UBE2J1

UBE2J1 is a tail-anchored E2 ubiquitin-conjugating enzyme embedded in the endoplasmic reticulum membrane that functions as a central hub linking ERAD, innate immune regulation, and endolysosomal organization through partnerships with multiple E3 ligases. It partners with HRD1 (recruited via the SEL1L–HRD1 interface) to ubiquitinate and dislocate misfolded ER substrates including MHC class I heavy chains and CFTR (PMID:21245296, PMID:12082160), with RNF26 to ubiquitinate SQSTM1/p62 at Lys435 and thereby position endolysosomes perinuclearly for EGFR-to-lysosome trafficking (PMID:33472082), and with c-IAP1 and TRIM25 to target TRAF2, IRF3, RPS3, and the androgen receptor for proteasomal degradation, modulating TNF signaling, type I interferon responses, NF-κB activity, and androgen receptor turnover (PMID:15861135, PMID:30157886, PMID:36567344, PMID:38030789). UBE2J1 is phosphorylated at Ser184 by MK2 downstream of p38 MAPK, a modification that governs its interaction with c-IAP1 and is required for recovery from ER stress, after which phosphorylated UBE2J1 itself is degraded by the proteasome (PMID:24020373, PMID:28321712). Ube2j1-knockout male mice are sterile owing to failed cytoplasm removal and spermatid release during spermiogenesis, demonstrating a non-redundant physiological role (PMID:25320092).

1. 2000 Medium

   Identification of UBE2J1 as a mammalian Ubc6p homologue with a C-terminal transmembrane anchor established it as an ER-resident E2 enzyme and predicted an ERAD function, answering whether mammals possess a membrane-embedded ubiquitin-conjugating enzyme analogous to the yeast ERAD E2.

   Evidence cDNA cloning, sequence analysis, and expression profiling of NCUBE1

   PMID:10708578

   Open questions at the time

   • No in vitro ubiquitination activity demonstrated for the human protein
   • Topology confirmed only by prediction
2. 2002 High

   Dominant-negative UBE2J1 blocked degradation of TCR-α and mutant CFTR, providing the first functional evidence that UBE2J1 participates in mammalian ERAD substrate turnover.

   Evidence Subcellular fractionation, dominant-negative overexpression, and ERAD degradation assays for TCR-α and CFTR in mammalian cells

   PMID:12082160

   Open questions at the time

   • Partner E3 ligase(s) not identified
   • Dominant-negative approach does not exclude indirect effects on other ER E2 enzymes
3. 2005 High

   Demonstration that UBE2J1 serves as the cognate E2 for c-IAP1 in TNF-R2-dependent TRAF2 ubiquitination expanded its role beyond classical ERAD to TNF/NF-κB signaling at the ER.

   Evidence In vitro ubiquitination reconstitution with c-IAP1, confocal co-localization, and catalytically inactive UBE2J1 blocking TRAF2 degradation

   PMID:15861135

   Open questions at the time

   • Ubiquitin chain type on TRAF2 not determined
   • Whether c-IAP1–UBE2J1 acts in ERAD or a distinct pathway unclear
4. 2011 High

   An siRNA screen identified UBE2J1 as essential within the HRD1–Derlin-1–p97 complex for selective ubiquitination and dislocation of misfolded MHC class I heavy chains, establishing its E3 partnership with HRD1 in a defined ERAD substrate pathway.

   Evidence siRNA functional screen, reciprocal Co-IP, ubiquitination and dislocation assays for MHC I and HFE-C282Y

   PMID:21245296

   Open questions at the time

   • Direct UBE2J1–HRD1 binding interface not mapped
   • Relative contributions of UBE2J1 vs UBE2J2 in this complex not fully resolved
5. 2013 High

   Identification of Ser184 phosphorylation by MK2 downstream of p38 MAPK revealed a stress-responsive regulatory switch on UBE2J1, linking inflammatory and stress kinase pathways to ERAD E2 activity.

   Evidence Phosphoproteomics, in vitro kinase assay with S184A mutant, pulldown in MK2/MK3-deficient cells

   PMID:24020373

   Open questions at the time

   • How Ser184 phosphorylation alters catalytic activity or substrate selection mechanistically unclear
   • Whether phosphorylation affects HRD1-dependent ERAD not tested
6. 2014 High

   Ube2j1-knockout mice showed male sterility due to defective spermatid remodeling, establishing an essential non-redundant in vivo role for UBE2J1 in spermiogenesis.

   Evidence Knockout mouse model with electron microscopy, histology, and fertility assays

   PMID:25320092

   Open questions at the time

   • Specific substrates ubiquitinated by UBE2J1 in spermatids not identified
   • Partner E3 ligase in spermiogenesis unknown
7. 2017 Medium

   Phospho-mimetic S184D UBE2J1 was required for ER stress recovery and preferentially bound c-IAP1, while phosphorylated UBE2J1 was itself degraded by the proteasome, revealing a feedback circuit that couples stress-induced phosphorylation to both substrate processing and E2 turnover.

   Evidence Ectopic WT/S184D/S184A expression, cell viability post-ER stress, Co-IP with c-IAP1, proteasome inhibitor treatment

   PMID:28321712

   Open questions at the time

   • Mechanism by which phosphorylation promotes c-IAP1 interaction not structurally defined
   • Whether c-IAP1 is the E3 that degrades UBE2J1 itself not determined
   • Single-lab study without independent replication
8. 2018 Medium

   UBE2J1 was shown to promote ubiquitination and degradation of IRF3, suppressing type I interferon signaling and facilitating Dengue virus infection, extending UBE2J1's role to antiviral innate immunity.

   Evidence RNAi screen, siRNA/overexpression, IFNβ reporter assay, IRF3 ubiquitination and degradation assay

   PMID:30157886

   Open questions at the time

   • Partner E3 ligase for IRF3 degradation not identified
   • Ubiquitin chain type and IRF3 ubiquitination sites not mapped
   • Single-lab study
9. 2021 High

   Pairing of UBE2J1 with the ER E3 ligase RNF26 to ubiquitinate p62/SQSTM1 at Lys435 revealed a novel non-ERAD function: perinuclear immobilization of endolysosomes to direct EGFR trafficking and terminate AKT signaling.

   Evidence Reciprocal Co-IP, mass spectrometry ubiquitination site mapping, live-cell endosome imaging, EGFR/AKT signaling readouts

   PMID:33472082

   Open questions at the time

   • Whether UBE2J1–RNF26 complex acts on additional substrates beyond p62 unknown
   • Transmembrane interaction interface not structurally resolved
10. 2022 Medium

    UBE2J1 was found to partner with the E3 ligase TRIM25 to poly-ubiquitinate RPS3 at Lys214, restraining NF-κB nuclear translocation in colorectal cancer cells, identifying yet another E3 partner and a ribosomal protein as substrate.

    Evidence Co-IP, ubiquitination assay, K214R mutagenesis, NF-κB reporter and nuclear fractionation

    PMID:36567344

    Open questions at the time

    • How an ER-anchored E2 accesses the cytosolic/nuclear RPS3–NF-κB axis not explained
    • Single-lab study
    • In vivo relevance not tested
11. 2023 Medium

    UBE2J1 was identified as the E2 responsible for androgen receptor ubiquitination and degradation; its loss in prostate cancer drives AR accumulation and antiandrogen resistance, connecting UBE2J1 to hormone receptor proteostasis and cancer therapy resistance.

    Evidence siRNA knockdown, overexpression, ubiquitination assay, prostate cancer cell models and proliferation assays

    PMID:38030789

    Open questions at the time

    • Partner E3 ligase for AR ubiquitination not identified
    • Whether AR is a direct substrate or indirectly affected not fully resolved
    • Single-lab study

• A unifying structural and regulatory model for how UBE2J1 selects among its multiple E3 partners (HRD1, RNF26, c-IAP1, TRIM25) and substrates remains unresolved, as does the mechanistic basis for Ser184 phosphorylation-dependent partner switching.
• No crystal or cryo-EM structure of UBE2J1 or any UBE2J1–E3 complex
• Partner E3 for several substrates (IRF3, AR) not identified
• Spermiogenesis-specific substrates and E3 partner unknown