Affinage

UBQLN4

Ubiquilin-4 · UniProt Q9NRR5

Length
601 aa
Mass
63.9 kDa
Annotated
2026-04-28
22 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBQLN4 is a UbL-UBA domain proteasomal shuttle factor that delivers diverse substrates for proteasomal degradation in contexts ranging from protein quality control to DNA damage repair and synaptic homeostasis. Its UBA domain directly binds the cytoplasmic tails of connexins (Cx43, Cx40, Cx45, Cx32) and mislocalized transmembrane domain proteins, while its UbL domain engages proteasomal subunits S2/RPN1 and S5a/RPN10 to effect substrate degradation, including ubiquitin-independent ERAD of connexins from the ER (PMID:18079109, PMID:20940304, PMID:25583071, PMID:27113755). Upon DNA double-strand breaks, ATM phosphorylates UBQLN4, enabling it to bind ubiquitylated MRE11, remove MRE11 from damaged chromatin via proteasomal degradation, and thereby suppress homologous recombination in favor of non-homologous end joining (PMID:30612738, PMID:33605536). UBQLN4 also regulates neuronal signaling by targeting beta-catenin and the NMDA receptor subunit GluN2B for proteasomal degradation; an ALS-associated variant impairs proteasomal function, causing beta-catenin accumulation and aberrant motor axon morphogenesis (PMID:28463112, PMID:40930427).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Identification of UBQLN4 as a proteasomal shuttle for connexin43 established its core molecular mechanism: UBA domain binds Cx43 while UbL domain docks on proteasomal subunits RPN1 and RPN10, accelerating Cx43 turnover.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, siRNA knockdown, and half-life measurements in mammalian cells

    PMID:18079109

    Open questions at the time
    • Whether UBQLN4 shuttle activity extends beyond connexins was unknown
    • Structural basis of UBA–Cx43 interaction not resolved at atomic level
  2. 2010 High

    Demonstration that UBQLN4 mediates ubiquitin-independent proteasomal degradation of ER-localized Cx43 revealed that substrate ubiquitylation is not always required for UBQLN4 shuttle function.

    Evidence Co-IP with lysine-less Cx43 mutant, ubiquitin-binding assays, and immunofluorescence in mammalian cells

    PMID:20940304

    Open questions at the time
    • How UBQLN4 recognizes non-ubiquitinated substrates structurally remained unclear
    • Whether ubiquitin-independent mode applies to non-connexin substrates was untested
  3. 2014 Medium

    Showing that deliberate Cx43 misfolding enhanced UBQLN4 binding linked UBQLN4 to ERAD-associated quality control, where it facilitates ER dislocation of misfolded substrates to the proteasome.

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

    PMID:24256120

    Open questions at the time
    • Whether UBQLN4 acts upstream or downstream of retrotranslocation machinery was not resolved
    • Only DTT-induced misfolding tested; physiological misfolding triggers uncharacterized
  4. 2015 High

    NMR-based demonstration that UBQLN4 UBA domain directly binds C-terminal domains of multiple connexin family members (Cx40, Cx45, Cx32, Cx43) established UBQLN4 as a broad connexin quality control factor.

    Evidence NMR spectroscopy for direct interaction, shRNA knockdown, and co-IP in mammalian cells

    PMID:25583071

    Open questions at the time
    • Selectivity determinants within connexin tails that define UBA binding affinity were not fully mapped
    • In vivo physiological significance for cardiac gap junction connexins not tested
  5. 2016 High

    Discovery that UBQLN4 recognizes mislocalized transmembrane domain proteins that fail ER insertion extended its role beyond connexins to a general cytoplasmic quality control pathway for aberrant secretory pathway substrates.

    Evidence SRP54 knockdown to generate mislocalized substrates, co-IP, proteasome inhibitor experiments in mammalian cells

    PMID:27113755

    Open questions at the time
    • Relationship between UBQLN4 and BAG6 in substrate handoff not mechanistically resolved
    • Whether UBQLN4 acts redundantly with other ubiquilins in this pathway was unclear
  6. 2017 High

    Identification of beta-catenin as a UBQLN4 degradation substrate in motor neurons, and rescue of axon defects by beta-catenin inhibition, linked UBQLN4 loss-of-function to ALS-associated motor neuron pathology through a defined proteasomal mechanism.

    Evidence ALS-linked UBQLN4 variant in mouse and zebrafish motor neuron models, proteasomal assays, beta-catenin epistasis rescue

    PMID:28463112

    Open questions at the time
    • Whether beta-catenin is a direct binding substrate or requires ubiquitination for UBQLN4 recognition was not determined
    • Whether other UBQLN4 substrates contribute to ALS pathology was untested
  7. 2019 High

    Demonstration that ATM phosphorylates UBQLN4 to promote its interaction with ubiquitylated MRE11 and MRE11 chromatin removal established UBQLN4 as a DNA damage response effector that channels DSB repair from HR toward NHEJ.

    Evidence Co-IP, ATM phosphorylation assays, in vitro and in vivo DSB repair assays, loss-of-function and overexpression experiments in mammalian cells

    PMID:30612738 PMID:31131301

    Open questions at the time
    • The ATM phosphosite(s) on UBQLN4 and their individual contributions were not fully dissected
    • Whether UBQLN4's HR-suppressive function operates in all tissue contexts was unknown
  8. 2020 Medium

    Binding of UBQLN4 to ER J proteins DNAJB12 and DNAJB14 via its H domain and STI1 motifs, and its role in SV40 ER-to-cytosol escape, revealed an unexpected function at the ER membrane in viral infection.

    Evidence Direct binding assays, domain deletion/mutagenesis, SV40 infection assays, knockdown in mammalian cells

    PMID:32161173

    Open questions at the time
    • Whether J protein binding reflects a constitutive ERAD-related function or is specific to viral exploitation was unresolved
    • Mechanism by which UBQLN4 facilitates membrane penetration of a non-enveloped virus is unclear
  9. 2021 Medium

    Independent confirmation that UBQLN4 degrades ubiquitinated MRE11A after DNA damage in esophageal cancer cells, and discovery that UBQLN4 stabilizes anti-apoptotic proteins BCL2A1/BCL2L10 in mesothelioma, expanded its DNA damage response role to therapy resistance and survival signaling.

    Evidence Co-IP and ubiquitination assays after cisplatin treatment; genetic screening and apoptosis assays in mesothelioma cells

    PMID:33605536 PMID:34245648

    Open questions at the time
    • Whether BCL2A1/BCL2L10 stabilization is proteasome-dependent or involves a distinct mechanism was not established
    • Generalizability of UBQLN4 cisplatin resistance mechanism across tumor types untested
  10. 2025 Medium

    Identification of GluN2B as a neuronal UBQLN4 substrate demonstrated that UBQLN4 regulates excitatory synapse composition and seizure susceptibility through proteasomal control of NMDA receptor subunit levels.

    Evidence AAV-mediated overexpression and knockdown in kainic acid mouse epilepsy model, synaptic fractionation, proteasome pathway assays

    PMID:40930427

    Open questions at the time
    • Whether UBQLN4 directly binds GluN2B or acts via an intermediary ubiquitin ligase is unresolved
    • Contribution of UBQLN4 to synaptic plasticity beyond seizure susceptibility is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBQLN4 achieves substrate selectivity among its diverse clients (connexins, MRE11, beta-catenin, GluN2B, transmembrane domain proteins, BCL2 family members), and how ATM phosphorylation rewires its specificity from quality control to DNA repair, remain central unresolved questions.
  • No structural model of full-length UBQLN4 bound to any substrate exists
  • Relative contributions of ubiquitin-dependent vs. ubiquitin-independent recognition across substrates are unclear
  • In vivo redundancy with UBQLN1/UBQLN2 in each functional context has not been systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3
Partners
CTNNB1DNAJB12DNAJB14GJA1GRIN2BMRE11PSMD1PSMD4

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 UBQLN4 is phosphorylated by ATM kinase and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DNA double-strand break repair (HRR). UBQLN4 removes MRE11 from damaged chromatin via proteasomal degradation, thereby curtailing HRR activity. Loss of UBQLN4 leads to chromatin retention of MRE11 and non-physiological HRR; overexpression represses HRR and favors non-homologous end joining (NHEJ). Co-immunoprecipitation, in vitro and in vivo DSB repair assays, ATM phosphorylation assays, loss-of-function and overexpression experiments with defined phenotypic readouts Cell High 30612738
2019 UBQLN4 promotes NHEJ by repressing DNA end-resection in an ATM-dependent manner; the ATM-UBQLN4-MRE11 axis limits excessive end resection after DSBs. Epistasis analysis and mechanistic commentary elaborating on the UBQLN4-MRE11-ATM interaction Molecular & cellular oncology Medium 31131301
2016 UBQLN4 recognizes mislocalized transmembrane domain proteins in the cytoplasm (via their exposed transmembrane segments) and targets them to the proteasome for degradation, acting as a BAG6-binding quality control factor for newly synthesized defective polypeptides that fail to reach the ER. Co-immunoprecipitation, knockdown of SRP54, model truncated transmembrane domain protein degradation assays, proteasome inhibitor experiments EMBO reports High 27113755
2017 An ALS-associated UBQLN4 variant impairs proteasomal function and leads to accumulation of beta-catenin (a UBQLN4 substrate), causing aberrant motor axon morphogenesis. Inhibition of beta-catenin function rescues the motor axon phenotype caused by the UBQLN4 variant. Mouse motor neuron and zebrafish in vivo models, proteasomal function assays, epistasis rescue experiment with beta-catenin inhibition eLife High 28463112
2007 UBQLN4 (CIP75) interacts with connexin43 (Cx43) via its UBA domain binding to the Cx43 PY motif/multiphosphorylation region (Lys264–Asn302), and its UbL domain interacts with proteasomal subunits S2/RPN1 and S5a/RPN10, mediating Cx43 proteasomal degradation and reducing its half-life. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, laser confocal microscopy, siRNA knockdown, overexpression with half-life measurements The Journal of biological chemistry High 18079109
2010 UBQLN4 (CIP75) mediates ubiquitin-independent proteasomal degradation of ER-localized Cx43; CIP75 interacts with non-ubiquitinated Cx43 at the ER and brings it to the proteasome, even though CIP75 can also bind poly-ubiquitin chains. Co-immunoprecipitation, immunofluorescence microscopy, in vitro ubiquitin-binding assays, ubiquitination-deficient Cx43 mutant analysis The Journal of biological chemistry High 20940304
2014 UBQLN4 (CIP75) interacts with ER-localized Cx43 and forms a complex with proteasomal subunits S2/Rpn1 and S5a/Rpn10; CIP75 is essential for Cx43–proteasome interaction and ER dislocation, with deliberate Cx43 misfolding enhancing CIP75 binding. Subcellular fractionation, co-immunoprecipitation, shRNA knockdown, DTT-induced misfolding experiment The Biochemical journal Medium 24256120
2015 UBQLN4 (CIP75) UBA domain directly interacts with the carboxyl-terminal domains of Cx40 and Cx45 (in addition to Cx43 and Cx32), mediating their ERAD-associated proteasomal degradation from the ER. NMR spectroscopy (direct interaction), shRNA knockdown, trafficking inhibitor experiments, co-immunoprecipitation The Biochemical journal High 25583071
2020 Ubqln4 binds directly to ER membrane J proteins B12 and B14 via its H domain and STI1 motifs (1-2) in a J-domain-independent manner, and captures SV40 virus emerging from the ER to facilitate its escape into the cytosol during infection. Direct binding assays, domain deletion/mutagenesis (H domain and STI1 motifs), viral infection assays, knockdown experiments Journal of virology Medium 32161173
2021 UBQLN4 is a substrate of ATM kinase and, upon DNA damage, interacts with and stabilizes anti-apoptotic proteins BCL2A1 and BCL2L10, thereby preventing mesothelioma cell apoptosis in response to DNA damage. Mammalian functional genetic screening, co-immunoprecipitation, knockdown experiments with apoptosis readout Molecular oncology Medium 34245648
2021 UBQLN4 binds to ubiquitinated MRE11A and promotes its degradation following DNA damage, thereby regulating MRE11A protein levels and promoting cisplatin resistance in esophageal squamous cell carcinoma. Co-immunoprecipitation, ubiquitination assays after cisplatin treatment, gene copy number analysis, cell line knockdown experiments Molecular oncology Medium 33605536
2025 UBQLN4 promotes proteasomal degradation of GluN2B (NMDA receptor NR2B subunit) at excitatory post-synapses in neurons; reduction of UBQLN4 increases GluN2B levels and seizure susceptibility, while overexpression is protective. AAV-mediated overexpression and knockdown in vivo (kainic acid epilepsy mouse model), proteasome pathway assays, synaptic fractionation/localization Neurobiology of disease Medium 40930427
2023 Full-length UBQLN4 undergoes liquid-liquid phase separation in vitro; UBQLN4 phase separates at a lower saturation concentration than UBQLN1 and lacks the temperature-dependent phase behavior conferred by the proline-rich (Pxx) region present in UBQLN2. The short N-terminal disordered region inhibits UBQLN4 phase separation via electrostatic interactions. In vitro phase separation assays, deletion constructs, charge variant analysis, comparison across UBQLN family members bioRxivpreprint Low 37808720

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 8 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