage-specific analysis Veterinary research Medium 40611336
2024 p53 promotes FoxO3a ubiquitination and proteasomal degradation by upregulating UBE2L6 expression in retinal endothelial cells, accelerating cellular senescence in diabetic retinopathy. p53 inhibition, siRNA knockdown, Western blotting, ubiquitination assay, scRNA-seq and bulk RNA-seq in db/db mice Experimental gerontology Low 38437929
2021 UBE2L6 upregulation induces proteasome-mediated degradation of Mcl-1 in FLT3-ITD AML cells; UBE2L6 knockdown protected Mcl-1 from degradation via the ubiquitin-proteasome system. UBE2L6 knockdown (shRNA), Western blotting for Mcl-1, proteasome inhibitor rescue Journal of oncology Low 34594375
2025 UBE2L6 mediates proteasomal degradation of FLT3-ITD protein; decursin increases UBE2L6 expression and UBE2L6 knockdown by shRNA reduces FLT3-ITD degradation and FLT3-ITD-linked apoptosis. shRNA knockdown, Western blotting, cell viability assays, patient-derived mouse model Cell communication and signaling Low 40176110
2020 UBE2L6 silencing in cisplatin-resistant cells reduced ABCB6 mRNA and ABCB6 promoter activity, suggesting UBE2L6 regulates cisplatin resistance through transcriptional control of ABCB6. siRNA knockdown, gene expression profiling, ABCB6 promoter reporter assay Anti-cancer agents in medicinal chemistry Low 32329696
2000 UBE2L6 maps to chromosome 11q12 and its genomic organization (intron/exon structure) is highly conserved with its paralog UBE2L3, consistent with functional redundancy analogous to yeast UBC4/UBC5. Genomic cloning, sequence analysis, chromosomal mapping Cytogenetics and cell genetics Low 10894956

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 UBE2L6/UBCH8 and ISG15 attenuate autophagy in esophageal cancer cells. Oncotarget 35 28186990
2020 E2 ubiquitin-conjugating enzyme UBE2L6 promotes Senecavirus A proliferation by stabilizing the viral RNA polymerase. PLoS pathogens 34 33104725
2005 Down-regulation of UCRP and UBE2L6 in BRCA2 knocked-down human breast cells. Biochemical and biophysical research communications 20 15670748
2024 p53 accelerates endothelial cell senescence in diabetic retinopathy by enhancing FoxO3a ubiquitylation and degradation via UBE2L6. Experimental gerontology 18 38437929
2023 UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. Oncogene 17 36906655
2020 Inhibition of UBE2L6 attenuates ISGylation and impedes ATRA-induced differentiation of leukemic cells. Molecular oncology 17 31820845
2013 Identification of a loss-of-function mutation in Ube2l6 associated with obesity resistance. Diabetes 17 23557705
2023 Ube2L6 Promotes M1 Macrophage Polarization in High-Fat Diet-Fed Obese Mice via ISGylation of STAT1 to Trigger STAT1 Activation. Obesity facts 14 37820603
2020 UBE2L6 is Involved in Cisplatin Resistance by Regulating the Transcription of ABCB6. Anti-cancer agents in medicinal chemistry 12 32329696
2020 Adipose-specific knockout of ubiquitin-conjugating enzyme E2L6 (Ube2l6) reduces diet-induced obesity, insulin resistance, and hepatic steatosis. Journal of pharmacological sciences 11 33712284
2018 Furosine Induced Apoptosis by the Regulation of STAT1/STAT2 and UBA7/UBE2L6 Genes in HepG2 Cells. International journal of molecular sciences 10 29857509
2024 MX1 and UBE2L6 are potential metaflammation gene targets in both diabetes and atherosclerosis. PeerJ 9 38406276
2021 Homoharringtonine Synergized with Gilteritinib Results in the Downregulation of Myeloid Cell Leukemia-1 by Upregulating UBE2L6 in FLT3-ITD-Mutant Acute Myeloid (Leukemia) Cell Lines. Journal of oncology 8 34594375
2000 Genomic organization of the human ubiquitin-conjugating enzyme gene, UBE2L6 on chromosome 11q12. Cytogenetics and cell genetics 7 10894956
2025 Decursin induces FLT3-ITD acute myeloid leukemia cell apoptosis by increasing the expression of the ubiquitin-conjugase UBE2L6. Cell communication and signaling : CCS 4 40176110
2025 Porcine reproductive and respiratory syndrome virus NSP5 exploited UBE2L6 to promote viral replication via antagonising host RLRs and ISGylation. Veterinary research 4 40611336
2023 Association of UBE2L6 and ABCB6 Expression With Platinum Resistance in Serous Ovarian Carcinoma. Anticancer research 4 37500176
2024 Characterizing the monomer-dimer equilibrium of UbcH8/Ube2L6: A combined SAXS and NMR study. bioRxiv : the preprint server for biology 0 37090523
2024 Characterizing the Monomer-Dimer Equilibrium of UbcH8/Ube2L6: A Combined SAXS and NMR Study. ACS omega 0 39346869

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