Affinage

UBE2J1

Ubiquitin-conjugating enzyme E2 J1 · UniProt Q9Y385

Length
318 aa
Mass
35.2 kDa
Annotated
2026-06-10
17 papers in source corpus 13 papers cited in narrative 13 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

UBE2J1 is an endoplasmic reticulum membrane-anchored E2 ubiquitin-conjugating enzyme that serves as a tethered ubiquitination hub for ER-associated degradation (ERAD) and related quality-control processes (PMID:12082160). Anchored to the cytoplasmic face of the ER through a C-terminal transmembrane domain, it functions in the dislocation and proteasomal degradation of misfolded ER substrates, including misfolded TCRα, mutant CFTR, and non-β2m-bound MHC class I heavy chains (PMID:12082160, PMID:21245296). In its principal ERAD role it acts as the cognate E2 for the SEL1L-HRD1 (Synoviolin) complex together with Derlin-1 and p97, with UBE2J1 recruitment dependent on direct SEL1L-HRD1 interaction; loss of this recruitment causes accumulation and aggregation of misfolded ER proteins [PMID:21245296, PMID:bio_10.1101_2025.08.01.668162]. UBE2J1 is phosphorylated at Ser184 by MK2 downstream of p38 MAPK, a modification that does not alter catalytic activity toward TCRα but governs preferential binding to the E3 ligase c-IAP1, drives proteasomal turnover of UBE2J1, and is required for recovery from transient ER stress and for MK2-dependent TNFα biosynthesis (PMID:24020373, PMID:28321712). Beyond classical ERAD, UBE2J1 pairs with distinct E3 ligases to act in trafficking and signaling: with RNF26 it ubiquitylates SQSTM1/p62 at K435 to immobilize endosomes/lysosomes perinuclearly and promote EGFR trafficking (PMID:33472082), and it controls degradation of the androgen receptor, where its loss confers antiandrogen resistance in prostate cancer (PMID:38030789). A Ube2j1 knockout mouse is subviable and male-sterile owing to defective late spermiogenesis, establishing a non-redundant physiological requirement (PMID:25320092).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 Low

    Established UBE2J1 as a distinct, ER-predicted E2 enzyme family member with a noncanonical active site, defining the molecular class before any functional assay existed.

    Evidence cDNA cloning and sequence analysis from chondrocyte differential display

    PMID:10708578

    Open questions at the time
    • Computational/sequence inference only, no direct enzymatic or localization assay
    • ER localization predicted not demonstrated
    • No substrate or E3 partner identified
  2. 2002 Medium

    Showed UBE2J1 is a bona fide functional ERAD E2 anchored to the ER membrane, answering whether the predicted enzyme actually drives misfolded-protein degradation in mammalian cells.

    Evidence Dominant-negative overexpression, subcellular localization, and ERAD substrate (TCRα, mutant CFTR) degradation assays

    PMID:12082160

    Open questions at the time
    • Cognate E3 ligase not identified
    • Mechanism of substrate selection unresolved
    • Dominant-negative approach without endogenous loss-of-function
  3. 2005 Medium

    Identified c-IAP1 as a UBE2J1 E3 partner and linked the enzyme to TNF-R2 signaling, extending its activity beyond housekeeping ERAD into receptor-coupled ubiquitination.

    Evidence In vitro ubiquitination, confocal co-localization, and catalytically inactive mutant in TNF-R2-engaged cells

    PMID:15861135

    Open questions at the time
    • Endogenous requirement not tested with knockout
    • Relationship to ER-anchoring of this activity unclear
  4. 2011 High

    Defined the HRD1/Derlin-1/p97 complex as the major UBE2J1 ERAD machinery and showed it discriminates misfolded from properly assembled MHC class I, clarifying how quality control selects substrates.

    Evidence siRNA functional screen, reciprocal co-IP, ubiquitination and dislocation assays

    PMID:21245296

    Open questions at the time
    • Structural basis of substrate discrimination not resolved
    • How UBE2J1 is recruited into the complex not yet defined
  5. 2013 High

    Identified MK2-mediated Ser184 phosphorylation as a stress-responsive regulatory input on UBE2J1 and showed it does not control catalytic activity directly, separating regulation from enzymatic function.

    Evidence Phosphoproteomics, in vitro kinase assay with S184A mutagenesis, MK2/MK3 knockout cells, ubiquitination assay

    PMID:24020373

    Open questions at the time
    • Functional consequence of Ser184 phosphorylation left open at this stage
    • Mechanistic link to TNFα biosynthesis not detailed
  6. 2014 High

    Demonstrated a non-redundant in vivo role for UBE2J1 in spermiogenesis, moving beyond cell-based ERAD assays to organismal physiology.

    Evidence Ube2j1 knockout mouse with ultrastructural and fertility analysis

    PMID:25320092

    Open questions at the time
    • Specific spermatid substrates not identified
    • E3 partner mediating the spermiogenesis function unknown
  7. 2017 Medium

    Resolved the function of Ser184 phosphorylation by showing it is required for ER stress recovery, drives c-IAP1 binding, and triggers UBE2J1's own proteasomal degradation, defining a self-limiting regulatory loop.

    Evidence Phospho-mimic/phospho-null rescue, co-IP, proteasome inhibition, viability assays

    PMID:28321712

    Open questions at the time
    • E3 responsible for phospho-UBE2J1 turnover not pinpointed
    • Single-lab phospho-mutant approach
  8. 2018 Medium

    Extended UBE2J1 into innate immunity by showing it degrades IRF3 to dampen type I interferon and favor RNA virus replication, revealing a pro-viral immunoregulatory role.

    Evidence RNAi screen, overexpression/knockdown, IFNβ reporter, ubiquitination assay in Dengue infection

    PMID:30157886

    Open questions at the time
    • Cognate E3 ligase for IRF3 ubiquitination not identified
    • Direct vs indirect action on IRF3 not fully separated
  9. 2021 High

    Defined the UBE2J1/RNF26 E2-E3 pair and its substrate SQSTM1 (K435), explaining how ER-anchored ubiquitination spatially organizes the endolysosomal system and terminates EGFR/AKT signaling.

    Evidence Reciprocal co-IP, site-specific ubiquitylation mapping, live imaging, endosomal motility and EGFR/AKT assays

    PMID:33472082

    Open questions at the time
    • Relationship between RNF26 and HRD1 pathways not integrated
    • Regulation of the perinuclear subdomain assembly unresolved
  10. 2022 Medium

    Identified a UBE2J1/TRIM25 pair degrading RPS3 at K214 to restrain NF-κB, adding a tumor-suppressive signaling output in colorectal cancer.

    Evidence Co-IP, K214 site-mapped ubiquitination, NF-κB reporter, overexpression/knockdown

    PMID:36567344

    Open questions at the time
    • In vivo relevance beyond cell lines limited
    • Whether ER anchoring is required for this activity untested
  11. 2023 Medium

    Established UBE2J1 as the critical E2 for androgen receptor ubiquitination and degradation, linking its loss to antiandrogen resistance in prostate cancer.

    Evidence Knockdown/knockout, ubiquitination assays, AR degradation and resistance assays

    PMID:38030789

    Open questions at the time
    • Cognate E3 for AR not defined in this work
    • Single-lab loss-of-function evidence
  12. 2025 Medium

    Showed that UBE2J1 recruitment to the ERAD machinery requires direct SEL1L-HRD1 interaction, and that disrupting it causes lethal accumulation of misfolded ER proteins, mechanistically anchoring UBE2J1 to complex assembly.

    Evidence Knock-in mouse models (L709P, P699T, S658P), biochemical interaction and ERAD substrate/aggregation assays (preprint)

    PMID:bio_10.1101_2025.08.01.668162

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct UBE2J1-SEL1L/HRD1 contact residues not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBE2J1 is partitioned among its many E3 partners (HRD1, RNF26, c-IAP1, TRIM25, PRKN) and substrates across distinct subcellular contexts, and what determines partner/substrate selection, remains unresolved.
  • No structural model of UBE2J1 in any of its E2-E3 complexes
  • Determinants of E3-partner choice unknown
  • Integration of stress-regulated phosphorylation with each pathway not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
C-IAP1HRD1MK2PRKNRNF26SEL1LSQSTM1TRIM25
Complex memberships
SEL1L-HRD1 ERAD complexUBE2J1/RNF26 E2-E3 complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 UBE2J1 (mammalian Ubc6 homologue) is localized to the cytoplasmic surface of the ER membrane via a C-terminal transmembrane domain, analogous to yeast Ubc6p. Overexpression of wild-type or dominant-negative alleles specifically affects ERAD of misfolded TCRα and mutant CFTR, establishing UBE2J1 as a functional E2 enzyme in mammalian ERAD. Dominant-negative allele overexpression, subcellular localization analysis, ERAD substrate degradation assays Journal of cell science Medium 12082160
2000 UBE2J1 (NCUBE1) encodes a noncanonical ubiquitin-conjugating enzyme with a conserved noncanonical active site and a C-terminal transmembrane domain, constituting a distinct UBC family related to yeast Ubc6 and predicted to localize to the ER. cDNA cloning, sequence analysis, differential display on chondrocytes Biochemical and biophysical research communications Low 10708578
2005 UBE2J1 (Ubc6) binds the E3 ligase c-IAP1 and serves as its cognate E2 in vitro. Upon TNF-R2 engagement, UBE2J1 co-localizes with translocated TRAF2/c-IAP1 in a perinuclear ER-associated compartment, and a catalytically inactive UBE2J1 mutant inhibits TNF-α-induced TRAF2 ubiquitination and degradation. In vitro ubiquitination assay, confocal co-localization, catalytically inactive mutant overexpression The EMBO journal Medium 15861135
2011 UBE2J1 partners with the E3 ligase HRD1 (Synoviolin) in a complex that also includes Derlin 1 and p97 to ubiquitinate and dislocate misfolded MHC class I heavy chains (non-β2m-bound) for ERAD. HRD1 and UBE2J1 discriminate misfolded MHC I from properly assembled MHC I-β2m-peptide heterotrimers. HRD1 is also required for degradation of the HFE-C282Y hemochromatosis mutant. siRNA functional screen, co-immunoprecipitation, ubiquitination assay, dislocation assay Proceedings of the National Academy of Sciences of the United States of America High 21245296
2013 UBE2J1 is phosphorylated at Ser184 by MK2 (MAPKAP kinase-2) upon p38 MAPK-activating cytosolic stress and LPS stimulation. MK2 directly interacts with UBE2J1 (pulldown) and phosphorylates recombinant UBE2J1 in vitro; the S184A mutant is not phosphorylated. UBE2J1 Ser184 phosphorylation is abrogated in MK2/MK3-deficient cells. UBE2J1 contributes to MK2-dependent TNFα biosynthesis. However, the S184A mutant retains ubiquitinating activity toward TCRα, so phosphorylation at Ser184 does not regulate catalytic activity directly. Phosphoproteomics, in vitro kinase assay with recombinant proteins, pulldown assay, MK2/MK3 knockout cells, ubiquitination assay The Biochemical journal High 24020373
2014 Ube2j1 knockout mice have reduced viability and male sterility due to a defect in late spermiogenesis (spermatid cytoplasm removal is incomplete), establishing a non-redundant physiological role for UBE2J1 in the ubiquitin-proteasome system during spermatogenesis. Ube2j1 knockout mouse model, ultrastructural analysis, fertility assays The Journal of biological chemistry High 25320092
2017 UBE2J1 phosphorylation at Ser184 (phospho-mimic S184D) is required for recovery from transient ER stress; the phospho-null S184A mutant cannot rescue cells. The E3 ligase c-IAP1 preferentially binds phosphorylated UBE2J1. Phosphorylated UBE2J1 is rapidly degraded by the proteasome during ER stress recovery. Ectopic expression of phospho-mimic and phospho-null mutants, co-immunoprecipitation, proteasome inhibitor treatment, cell viability assays Journal of cell communication and signaling Medium 28321712
2018 UBE2J1 negatively regulates type I interferon signaling by facilitating ubiquitination and degradation of transcription factor IRF3, thereby promoting RNA virus (Dengue) infection. Silencing UBE2J1 increases IFNβ production and impairs DENV infection; overexpression suppresses RIG-I-directed IFNβ promoter activation. RNAi screen, gene overexpression/knockdown, reporter assay, ubiquitination assay Virology journal Medium 30157886
2021 UBE2J1 partners with the ER-anchored E3 ligase RNF26 as an E2/E3 pair localized in a perinuclear ER subdomain. The UBE2J1/RNF26 complex ubiquitylates SQSTM1/p62 on lysine 435, recruiting endosomal adaptors to immobilize endosomes/lysosomes in the perinuclear region, promoting EGFR trafficking to lysosomes and facilitating termination of EGF-induced AKT signaling. Co-immunoprecipitation, site-specific ubiquitylation mapping, live imaging, endosomal motility assays, EGFR/AKT signaling assays Cell reports High 33472082
2022 UBE2J1 forms an E2-E3 complex with TRIM25 and targets ribosomal protein RPS3 for ubiquitination and degradation at lysine 214. Degradation of RPS3 by UBE2J1/TRIM25 restrains NF-κB nuclear translocation and inactivates NF-κB signaling, suppressing colorectal cancer cell proliferation and metastasis. Co-immunoprecipitation, ubiquitination assay with K214 site mapping, NF-κB reporter, overexpression/knockdown in cell lines Oncogene Medium 36567344
2023 UBE2J1 is the critical E2 ubiquitin-conjugating enzyme responsible for androgen receptor (AR) ubiquitination and degradation. Loss of UBE2J1 disrupts AR ubiquitination, leading to AR protein accumulation and antiandrogen resistance in prostate cancer cells. UBE2J1 knockdown/knockout, ubiquitination assays, AR protein level and degradation assays, antiandrogen resistance assays Oncogene Medium 38030789
2025 The SEL1L-HRD1 ERAD complex requires direct SEL1L-HRD1 interaction for recruitment of UBE2J1. A knock-in L709P mutation in SEL1L that abolishes SEL1L-HRD1 binding impairs UBE2J1 recruitment, disrupts substrate ubiquitination, and causes accumulation and aggregation of misfolded ER proteins, resulting in neonatal lethality in mice. Knock-in mouse models (L709P, P699T, S658P mutations), biochemical interaction assays, ERAD substrate assays, protein aggregation analysis bioRxivpreprint Medium bio_10.1101_2025.08.01.668162
2025 UBE2J1 (UBC6) facilitates PRKN (Parkin)-mediated ubiquitination and degradation of AURKA, promoting AMPK phosphorylation at Thr172 in ovarian cancer cells. UBC6 interacts with PRKN as demonstrated by co-immunoprecipitation. Co-immunoprecipitation, ubiquitination assay, lentiviral knockdown, xenograft mouse model, AMPK phosphorylation assay International immunopharmacology Low 41237699

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation. Proceedings of the National Academy of Sciences of the United States of America 120 21245296
2002 A role for mammalian Ubc6 homologues in ER-associated protein degradation. Journal of cell science 97 12082160
2005 TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. The EMBO journal 88 15861135
2022 UBE2J1 inhibits colorectal cancer progression by promoting ubiquitination and degradation of RPS3. Oncogene 37 36567344
2014 The E2 ubiquitin-conjugating enzyme UBE2J1 is required for spermiogenesis in mice. The Journal of biological chemistry 37 25320092
2021 The ER-embedded UBE2J1/RNF26 ubiquitylation complex exerts spatiotemporal control over the endolysosomal pathway. Cell reports 34 33472082
2018 Ubiquitin-conjugating enzyme UBE2J1 negatively modulates interferon pathway and promotes RNA virus infection. Virology journal 30 30157886
2000 Identification of a family of noncanonical ubiquitin-conjugating enzymes structurally related to yeast UBC6. Biochemical and biophysical research communications 29 10708578
2017 The role of ubiquitin-conjugating enzyme Ube2j1 phosphorylation and its degradation by proteasome during endoplasmic stress recovery. Journal of cell communication and signaling 28 28321712
2013 Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. The Biochemical journal 21 24020373
2023 UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene 16 38030789
2023 UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling. Open medicine (Warsaw, Poland) 12 36852267
2014 The human ubiquitin conjugating enzyme UBE2J2 (Ubc6) is a substrate for proteasomal degradation. Biochemical and biophysical research communications 12 25083800
2021 Zfx-induced upregulation of UBE2J1 facilitates endometrial cancer progression via PI3K/AKT pathway. Cancer biology & therapy 10 33632059
2024 Endoplasmic reticulum and inner nuclear membrane ubiquitin-conjugating enzymes Ubc6 and Ubc7 confer resistance to hygromycin B in Saccharomyces cerevisiae. microPublication biology 2 39139584
2024 UBE2J1 promotes ALV-A proviral DNA synthesis through the STAT3/IRF1 signaling pathway. Veterinary microbiology 1 38387235
2025 UBC6 mediated the inhibitory effect of quercetin on ovarian cancer through the PRKN-AURKA-AMPK axis. International immunopharmacology 0 41237699

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