Affinage

UBQLN4

Ubiquilin-4 · UniProt Q9NRR5

Length
601 aa
Mass
63.9 kDa
Annotated
2026-06-10
22 papers in source corpus 16 papers cited in narrative 16 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

UBQLN4 is a UbL-UBA domain proteasomal shuttle factor that recognizes defective, mislocalized, and ubiquitinated client proteins across multiple cellular compartments and routes them to the proteasome for degradation (PMID:20940304, PMID:27113755, PMID:30612738). At the endoplasmic reticulum it engages connexins (Cx43, Cx40, Cx45, Cx32) through direct UBA-domain contacts with their C-terminal regions and links them to the proteasome via UbL-domain interactions with the subunits S2/Rpn1 and S5a/Rpn10, accelerating connexin turnover; for Cx43 this degradation can proceed ubiquitin-independently (PMID:18079109, PMID:20940304, PMID:25583071). In the cytoplasm UBQLN4 partners with BAG6 to capture transmembrane segments of mislocalized proteins for proteasomal clearance (PMID:27113755). UBQLN4 binds polyubiquitin through its UBA domain and, complexed with POST, exports polyubiquitinated proteins from the nucleus to the cytosol in a CRM1-dependent manner to maintain nuclear proteostasis (PMID:29666234). In the DNA damage response, ATM phosphorylates UBQLN4, which then binds ubiquitylated MRE11 and drives its removal from damaged chromatin by proteasomal degradation, thereby restraining homologous recombination and favoring non-homologous end joining; this activity also contributes to cisplatin resistance through control of MRE11A levels (PMID:30612738, PMID:33605536). Additional substrates and binding partners include beta-catenin in motor neurons, the anti-apoptotic proteins BCL2A1/BCL2L10 in mesothelioma, and the NMDA receptor subunit GluN2B at excitatory post-synapses, where UBQLN4 regulates synaptic function and seizure susceptibility (PMID:28463112, PMID:34245648, PMID:40930427). An ALS-associated UBQLN4 variant impairs proteasomal function and causes motor axon morphogenesis defects, a phenotype rescued by beta-catenin inhibition (PMID:28463112).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 Low

    Established the earliest functional clue that UBQLN4 recognizes ER-targeting signal sequences, distinguishing secretory/ER-luminal clients from mitochondrial targets.

    Evidence Yeast two-hybrid screening against signal sequences including HSP47

    PMID:11162551

    Open questions at the time
    • Single Y2H method without functional follow-up
    • No demonstration of degradation or proteasome linkage
    • Physiological relevance of signal-sequence binding unresolved
  2. 2008 High

    Defined UBQLN4 as a bridging shuttle factor that links ER-localized Cx43 to the proteasome and controls its turnover, resolving how a connexin is delivered for degradation.

    Evidence Y2H, GST pull-down, co-IP, confocal microscopy and Cx43 half-life measurement under overexpression/knockdown

    PMID:18079109

    Open questions at the time
    • Did not determine whether degradation requires substrate ubiquitination
    • Generality beyond Cx43 untested at this stage
  3. 2010 High

    Showed UBQLN4 can mediate ubiquitin-independent proteasomal degradation of Cx43, since CIP75-associated Cx43 is non-ubiquitinated and a lysine-free mutant still binds.

    Evidence Co-IP, immunofluorescence, in vitro ubiquitin-binding assay and lysine-free Cx43 mutant analysis

    PMID:20940304

    Open questions at the time
    • Mechanism of substrate recognition independent of ubiquitin not fully defined
    • Does not exclude ubiquitin-dependent routes for other substrates
  4. 2014 Medium

    Established that UBQLN4 is required for the Cx43-proteasome association but that compensatory routes permit Cx43 dislocation and degradation in its absence.

    Evidence Subcellular fractionation, co-IP, DTT-induced misfolding and shRNA knockdown

    PMID:24256120

    Open questions at the time
    • Identity of compensatory degradation machinery unknown
    • Quantitative contribution of UBQLN4 to total Cx43 flux unresolved
  5. 2015 High

    Generalized the connexin-targeting role by showing direct UBA-domain binding to Cx40, Cx45 and Cx32 undergoing ERAD, with structural mapping by NMR.

    Evidence NMR spectroscopy, shRNA knockdown with western blot, trafficking inhibitor and co-IP assays

    PMID:25583071

    Open questions at the time
    • Whether all connexin substrates use the same ubiquitin dependence differs (Cx32 via ubiquitination) and is not unified
    • In vivo physiological consequence of connexin regulation untested
  6. 2016 Medium

    Extended UBQLN4 to a cytoplasmic quality-control role recognizing exposed transmembrane segments of mislocalized proteins as a BAG6-binding factor.

    Evidence Co-IP for BAG6, truncated TMD degradation assay, SRP54 depletion and proteasome inhibitor treatment

    PMID:27113755

    Open questions at the time
    • Structural basis of TMD recognition not defined
    • Relative roles of UBQLN4 versus other UBQLNs in this pathway unresolved
  7. 2017 Medium

    Linked UBQLN4 to motor neuron disease, identifying beta-catenin as a substrate and demonstrating that an ALS variant impairs proteasome function with rescuable axon defects.

    Evidence ALS-variant expression in mouse motor neurons and zebrafish, proteasomal activity assays and beta-catenin inhibition rescue

    PMID:28463112

    Open questions at the time
    • Mechanism by which the variant impairs proteasome function unclear
    • Direct biochemical UBQLN4-beta-catenin interaction not detailed
  8. 2018 High

    Revealed a nuclear proteostasis function: UBQLN4 binds polyubiquitin and, with POST, exports polyubiquitinated proteins from nucleus to cytosol via CRM1.

    Evidence Nuclear/cytosol fractionation, CRM1 inhibition, co-IP, combined proteasome/CRM1 inhibitor treatment and UBA binding assays

    PMID:29666234

    Open questions at the time
    • Range of nuclear substrates exported is undefined
    • Whether DSB-related MRE11 handling uses the same export route is not connected
  9. 2019 High

    Placed UBQLN4 in the DNA double-strand break response, showing ATM phosphorylates it to drive proteasomal removal of ubiquitylated MRE11 from chromatin and bias repair from HR toward NHEJ.

    Evidence Co-IP, ATM phosphorylation assay, chromatin fractionation, in vitro and in vivo HRR assays, loss/gain-of-function and patient mutations; with synthesizing commentary

    PMID:30612738 PMID:31131301

    Open questions at the time
    • E3 ligase that ubiquitylates MRE11 not identified
    • How phosphorylation switches UBQLN4 substrate selectivity is unresolved
  10. 2020 Medium

    Identified a membrane-proximal interaction whereby UBQLN4 binds ER J proteins B12/B14 via its H domain and STI1 motifs and is hijacked by SV40 for ER escape.

    Evidence Direct binding with purified proteins, J-domain mutant and domain-deletion mapping, SV40 infection assays

    PMID:32161173

    Open questions at the time
    • Endogenous (non-viral) function of B12/B14 binding unknown
    • Relationship to proteasomal shuttling activity unclear
  11. 2021 Medium

    Expanded UBQLN4's cancer roles by showing it stabilizes anti-apoptotic BCL2A1/BCL2L10, controls MRE11A levels to confer cisplatin resistance, and is transcriptionally driven by C/EBPbeta to activate Wnt/beta-catenin signaling.

    Evidence ATM-substrate genetic screen, co-IP, apoptosis assays, ubiquitination/degradation assays after cisplatin, ChIP and luciferase reporter assays

    PMID:33605536 PMID:34245648 PMID:34930912

    Open questions at the time
    • How UBQLN4 stabilizes rather than degrades BCL2A1/BCL2L10 mechanistically unclear
    • Direct versus indirect activation of Wnt/beta-catenin not fully separated
  12. 2023 Medium

    Characterized UBQLN4 biophysics, showing it phase separates in vitro at a lower saturation concentration than UBQLN1 and that its N-terminal disordered region inhibits condensation electrostatically.

    Evidence In vitro phase separation assays, charge-variant mutagenesis and domain-deletion constructs (preprint)

    PMID:37808720

    Open questions at the time
    • Preprint not peer-reviewed
    • Cellular relevance of phase separation to proteostasis function untested
  13. 2025 Medium

    Established a synaptic function by showing UBQLN4 drives proteasomal degradation of GluN2B at excitatory post-synapses and modulates seizure susceptibility in vivo.

    Evidence AAV-mediated overexpression/knockdown in mice, kainic acid epilepsy model, proteasome inhibitor assay and immunostaining

    PMID:40930427

    Open questions at the time
    • Whether GluN2B degradation is ubiquitin-dependent not defined
    • Direct UBQLN4-GluN2B binding interface not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how UBQLN4 selects among its diverse substrates across the ER, cytosol, nucleus, and synapse, and how phosphorylation, phase separation, and partner binding integrate to switch between degradative and stabilizing outcomes.
  • No unifying model of substrate-selectivity switching
  • E3 ligases acting upstream of most substrates unidentified
  • In vivo relevance of phase separation to proteostasis untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 3 GO:0031386 protein tag activity 2
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2
Partners
BAG6BCL2A1BCL2L10DNAJB12DNAJB14GJA1MRE11POST
Complex memberships
UBIN-POST nuclear export complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 UBQLN4 (UBIN) binds to ER-targeting signal sequences of various secretory and ER-luminal proteins (including HSP47) but does not interact with mitochondrial targeting sequences, as determined by yeast two-hybrid screening. Yeast two-hybrid screening Biochemical and biophysical research communications Low 11162551
2007 UBQLN4 (CIP75) interacts with connexin43 (Cx43) via its UBA domain binding to a region in Cx43 between Lys264 and Asn302 (containing PY motif and multiphosphorylation sites), and its UbL domain interacts with proteasomal subunits S2/RPN1 and S5a/RPN10; overexpression stimulates Cx43 degradation and reduces its half-life, while siRNA knockdown has the opposite effect. CIP75 localizes primarily at the ER, co-localizing with Cx43 in the perinuclear region. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, laser confocal microscopy, overexpression and siRNA knockdown with Cx43 half-life measurement The Journal of biological chemistry High 18079109
2010 UBQLN4 (CIP75) mediates ubiquitin-independent proteasomal degradation of ER-localized Cx43: CIP75 interacts with Cx43 at the ER, can bind free monoubiquitin and K48-linked tetraubiquitin chains in vitro, but the Cx43 associated with CIP75 is not ubiquitinated and a lysine-free Cx43 mutant retains the ability to interact with CIP75. Co-immunoprecipitation, immunofluorescence microscopy, in vitro ubiquitin-binding assay, lysine-free Cx43 mutant analysis The Journal of biological chemistry High 20940304
2014 UBQLN4 (CIP75) forms a complex with ER-localized Cx43 and proteasomal subunits S2/Rpn1 and S5a/Rpn10; deliberate misfolding of Cx43 by DTT enhanced CIP75 binding; shRNA-mediated knockdown of CIP75 diminished Cx43-proteasome association but still allowed ER dislocation and degradation, indicating CIP75 is essential for Cx43-proteasome interaction but alternate compensatory mechanisms exist for degradation. Subcellular fractionation, co-immunoprecipitation, DTT-induced misfolding, shRNA knockdown The Biochemical journal Medium 24256120
2015 UBQLN4 (CIP75) UBA domain directly interacts with the C-terminal domains of Cx40 and Cx45 (in addition to Cx43), as determined by NMR; shRNA knockdown of CIP75 in HeLa cells increases Cx40 and Cx45 levels; CIP75 preferentially interacts with connexins undergoing ERAD and also interacts with ER-localized Cx32 likely via Cx32 ubiquitination. NMR spectroscopy, shRNA knockdown with western blot, trafficking inhibitor assays, co-immunoprecipitation The Biochemical journal High 25583071
2016 UBQLN4 acts as a BAG6-binding factor that recognizes mislocalized transmembrane domain proteins in the cytoplasm (via their exposed transmembrane segment) and targets them to the proteasome for degradation; UBQLN4 also recognizes endogenous defective proteins induced by SRP54 depletion. Co-immunoprecipitation (BAG6 binding), truncated transmembrane domain protein degradation assay, SRP54 depletion, proteasome inhibitor treatment EMBO reports Medium 27113755
2017 An ALS-associated variant of UBQLN4 impairs proteasomal function and causes motor axon morphogenesis defects in mouse motor neurons and zebrafish; beta-catenin (a Wnt signaling effector) was identified as a UBQLN4 substrate, and inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. Expression of ALS-variant in mouse motor neurons and zebrafish (in vivo), proteasomal activity assays, beta-catenin inhibition rescue experiments eLife Medium 28463112
2018 UBQLN4 (UBIN) shuttles between the nucleus and cytosol in a CRM1-dependent manner via its binding partner POST (which harbors a nuclear export signal); UBIN binds polyubiquitin chains through its UBA domain, and the UBIN-POST complex exports polyubiquitinated proteins from the nucleus to the cytosol for proteasomal degradation, maintaining nuclear protein homeostasis. Nuclear/cytosol fractionation, CRM1 inhibition, co-immunoprecipitation, proteasome inhibitor and CRM1 inhibitor co-treatment, UBA domain binding assays Proceedings of the National Academy of Sciences of the United States of America High 29666234
2019 UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR); UBQLN4 promotes removal of MRE11 from damaged chromatin via proteasomal degradation. Loss of UBQLN4 leads to chromatin retention of MRE11 and non-physiological HRR activity, while UBQLN4 overexpression represses HRR and favors non-homologous end joining (NHEJ). Co-immunoprecipitation (UBQLN4-MRE11 interaction), ATM phosphorylation assay, chromatin fractionation, in vitro and in vivo HRR assays, loss-of-function and overexpression studies, patient-derived mutations Cell High 30612738
2019 The UBQLN4-MRE11 interaction is ATM-dependent, indicating that ATM (which initiates HR) also limits excessive end-resection by phosphorylating UBQLN4 to promote MRE11 degradation and repress HR. Review/commentary of experimental data from PMID:30612738, epistasis analysis Molecular & cellular oncology Medium 31131301
2020 UBQLN4 (Ubqln4) directly binds ER membrane J proteins B12 and B14 at the ER-cytosol interface (in a J-domain-independent manner via its H domain and STI1 motifs 1-2) and captures SV40 virus emerging from the ER, facilitating viral escape from the ER to the cytosol and promoting infection. Direct binding assays (purified proteins), J-domain mutant analysis, domain deletion mapping (H domain, STI1 motifs), SV40 infection assays with knockdown/overexpression Journal of virology Medium 32161173
2021 UBQLN4 is a substrate for ATM kinase (phosphorylated by ATM); UBQLN4 interacts with and stabilizes the anti-apoptotic proteins BCL2A1 and BCL2L10, preventing mesothelioma cell apoptosis in response to DNA damage. Mammalian functional genetic screening for ATM substrates, co-immunoprecipitation (UBQLN4-BCL2A1/BCL2L10), apoptosis assays with UBQLN4 knockdown/overexpression Molecular oncology Medium 34245648
2021 UBQLN4 binds ubiquitinated MRE11A and promotes its proteasomal degradation following cisplatin-induced DNA damage; MRE11A was found to be ubiquitinated after cisplatin treatment, and UBQLN4 binding to ubiquitinated MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels and promoting cisplatin resistance. Co-immunoprecipitation (UBQLN4-ubiquitinated MRE11A), ubiquitination assay after cisplatin treatment, UBQLN4 knockdown with MRE11A protein level measurement, gene copy number analysis Molecular oncology Medium 33605536
2021 UBQLN4 activates the Wnt/β-catenin signaling pathway, upregulating β-catenin and c-Myc expression; the transcription factor C/EBPβ directly binds to the UBQLN4 core promoter and activates its transcription. GSEA, western blot, rescue experiments, dual luciferase reporter assay, ChIP assay, RT-qPCR Cell death discovery Medium 34930912
2023 Full-length UBQLN4 phase separates in vitro at a lower saturation concentration than UBQLN1; the short N-terminal disordered region of UBQLN4 inhibits its phase separation via electrostatic interactions; UBQLN4 lacks the proline-rich (Pxx) region present in UBQLN2, which accounts for the absence of temperature-dependent phase behavior in UBQLN4. In vitro phase separation assays with full-length proteins, charge variant mutagenesis, domain deletion constructs bioRxivpreprint Medium 37808720
2025 UBQLN4 promotes proteasomal degradation of the NMDA receptor subunit GluN2B, thereby regulating synaptic function; UBQLN4 is localized in neurons at excitatory post-synapses, and its reduction increases seizure susceptibility, while overexpression is protective in a kainic acid-induced chronic epilepsy mouse model. AAV-mediated overexpression and knockdown in mice, kainic acid epilepsy model, proteasome inhibitor assay to confirm degradation pathway, subcellular localization by immunostaining Neurobiology of disease Medium 40930427

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell 105 30612738
2016 UBQLN4 recognizes mislocalized transmembrane domain proteins and targets these to proteasomal degradation. EMBO reports 61 27113755
2007 A novel connexin43-interacting protein, CIP75, which belongs to the UbL-UBA protein family, regulates the turnover of connexin43. The Journal of biological chemistry 54 18079109
2010 Ubiquitin-independent proteasomal degradation of endoplasmic reticulum-localized connexin43 mediated by CIP75. The Journal of biological chemistry 45 20940304
2017 A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis. eLife 42 28463112
2018 Nuclear export of ubiquitinated proteins via the UBIN-POST system. Proceedings of the National Academy of Sciences of the United States of America 28 29666234
2020 UBQLN4 promotes progression of HCC via activating wnt-β-catenin pathway and is regulated by miR-370. Cancer cell international 22 31911755
2021 Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma. Molecular oncology 19 33605536
2001 Molecular cloning of a novel ubiquitin-like protein, UBIN, that binds to ER targeting signal sequences. Biochemical and biophysical research communications 19 11162551
2021 UBQLN4 is activated by C/EBPβ and exerts oncogenic effects on colorectal cancer via the Wnt/β-catenin signaling pathway. Cell death discovery 17 34930912
2015 Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). The Biochemical journal 16 25583071
2014 CIP75 (connexin43-interacting protein of 75 kDa) mediates the endoplasmic reticulum dislocation of connexin43. The Biochemical journal 15 24256120
2018 Overexpression of the Ubiquilin-4 (UBQLN4) is Associated with Cell Cycle Arrest and Apoptosis in Human Normal Gastric Epithelial Cell Lines GES-1 Cells by Activation of the ERK Signaling Pathway. Medical science monitor : international medical journal of experimental and clinical research 12 29807370
2021 UBQLN4 is an ATM substrate that stabilizes the anti-apoptotic proteins BCL2A1 and BCL2L10 in mesothelioma. Molecular oncology 10 34245648
2020 Ubqln4 Facilitates Endoplasmic Reticulum-to-Cytosol Escape of a Nonenveloped Virus during Infection. Journal of virology 9 32161173
2019 UBQLN4 promotes non-homologous end joining by repressing DNA end-resection. Molecular & cellular oncology 7 31131301
2009 Generation and characterization of mouse monoclonal antibodies against CIP75, an UbL-UBA domain-containing protein. Hybridoma (2005) 6 19249996
2023 UbiN, a novel Rhodobacter capsulatus decarboxylative hydroxylase involved in aerobic ubiquinone biosynthesis. FEBS open bio 4 37716914
2025 UBQLN4 regulates seizures by promoting the proteasomal degradation of GluN2B. Neurobiology of disease 2 40930427
2024 UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway. Journal of cancer research and clinical oncology 2 38969831
2023 Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4. bioRxiv : the preprint server for biology 1 37808720
2024 Circ_0000006 and circ_0000160 regulate hsa-let-7e-5p/UBQLN4 axis in aortic dissection progression. PloS one 0 38820386

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