Affinage

UBQLN2

Ubiquilin-2 · UniProt Q9UHD9

Length
624 aa
Mass
65.7 kDa
Annotated
2026-06-10
96 papers in source corpus 32 papers cited in narrative 32 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

UBQLN2 is a ubiquitin-binding shuttle factor that couples client recognition to the 26S proteasome, serving as a central node in cellular protein quality control (PMID:27477512, PMID:30664872). It engages the proteasome through its UBL domain, which binds the receptor hRpn10 with strong preference for the N-terminal UIM-1 helix (PMID:30664872), while its UBA domain binds polyubiquitin with selectivity for K63-linked chains and recognizes ubiquitin conjugated to aggregated proteins (PMID:36423739, PMID:29401586). Acting together with the HSP70-HSP110 disaggregase machinery, UBQLN2 recognizes client-bound and ubiquitinated HSP70 to deliver misfolded proteins for proteasomal clearance, a route operative even in the nucleus where autophagy is absent (PMID:27477512, PMID:33991504). Its STI1 low-complexity region drives liquid-liquid phase separation under physiological and stress conditions, a behavior switched off by ubiquitin/polyubiquitin binding and tuned by reciprocal UBL:UBA contacts (PMID:29526694, PMID:34029402); substrate fate within these condensates is governed by polyubiquitin chain linkage, with K63 chains promoting condensation and protecting substrates from the proteasome and deubiquitinases (PMID:39121161). Beyond degradation, UBQLN2 can stabilize substrates by recruiting E3 ligases such as SCFbxo7 to condensates (PMID:40631187). UBQLN2 has defined substrates and pathways including ERAD via UBXD8 (PMID:24215460), TDP-43 clearance (PMID:23541532), autophagosome acidification via the V-ATPase subunit ATP6v1g1 (PMID:32513711), Parkin-dependent mitophagy and mitochondrial protein import via TIMM44 (PMID:37501540, PMID:33891006), and UBE3A-dependent degradation of the retrotransposon-derived PEG10 gag-pol (PMID:41234208). ALS/FTD-causing mutations, clustered in the Pxx region, consistently impair HSP70 binding, aggregate and substrate clearance, autophagy, mitochondrial function, and alter phase-separation dynamics toward solid-like aggregates (PMID:27477512, PMID:30982635, PMID:30333186, PMID:32513711, PMID:33991504, PMID:28716533), establishing UBQLN2 dysfunction as a driver of motor neuron degeneration.

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2008 Medium

    Before its quality-control role was defined, UBQLN2 was shown to act at the membrane, establishing it as a negative regulator of receptor endocytosis through its UBL domain.

    Evidence Overexpression/knockdown live-cell endocytosis assays with domain deletion and Co-IP in receptor-expressing cells

    PMID:18199683

    Open questions at the time
    • Mechanism of UBL-dependent inhibition of clathrin-coated pit concentration unresolved
    • Physiological relevance to neurodegeneration not addressed
  2. 2011 Medium

    The founding ALS link established that UBQLN2 mutations impair degradation of ubiquitinated proteins, connecting the protein to ubiquitin-proteasome dysfunction and aggregation.

    Evidence Functional degradation assays in patient-derived cells

    PMID:21857683

    Open questions at the time
    • Molecular step in the UPS that is disrupted not pinpointed
    • Direct substrates not identified
  3. 2013 Medium

    Specific clients and pathways were assigned, showing UBQLN2 binds TDP-43 with high affinity to promote its clearance and partners with UBXD8 for ER-associated degradation.

    Evidence Quantitative in vitro binding (KD), Co-IP, and ERAD/TDP-43 clearance assays in cells

    PMID:23541532 PMID:24215460

    Open questions at the time
    • Whether TDP-43 binding requires ubiquitination not resolved
    • In vivo contribution of UBXD8 axis untested
  4. 2016 High

    The core delivery mechanism was defined: UBQLN2 recognizes client-bound HSP70 and links the HSP70-HSP110 disaggregase to the proteasome, with ALS mutants defective in HSP70 binding and aggregate clearance, including in the nucleus.

    Evidence In vitro reconstitution, Co-IP, cellular aggregate clearance, and mouse behavioral assays

    PMID:27477512

    Open questions at the time
    • Stoichiometry of the HSP70-UBQLN2-proteasome handoff not defined
    • Determinants of nuclear vs cytoplasmic routing unclear
  5. 2017 Medium

    The HSP70 binding interface and mutation sensitivity were mapped, localizing chaperone engagement to the STI1/PXX regions and tying mutant defects to autophagy impairment.

    Evidence Co-IP and autophagy assays in patient lymphoblasts

    PMID:28716533

    Open questions at the time
    • Residue-level HSP70 contacts not resolved
    • Causality between HSP70 loss and autophagy defect not separated
  6. 2018 High

    UBQLN2 was shown to phase separate via its STI1-II low-complexity region as a ubiquitin-switchable process, providing a biophysical framework for both its function and pathological aggregation.

    Evidence NMR, in vitro LLPS reconstitution, deletion analysis, and live-cell imaging; ALS Pxx-mutant biophysics by SEC/AUC/NMR; amyloid and transgenic mouse models

    PMID:29526694 PMID:30333186 PMID:30982635

    Open questions at the time
    • In vivo functional output of condensates not directly measured
    • How ubiquitin disassembly couples to substrate handoff unclear
  7. 2018 High

    A new substrate axis was uncovered: the MTM1-UBQLN2 complex routes misfolded desmin and vimentin to the proteasome to preserve cytoskeletal integrity.

    Evidence Co-IP, knockdown/knockout in muscle cells, proteasome substrate assays, EM

    PMID:29358706

    Open questions at the time
    • Relevance of MTM1 partnership to neuronal UBQLN2 function unknown
    • Recognition determinants for intermediate filaments undefined
  8. 2019 High

    The structural basis of proteasome delivery was solved, defining UBL:hRpn10 UIM-1 recognition; in parallel ALS mutants were shown to disrupt ER-to-Golgi transport.

    Evidence NMR structure and titration of hRpn10:UBL complex; ER/Golgi imaging and ER stress markers in neuronal cells and patient tissue

    PMID:30664872 PMID:31802140

    Open questions at the time
    • Whether secretory-pathway defect is direct or downstream of UPS collapse unresolved
  9. 2020 High

    UBQLN2 was placed in autophagy and innate immune signaling, regulating autophagosome acidification via ATP6v1g1 and modulating TBK1-IRF3 signaling.

    Evidence CRISPR knockout with WT/mutant rescue, autophagic flux and lysosomal pH assays, proteomics; Co-IP and IFN-β/phosphorylation assays in IRF-knockout cells

    PMID:32413959 PMID:32513711

    Open questions at the time
    • How UBQLN2 stabilizes ATP6v1g1 mechanistically unclear
    • Physiological role of TBK1 modulation in disease untested
  10. 2021 Medium

    UBQLN2 was tied to mitochondrial quality control on two fronts: UBA-dependent recruitment to Parkin-ubiquitinated mitochondria for OMM protein degradation, and a loss-of-function role in mitochondrial protein import via TIMM44.

    Evidence Co-IP, mitophagy assays, domain deletion, primary neurons; KO with in vitro TIMM44 binding, OXPHOS assays, and WT/mutant rescue

    PMID:33891006 PMID:37501540

    Open questions at the time
    • Direct vs indirect role in import not fully separated
    • Single-lab findings without reciprocal validation
  11. 2021 High

    Recognition of ubiquitinated HSP70 was shown to drive clearance of the C9orf72 dipeptide poly-GA, with mutants failing to bind HSP70 and clear aggregates in patient iPSC neurons; biophysical work defined a temperature-induced conformational switch and K63>K48 ubiquitin and LC3 binding.

    Evidence Co-IP, in vitro binding, iPSC-neuron and animal models, HSP70 enhancer treatment; tryptophan fluorescence, chain-binding and LC3 pulldown assays

    PMID:33991504 PMID:36423739

    Open questions at the time
    • Structural basis of conformational switch undefined
    • Functional consequence of LC3 binding not established
  12. 2021 High

    The domain logic of phase separation was refined, showing UBL and UBA contribute asymmetrically through canonical and newly identified non-canonical contacts.

    Evidence NMR with domain deletion constructs and in vitro LLPS assays

    PMID:34029402

    Open questions at the time
    • Cellular relevance of non-canonical UBL contacts not tested
  13. 2022 Medium

    A regulator of UBQLN2 subcellular targeting was identified: RTL8 promotes UBQLN2 nuclear translocation to ubiquitin-enriched quality-control structures, selectively among ubiquilins.

    Evidence MS interactome, in vitro pulldown, in vivo mouse brain Co-IP, live imaging

    PMID:35247097

    Open questions at the time
    • Mechanism of selectivity for UBQLN2 over paralogs unknown
    • Functional output of nuclear targeting not quantified
  14. 2023 Medium

    UBQLN2 was linked to control of the domesticated retrotransposon protein PEG10 gag-pol via proteasomal degradation, with elevated gag-pol in ALS patient spinal cord.

    Evidence Cell-based degradation assays, subcellular fractionation, RNA-seq, ALS tissue IHC

    PMID:36951542

    Open questions at the time
    • E3 ligase and recognition determinants not yet identified in this study
    • Whether gag-pol accumulation is cause or consequence of disease unclear
  15. 2023 Medium

    Recruitment to disease inclusions was shown to be ubiquitin-dependent, with polyQ aggregates sequestering UBQLN2 through its UBA domain.

    Evidence Co-IP and UBA-deletion analysis in cell-based inclusion assays

    PMID:29401586

    Open questions at the time
    • Single-lab cell model only
    • Consequence of sequestration for UBQLN2 function not measured
  16. 2024 High

    Substrate fate within condensates was shown to be linkage-encoded: K63 chains drive condensation and shield substrates from the proteasome and deubiquitinases, revealing condensates as a regulatory rather than purely degradative compartment.

    Evidence Sedimentation, microscopy, in vitro LLPS with defined polyubiquitinated substrates, proteasome activity assays in condensates

    PMID:39121161

    Open questions at the time
    • How condensate-sequestered substrates are eventually released or degraded unclear
    • In-cell relevance of in vitro linkage selectivity untested
  17. 2025 High

    The PEG10 degradation pathway was assembled stepwise, showing UBE3A ubiquitinates gag-pol on pol-region lysines and that degradation requires both UBE3A and UBQLN2, while binding is ubiquitination-independent.

    Evidence KO of UBQLN2/UBE3A, lysine mutagenesis, cycloheximide chase, proteasome inhibition, Co-IP

    PMID:41234208

    Open questions at the time
    • Why only gag-pol and not gag is degraded mechanistically unresolved
  18. 2025 Medium

    Autoregulation was uncovered: ubiquitylation of UBQLN2's own UBL domain stabilizes the protein and influences condensate localization, indicating self-regulation of abundance.

    Evidence MS ubiquitylation-site mapping, lysine mutagenesis, proteasome inhibition, ubiquitin-fusion microscopy

    PMID:41428212

    Open questions at the time
    • Responsible E3 ligase(s) not identified
    • Single-lab finding
  19. 2025 Medium

    A non-canonical protective function was defined: UBQLN2 can stabilize substrates such as APP by recruiting E3 ligases including SCFbxo7 to condensates, with phase-separation-altering ALS mutants impaired in this activity.

    Evidence Isogenic triple-knockout with single-paralog rescue, substrate degradation assays, E3 Co-IP, phase separation assays (preprint)

    PMID:40631187

    Open questions at the time
    • Preprint, not peer-reviewed
    • Mechanism distinguishing stabilization from degradation outcomes unclear
  20. 2026 High

    New metabolic substrates were identified, with UBQLN2 degrading ILVBL and ALDH3A2 and mutant-driven failure causing lipid metabolic dysfunction and neurodegeneration across multiple models.

    Evidence Multi-omics in iPSC neurons, cycloheximide chase, proteasome inhibition, rescue in neurons/organoids/mice

    PMID:41912662

    Open questions at the time
    • Direct vs indirect recognition of these substrates not fully established
  21. 2026 Medium

    Condensate partnerships with E3 ligases were extended, showing TRIM32 (and earlier TRIM9/TRIM26 toward mutant protein) form quality-control condensates capturing TDP-43 and ANXA11 via the STI1 domain, modulating aggregation.

    Evidence Co-IP, condensate/FRAP assays, E3 activity assays, human brain IHC (TRIM32 preprint); APEX2 proximity labeling and knockdown for TRIM9/TRIM26

    PMID:41582437 PMID:41727138

    Open questions at the time
    • TRIM32 study is a preprint
    • How E3 recruitment biases capture vs degradation undefined
  22. 2025 Medium

    UBQLN2 was implicated beyond ALS, with droplet liquid-to-solid transition catalyzing α-synuclein fibril formation and colocalization with Lewy bodies, plus a small-molecule inhibitor of STI1-mediated self-association.

    Evidence In vitro LLPS/fibril assays, live imaging, PD brain IHC, inhibitor characterization (preprint)

    PMID:bio_10.1101_2025.03.17.643602

    Open questions at the time
    • Preprint, not peer-reviewed
    • Causal role of UBQLN2 in Parkinson's pathology not established in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBQLN2 toggles between promoting degradation and protecting substrates within condensates, and how this balance is set by ubiquitin chain linkage, E3 recruitment, and ALS mutations in vivo, remains the central open question.
  • No unified model linking condensate state to substrate fate in cells
  • Determinants selecting degradation vs stabilization E3 partners unknown
  • In vivo measurement of condensate function in neurons lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ATP6V1G1HSPA1BPEG10RPN10RTL8TIMM44UBE3AUBXD8
Complex memberships
MTM1-UBQLN2 complexTRIM32-UBQLN2-p62 condensateUBQLN2-HSP70-HSP110 disaggregase machinery

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 UBQLN2 mutations impair ubiquitinated protein degradation. Functional analysis in patient-derived cells showed that ALS-linked UBQLN2 mutations lead to impairment of the protein degradation pathway, linking ubiquilin 2 abnormalities to defects in the ubiquitin-proteasome system and abnormal protein aggregation. Functional degradation assays in patient-derived cells Nature Medium 21857683
2013 UBQLN2 interacts with UBXD8 (an ER membrane protein involved in ERAD substrate translocation) both in vitro and in vivo via co-IP and in vitro binding assays; ALS-linked pathogenic mutation impairs this interaction, disrupting ER-associated protein degradation and causing greater accumulation of ERAD substrates. Co-immunoprecipitation, in vitro binding assay, ERAD substrate accumulation assay Journal of neurochemistry Medium 24215460
2013 UBQLN2 binds directly to the C-terminal region of TDP-43 with high affinity (KD ~6–9 nM), as demonstrated by binding assays and co-IP in H4 cells. Overexpression of UBQLN2 enhances clearance of TDP-43 and C-terminal TDP-43 fragments, reducing their steady-state levels. In vitro binding assay (KD determination), co-immunoprecipitation, cell overexpression with immunoblot Biochimica et biophysica acta Medium 23541532
2016 UBQLN2 acts together with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome, independent of autophagy. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome. ALS-linked UBQLN2 mutations are defective in chaperone (HSP70) binding and impair aggregate clearance. This pathway is active in the nucleus where autophagy does not operate. In vitro reconstitution, co-immunoprecipitation, cellular aggregate clearance assays, mouse behavioral tests, nucleus-specific assays Cell High 27477512
2008 UBQLN2 (PLIC-2) is a negative regulator of GPCR endocytosis. Overexpression delays ligand-induced endocytosis of V2 vasopressin receptor and β2-adrenergic receptor by inhibiting their concentration in clathrin-coated pits, without affecting arrestin-3 membrane recruitment. The UBL domain of PLIC-2 is required for endocytic inhibition. PLIC-2 preferentially binds UIM-containing endocytic adaptors Eps15 and Epsin over PLIC-1. Overexpression/knockdown with live-cell endocytosis assays, domain deletion analysis, co-immunoprecipitation Molecular biology of the cell Medium 18199683
2018 UBQLN2 undergoes liquid-liquid phase separation (LLPS) at physiological conditions driven by multivalent weak interactions in its STI1-II low-complexity region. Oligomerization is required for LLPS and stress-induced cytoplasmic puncta formation in cells. Ubiquitin or polyubiquitin binding disrupts UBQLN2 LLPS, serving as a molecular switch between condensed and dispersed phases. NMR spectroscopy, in vitro LLPS assay, deletion mutant analysis, live-cell imaging, fluorescence microscopy Molecular cell High 29526694
2018 ALS-linked mutations in the Pxx domain of UBQLN2 differentially enhance oligomerization, lower the saturation concentration for LLPS, and promote solid-like/viscoelastic morphological changes to UBQLN2 liquid assemblies in a position- and amino acid-dependent manner. Ubiquitin disassembles all LLPS-induced mutant UBQLN2 aggregates. Size-exclusion chromatography, analytical ultracentrifugation, NMR spectroscopy, microscopy Structure High 30982635
2018 UBQLN2 self-assembly into liquid droplets and amyloid aggregates is regulated by reciprocal modulation between its UBL and UBA domains. A pathogenic missense mutation impairs droplet dynamics and favors amyloid-like aggregation associated with neurotoxicity. In vitro protein analysis (LLPS, amyloid assays), fluorescence imaging, cellular and neuronal models, transgenic mouse models PNAS High 30333186
2018 The MTM1-UBQLN2 complex recognizes and guides misfolded intermediate filament proteins desmin and vimentin to the proteasome for degradation prior to aggregate formation in muscle cells, providing cytoskeletal integrity. Co-immunoprecipitation, knockdown/knockout studies in muscle cells, proteasome substrate assays, electron microscopy Nature cell biology High 29358706
2019 The UBQLN2 UBL domain binds to hRpn10 (proteasome receptor) with 25-fold higher affinity for the N-terminal UIM-1 over UIM-2, exploiting additional contacts from the longer UIM-1 helix. NMR structure of the hRpn10:UBQLN2 UBL complex was solved, defining the structural basis of shuttle factor delivery to the proteasome. NMR spectroscopy (structure determination), NMR titration assay (affinity measurement) Journal of molecular biology High 30664872
2019 ALS/FTD mutant UBQLN2 proteins (P497H, P506T) inhibit ER-to-Golgi protein transport in neuronal cells, causing clustering of ER exit sites, disorganization and fragmentation of ERGIC and Golgi, activation of ER stress, and inhibition of ERAD. Fluorescence imaging of ER/Golgi markers, patient spinal cord immunostaining, ER stress markers (Western blot), functional transport assay Cellular and molecular life sciences Medium 31802140
2020 UBQLN2 functions in autophagy by regulating autophagosome acidification. Knockout of UBQLN2 in HeLa cells reduces autophagic flux and autophagosome acidification; this is rescued by WT but not by ALS/FTD mutant UBQLN2. UBQLN2 interacts with ATP6v1g1 (V-ATPase subunit), and mutant UBQLN2 shows weaker binding and reduced ATP6v1g1 stability. Overexpression of ATP6v1g1 rescues the acidification defect in UBQLN2 knockout cells. UBQLN2 knockout (CRISPR), rescue experiments, autophagic flux assay, lysosomal pH assay, proteomic analysis, immunoblot, in vitro interaction assay PNAS High 32513711
2021 UBQLN2 is recruited to polyubiquitinated mitochondria via its UBA domain after Parkin-dependent ubiquitination of damaged mitochondria. UBQLN2 cooperates with HSP70 to promote UPS-driven degradation of outer mitochondrial membrane (OMM) proteins, causing OMM rupture that triggers autophagosomal recognition of inner mitochondrial membrane receptor PHB2. ALS/FTD UBQLN2 mutations impair this mitophagy pathway. Co-immunoprecipitation, mitophagy assays, domain deletion analysis, primary neuron cultures, mutant analysis EMBO reports Medium 37501540
2021 UBQLN2 knockouts in HeLa cells show defects in mitochondrial protein import: TIMM44 mislocalizes to abnormal foci. ALS/FTD UBQLN2 mutants bind TIMM44 more weakly than WT UBQLN2 by in vitro binding assay. OXPHOS deficits and TIMM44 targeting defects are rescued by WT but not ALS/FTD mutant UBQLN2, indicating a loss-of-function mechanism in mitochondrial import. UBQLN2 knockout, in vitro binding assay, OXPHOS functional assay, immunofluorescence for TIMM44 targeting, rescue experiments Human molecular genetics Medium 33891006
2021 UBQLN2 recognizes HSP70 ubiquitination, facilitating UBQLN2-HSP70-poly-GA complex formation and promoting poly-GA degradation. ALS/FTD-linked UBQLN2 mutants fail to bind HSP70 and cannot clear poly-GA aggregates. Disruption of the UBQLN2-HSP70 interaction inhibits poly-GA clearance in C9-ALS/FTD iPSC-derived neurons. Co-immunoprecipitation, in vitro binding, iPSC-derived neuron experiments, animal model behavioral assays, HSP70 enhancer (17AAG) treatment Neuron High 33991504
2021 UBL and UBA domains of UBQLN2 contribute asymmetrically to LLPS: UBA domain removal inhibits LLPS while UBL domain removal enhances LLPS. NMR spectroscopy revealed novel non-canonical interactions between the UBL domain and disordered STI1-I and C-terminal residues 555–570, in addition to the canonical UBL:UBA interaction. NMR spectroscopy, domain deletion constructs, in vitro LLPS assay Protein science High 34029402
2022 RTL8 proteins interact with UBQLN2 (confirmed by MS, in vitro pulldown, and in vivo mouse brain Co-IP) and promote nuclear translocation of UBQLN2 to ubiquitin-enriched subnuclear structures containing protein quality control components. RTL8 specifically affects UBQLN2 but not UBQLN1 or UBQLN4 nuclear localization. UBQLN2 preferentially stabilizes RTL8 levels compared to other UBQLNs. Mass spectrometry interactome screen, in vitro pulldown with recombinant proteins, co-immunoprecipitation from mouse brain, live-cell imaging, immunofluorescence Cellular and molecular life sciences Medium 35247097
2022 UBQLN2 undergoes a reversible temperature-induced conformational switch (detected by intrinsic tryptophan fluorescence) that increases binding to HSPA1B (HSP70) at 42°C. ALS/FTD mutant UBQLN2 proteins have attenuated conformational switching. UBQLN2 binds more avidly to K63 than K48 polyubiquitin chains. UBQLN2 binds directly to LC3 (autophagosome membrane protein). UBQLN2 homodimerizes and heterodimerizes with UBQLN1. Fluorescence spectroscopy (tryptophan), in vitro binding assays, polyubiquitin chain binding assay, LC3 pulldown, dimerization assays Biochimica et biophysica acta. General subjects Medium 36423739
2023 UBQLN2 regulates PEG10 gag-pol (a domesticated retrotransposon protein) through proteasomal degradation in human cells and tissues. PEG10 gag-pol self-cleaves to generate a nucleocapsid fragment that localizes to the nucleus and alters gene expression. PEG10 gag-pol is elevated in spinal cord from ALS patients versus controls. Cell-based protein degradation assays, subcellular fractionation, RNA-seq/gene expression analysis, immunohistochemistry of ALS patient tissue eLife Medium 36951542
2023 PolyQ-expanded Htt-N552 and Atx-3 sequester UBQLN2 into inclusions through the UBA domain of UBQLN2 and conjugated ubiquitin on the aggregated proteins, demonstrating that UBQLN2 recruitment to inclusions is ubiquitin-dependent. Co-immunoprecipitation, domain deletion analysis (UBA domain requirement), cell-based inclusion assay FASEB journal Medium 29401586
2024 Polyubiquitinated substrates induce UBQLN2 phase separation and incorporate into UBQLN2 condensates in a chain linkage-dependent manner: K63-linked substrates most strongly promote condensation, K48-linked substrates least. Proteasome activity toward K63 and mixed-linkage substrates is inhibited within condensates, and substrates are protected from deubiquitinases by phase separation. Sedimentation assays, microscopy, in vitro LLPS assay with polyubiquitinated substrates, proteasome activity assay in condensates PNAS High 39121161
2025 UBQLN2-mediated degradation of PEG10 gag-pol requires the E3 ubiquitin ligase UBE3A: UBE3A ubiquitinates gag-pol on key lysine residues in the pol region, and UBE3A cannot regulate gag-pol in the absence of UBQLN2. UBQLN2 binds PEG10 (both gag and gag-pol) independently of their ubiquitylation status, but only gag-pol is degraded in a UBQLN2-, ubiquitin-, and proteasome-dependent fashion. Knockdown/knockout of UBQLN2 and UBE3A, lysine mutation of PEG10, cycloheximide chase, proteasome inhibitor treatment, co-immunoprecipitation Journal of cell science High 41234208
2025 UBQLN2 is ubiquitylated on lysine residues in its N-terminal UBL domain; the UBL domain stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus increases its propensity to localize in puncta, suggesting ubiquitylation of the UBL domain regulates UBQLN2 abundance and condensate localization. Mass spectrometry (ubiquitylation site mapping), lysine mutagenesis, proteasome inhibitor assay, ubiquitin fusion constructs with microscopy Biochemistry Medium 41428212
2025 UBQLN2 has a unique ability to protect substrates from proteasomal degradation (in addition to promoting degradation), and substrate stabilization correlates with recruitment of E3 ligases including SCFbxo7 to UBQLN2 condensates. ALS-linked mutants with altered phase separation also show defects in substrate stabilization. APP is also protected from degradation by UBQLN2 condensate formation. Triple-knockout cell lines with single paralog rescue (isogenic background), substrate degradation assays, E3 ligase co-IP, phase separation assays bioRxivpreprint Medium 40631187
2025 PEG10, a core stress granule component, drives recruitment of UBQLN2 to stress granules, but only when RTL8 is present (RTL8 enables UBQLN2-PEG10 complex formation). Changes in UBQLN2, RTL8, or PEG10 levels remodel kinetics of stress granule disassembly and translation recovery. Co-immunoprecipitation, live-cell imaging of stress granule dynamics, stress granule composition proteomics, genetic manipulation of RTL8/PEG10 levels Science advances Medium 40680123
2020 UBQLN2 interacts with TBK1; co-expression of UBQLN2 with TBK1 elevates TBK1 protein levels and phosphorylation of TBK1 and IRF3 in a dose-dependent manner, promoting IFN-β production via the TBK1-IRF3 pathway. ALS/FTD-mutant UBQLN2 reduces TBK1 phosphorylation and impairs IRF3/p62/OPTN binding to TBK1. Co-immunoprecipitation, IRF3/IRF7 knockout cells (CRISPR), phosphorylation assays, IFN-β production assay Cells Medium 32413959
2026 UBQLN2 mediates proteasomal degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase involved in mitochondrial lipid catabolism); ALS/FTD UBQLN2 mutations impair degradation of these substrates leading to lipid metabolic dysfunction and neurodegeneration in iPSC-derived neurons, organoids, and mice. Multi-omic analysis of iPSC-derived neurons, cycloheximide chase, proteasome inhibitor assays, substrate degradation rescue experiments in neurons/organoids/mice Nature neuroscience High 41912662
2026 TRIM32 and UBQLN2 together with p62 form condensates (dependent on TRIM32 E3 ligase activity) that capture client proteins including TDP-43 and ANXA11 via the UBQLN2 STI1 domain. TRIM32 promotes amyloid aggregation of TDP-43, an effect exacerbated by pathogenic UBQLN2 mutation. TRIM32 co-localizes with pTDP-43 inclusions in human neurodegenerative disease brains. Co-immunoprecipitation, condensate formation assays, FRAP, E3 ligase activity assays, fluorescence microscopy, immunohistochemistry in human brain tissue bioRxivpreprint Medium 41727138
2026 TRIM9 and TRIM26 E3 ubiquitin ligases selectively interact with and ubiquitinate ALS-mutant UBQLN2P497H (but not WT or P497S) and promote proteasomal degradation of a C-terminal UBQLN2 fragment generated specifically from P497H mutant; individual knockdown of TRIM9 or TRIM26 increases accumulation of this fragment. APEX2 proximity labeling, co-immunoprecipitation, siRNA knockdown, fractionation assay, proteasome inhibitor assay ACS chemical biology Medium 41582437
2017 ALS-linked UBQLN2 mutations cause disrupted binding with HSP70 and impaired autophagic pathway in patient lymphoblasts. HSP70 binding occurs through the UBQLN2 STI1 domain regions, and the PXX repeat region is important for this interaction. Patient lymphoblast analysis, co-immunoprecipitation (HSP70 binding assay), autophagic pathway assay Neurobiology of aging Medium 28716533
2023 The Pxx (proline-rich) region of UBQLN2 confers unique temperature-dependent LLPS behavior absent in UBQLN1 and UBQLN4. Short N-terminal disordered regions of UBQLN1, UBQLN2, and UBQLN4 inhibit phase separation via electrostatic interactions. STI1-II is essential for baseline puncta formation in cells under all conditions, while both STI1 domains are required for heat stress-induced condensate formation. In vitro LLPS assay (turbidity, microscopy), domain deletion constructs, live-cell imaging bioRxivpreprint Medium 37808720
2025 UBQLN2 liquid droplets catalyze α-synuclein fibril formation in vitro and in cells; during liquid-to-gel/solid transition of UBQLN2 droplets, α-synuclein within droplets converts to pathogenic fibrils. UBQLN2 co-localizes with Lewy bodies in substantia nigra of Parkinson's disease patients. The small molecule SO286 inhibits UBQLN2 self-association and its interaction with α-synuclein by binding to the STI1 domain. In vitro LLPS and fibril formation assay, live-cell imaging, immunohistochemistry of PD patient brain sections, small molecule inhibitor characterization bioRxivpreprint Medium bio_10.1101_2025.03.17.643602

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 956 21857683
2018 Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Molecular cell 282 29526694
2016 UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome. Cell 244 27477512
2012 UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiology of aging 141 22717235
2019 Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. Acta neuropathologica communications 97 31319884
2019 ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner. Structure (London, England : 1993) 78 30982635
2016 Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proceedings of the National Academy of Sciences of the United States of America 77 27834214
2020 ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function. Proceedings of the National Academy of Sciences of the United States of America 72 32513711
2014 Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta neuropathologica 66 25388785
2014 Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proceedings of the National Academy of Sciences of the United States of America 64 25246588
2013 Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation. Journal of neurochemistry 60 24215460
2014 UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Annals of neurology 55 24771548
2013 Ubiquilin-2 (UBQLN2) binds with high affinity to the C-terminal region of TDP-43 and modulates TDP-43 levels in H4 cells: characterization of inhibition by nucleic acids and 4-aminoquinolines. Biochimica et biophysica acta 54 23541532
2018 Mutant UBQLN2 promotes toxicity by modulating intrinsic self-assembly. Proceedings of the National Academy of Sciences of the United States of America 51 30333186
2017 Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis. Neurobiology of aging 50 28716533
2012 UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Muscle & nerve 44 22246868
2021 UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model. Neuron 41 33991504
2018 The MTM1-UBQLN2-HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle. Nature cell biology 40 29358706
2021 UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD. The FEBS journal 39 34273246
2019 Structure of hRpn10 Bound to UBQLN2 UBL Illustrates Basis for Complementarity between Shuttle Factors and Substrates at the Proteasome. Journal of molecular biology 39 30664872
2018 Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats. Acta neuropathologica communications 38 30409191
2012 UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis. Neurobiology of aging 38 22560112
2020 Global proteomics of Ubqln2-based murine models of ALS. The Journal of biological chemistry 37 33277362
2013 Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients. Neurobiology of aging 34 23312802
2019 Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress. Cellular and molecular life sciences : CMLS 32 31802140
2013 Clinical variability and female penetrance in X-linked familial FTD/ALS caused by a P506S mutation in UBQLN2. Amyotrophic lateral sclerosis & frontotemporal degeneration 32 23944734
2008 The ubiquitin-like protein PLIC-2 is a negative regulator of G protein-coupled receptor endocytosis. Molecular biology of the cell 32 18199683
2016 Increased Ubqln2 expression causes neuron death in transgenic rats. Journal of neurochemistry 31 27456931
2011 Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis. Neurobiology of aging 31 22169395
2023 UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS. eLife 30 36951542
2023 UBQLN2 and HSP70 participate in Parkin-mediated mitophagy by facilitating outer mitochondrial membrane rupture. EMBO reports 30 37501540
2021 Previously uncharacterized interactions between the folded and intrinsically disordered domains impart asymmetric effects on UBQLN2 phase separation. Protein science : a publication of the Protein Society 30 34029402
2018 Mutation-dependent aggregation and toxicity in a Drosophila model for UBQLN2-associated ALS. Human molecular genetics 29 29161404
2018 PolyQ-expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 29401586
2014 Mutations in UBQLN2 and SIGMAR1 genes are rare in Korean patients with amyotrophic lateral sclerosis. Neurobiology of aging 25 24684794
2021 ALS-linked mutations impair UBQLN2 stress-induced biomolecular condensate assembly in cells. Journal of neurochemistry 23 34129687
2020 Modeling UBQLN2-mediated neurodegenerative disease in mice: Shared and divergent properties of wild type and mutant UBQLN2 in phase separation, subcellular localization, altered proteostasis pathways, and selective cytotoxicity. Neurobiology of disease 23 32653673
2018 Neuronal Expression of UBQLN2P497H Exacerbates TDP-43 Pathology in TDP-43G348C Mice through Interaction with Ubiquitin. Molecular neurobiology 22 30377984
2021 ALS/FTD mutations in UBQLN2 are linked to mitochondrial dysfunction through loss-of-function in mitochondrial protein import. Human molecular genetics 21 33891006
2015 Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3. Neurobiology of disease 21 26141599
2013 Iron, oxidative stress, and virulence: roles of iron-sensitive transcription factor Sre1 and the redox sensor ChAp1 in the maize pathogen Cochliobolus heterostrophus. Molecular plant-microbe interactions : MPMI 20 23980626
2018 Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia. Neurobiology of aging 18 30348461
2016 C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue. Neurobiology of aging 18 27480424
2024 Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate. Proceedings of the National Academy of Sciences of the United States of America 16 39121161
2022 RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control. Cellular and molecular life sciences : CMLS 15 35247097
2019 Lou Gehrig's Disease (ALS): UBQLN2 Mutations Strike Out of Phase. Structure (London, England : 1993) 15 31167121
2024 Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity. Scientific reports 14 38472280
2023 Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2. eLife 14 37039476
2020 Overexpression of UBQLN1 reduces neuropathology in the P497S UBQLN2 mouse model of ALS/FTD. Acta neuropathologica communications 14 33028421
2016 Early Impairment of Synaptic and Intrinsic Excitability in Mice Expressing ALS/Dementia-Linked Mutant UBQLN2. Frontiers in cellular neuroscience 14 27703430
2013 Role of the transcription factor ChAP1 in cytoplasmic redox homeostasis: imaging with a genetically encoded sensor in the maize pathogen Cochliobolus heterostrophus. Molecular plant pathology 14 23745603
2022 Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 13 35082119
2014 UBQLN2 variant of unknown significance in frontotemporal lobar degeneration. Neurobiology of aging 13 25179229
2024 Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia. Brain : a journal of neurology 12 38703371
2013 Screening UBQLN-2 in French frontotemporal lobar degeneration and frontotemporal lobar degeneration-amyotrophic lateral sclerosis patients. Neurobiology of aging 12 23582661
2013 Genetic interaction of the stress response factors ChAP1 and Skn7 in the maize pathogen Cochliobolus heterostrophus. FEMS microbiology letters 11 24164316
2023 Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia. Brain pathology (Zurich, Switzerland) 10 38115557
2020 UBQLN2 Promotes the Production of Type I Interferon via the TBK1-IRF3 Pathway. Cells 10 32413959
2012 UBQLN2 in familial amyotrophic lateral sclerosis in The Netherlands. Neurobiology of aging 9 22676852
2025 Endogenous retrovirus-like proteins recruit UBQLN2 to stress granules and shape their functional biology. Science advances 8 40680123
2020 The Impact of ALS-Associated Genes hnRNPA1, MATR3, VCP and UBQLN2 on the Severity of TDP-43 Aggregation. Cells 8 32731393
2017 No Evidence for Pathogenic Role of UBQLN2 Mutations in Sporadic Amyotrophic Lateral Sclerosis in the Mainland Chinese Population. PloS one 8 28125704
2013 UBQLN2 mutations are not a frequent cause of amyotrophic lateral sclerosis in Ireland. Neurobiology of aging 8 23973441
2025 E3 ligase recruitment by UBQLN2 protects substrates from proteasomal degradation. bioRxiv : the preprint server for biology 7 40631187
2022 Multi-omics profiling identifies a deregulated FUS-MAP1B axis in ALS/FTD-associated UBQLN2 mutants. Life science alliance 7 35777956
2021 Impaired 26S Proteasome Assembly Precedes Neuronal Loss in Mutant UBQLN2 Rats. International journal of molecular sciences 7 33919255
2017 Investigation of the adaptor protein PLIC-2 in multiple pathways. Biochemistry and biophysics reports 7 28286874
2023 A Spectrophotometric Turbidity Assay to Study Liquid-Liquid Phase Separation of UBQLN2 In Vitro. Methods in molecular biology (Clifton, N.J.) 6 36310223
2025 UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential. Biochemical Society transactions 5 40663766
2022 Towards a molecular understanding of the overlapping and distinct roles of UBQLN1 and UBQLN2 in lung cancer progression and metastasis. Neoplasia (New York, N.Y.) 5 35063704
2022 UBQLN2 undergoes a reversible temperature-induced conformational switch that regulates binding with HSPA1B: ALS/FTD mutations cripple the switch but do not destroy HSPA1B binding. Biochimica et biophysica acta. General subjects 5 36423739
2021 Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD. Brain pathology (Zurich, Switzerland) 5 33780087
2023 Silencing UBQLN2 Enhances the Radiosensitivity of Esophageal Squamous Cell Carcinoma (ESCC) via Activating p38 MAPK. Journal of oncology 4 36644234
2022 Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2P497H Mutation. International journal of molecular sciences 4 36232630
2019 The AP-1-like transcription factor ChAP1 balances tolerance and cell death in the response of the maize pathogen Cochliobolus heterostrophus to a plant phenolic. Current genetics 4 31312934
2024 Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets. International journal of molecular sciences 2 39769213
2023 An Optimized Stress Granule Detection Method: Investigation of UBQLN2 Effect on Stress Granule Formation. Methods in molecular biology (Clifton, N.J.) 2 36310224
2023 Neuronal Puncta/Aggregate Formation by WT and Mutant UBQLN2. Methods in molecular biology (Clifton, N.J.) 2 36310225
2020 First case of an UBQLN2 gene mutation causing frontotemporal dementia preceded by adult onset psychiatric symptoms. Amyotrophic lateral sclerosis & frontotemporal degeneration 2 32290710
2016 New transgenic ALS/FTD models on the rat-walk: An Editorial Highlight for 'Increased Ubqln2 expression causes neuron death in transgenic rats'. Journal of neurochemistry 2 27723099
2025 UBQLN2 is necessary for UBE3A-mediated proteasomal degradation of the domesticated retroelement PEG10. Journal of cell science 1 41234208
2024 Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate. bioRxiv : the preprint server for biology 1 38559018
2024 Analysis of translatomic changes in the Ubqln2 model of ALS reveals that motor neurons express muscle-associated genes in non-disease states. Frontiers in neurology 1 39628898
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
2021 [Association between rare UBQLN2 variants and amyotrophic lateral sclerosis in Chinese population]. Zhonghua yi xue za zhi 1 33789365
2026 Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD. Frontiers in molecular neuroscience 0 41561437
2026 TRIM9 and TRIM26 Interact with UBQLN2P497H to Modulate Its Proteasomal Degradation. ACS chemical biology 0 41582437
2026 TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates. bioRxiv : the preprint server for biology 0 41727138
2026 UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration. Nature neuroscience 0 41912662
2026 STI1 domains coordinate partitioning of UBQLN2 into stress-induced condensates. bioRxiv : the preprint server for biology 0 41959388
2025 A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant. Journal of human genetics 0 40841583
2025 A meta-analysis of genetic variant pathogenicity and sex differences in UBQLN2-linked amyotrophic lateral sclerosis and frontotemporal dementia. Neurobiology of disease 0 41016645
2025 Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS-dementia. bioRxiv : the preprint server for biology 0 41278912
2025 The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization. Biochemistry 0 41428212
2024 Two new cases with the UBQLN2 gene mutation in Han Chinese. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 0 38943019
2024 ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2ALS phenotypes in Drosophila melanogaster. Progress in neurobiology 0 39395630

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