Affinage

USP34

Ubiquitin carboxyl-terminal hydrolase 34 · UniProt Q70CQ2

Length
3546 aa
Mass
404.2 kDa
Annotated
2026-06-11
23 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP34 is a deubiquitylase that controls the abundance of diverse substrate proteins by removing polyubiquitin chains to oppose their proteasomal degradation, thereby acting as a positive or negative tuning node across developmental signaling, DNA repair, and cancer-associated pathways (PMID:21383061, PMID:30181118, PMID:23863847). Its founding role is in Wnt/β-catenin signaling, where it was purified in axin-containing complexes and stabilizes axin by counteracting tankyrase-dependent ubiquitination, functioning downstream of the β-catenin destruction complex (PMID:21383061). In the DNA damage response, USP34 stabilizes the E3 ligase RNF168 to sustain double-strand-break ubiquitin signaling and the recruitment of BRCA1 and 53BP1, with loss compromising survival after ionizing radiation (PMID:23863847), consistent with an indispensable requirement for Usp34 in homologous recombination repair (PMID:35393473). A recurring theme is opposition to specific E3 ligases: USP34 stabilizes Smad1 and RUNX2 against Smurf1-mediated degradation to drive BMP2 osteogenesis (PMID:30181118), stabilizes the transcription factor NFIC to support odontogenic differentiation (PMID:33686052), and stabilizes ANT1 to enable PINK1-Parkin mitophagy in chondrocytes (PMID:41631201); conditional knockout mice reveal skeletal, dental, and joint phenotypes from these activities (PMID:30181118, PMID:33686052, PMID:41631201). In cancer contexts USP34 stabilizes a range of pro-tumorigenic factors—Pin1 (driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells) (PMID:38167292), SOX2 (PMID:32783291), FOXC1 (PMID:38686761), c-Myc (PMID:40260316), and eIF3m (PMID:42023842). USP34 also acts as a negative regulator of TCR-driven NF-κB activation (PMID:23590831) and modulates thrombin-PAR1-p38 MAPK signaling, in the latter case through transcriptional control of F2R rather than receptor deubiquitination (PMID:37865315, PMID:39705380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2011 High

    Established USP34's founding function by asking how axin stability is maintained against tankyrase-driven turnover, placing a deubiquitylase within the Wnt/β-catenin destruction-complex axis.

    Evidence LC-MS/MS of purified axin complexes with RNAi and Wnt reporter assays

    PMID:21383061

    Open questions at the time
    • Direct in vitro deubiquitylation of axin by USP34 not reconstituted
    • Chain-type specificity of USP34 not defined
  2. 2013 High

    Extended USP34 into the DNA damage response by showing it stabilizes the E3 ligase RNF168 to sustain DSB ubiquitin signaling and downstream repair-factor recruitment.

    Evidence siRNA knockdown, immunofluorescence for BRCA1/53BP1, ubiquitylation and clonogenic survival assays

    PMID:23863847

    Open questions at the time
    • Whether USP34 acts directly on RNF168 ubiquitin chains vs indirectly not fully resolved
    • Recruitment dynamics of USP34 to damage sites unknown
  3. 2013 Medium

    Identified USP34 as a negative regulator of TCR-driven NF-κB signaling, expanding its roles beyond stabilization to immune signal attenuation.

    Evidence Genome-wide siRNA DUB screen in T lymphocytes with NF-κB reporter, IκBα degradation and DNA-binding readouts

    PMID:23590831

    Open questions at the time
    • No direct USP34 substrate identified in the NF-κB pathway
    • Screen-based hit without reciprocal biochemical validation
  4. 2018 High

    Demonstrated an in vivo developmental role by showing USP34 opposes Smurf1-mediated degradation of Smad1/RUNX2 to enable BMP2-driven osteogenesis.

    Evidence Conditional KO mice, Smurf1 co-depletion epistasis rescue, ubiquitylation assays, micro-CT/histology

    PMID:30181118

    Open questions at the time
    • Direct biochemical deubiquitylation of Smad1/RUNX2 not reconstituted
    • Tissue-specificity of the USP34-Smurf1 antagonism unclear
  5. 2018 Medium

    Linked USP34 to ER-associated/lipid biology by identifying gp78 as an interactor whose stability and lipid-droplet function depend on USP34.

    Evidence Co-IP/LC-MS/MS, siRNA knockdown, lipid droplet formation assay

    PMID:30585151

    Open questions at the time
    • Single lab, no reciprocal validation of direct deubiquitylation
    • Mechanism connecting gp78 stability to lipid droplets incomplete
  6. 2020 Medium

    Began establishing USP34 as a stabilizer of oncogenic transcription factors by showing it deubiquitylates SOX2 to promote survival and cisplatin resistance.

    Evidence Co-IP, ubiquitylation assay, siRNA knockdown, overexpression rescue, viability assay

    PMID:32783291

    Open questions at the time
    • Single-lab Co-IP without reciprocal validation
    • Specificity of USP34 for SOX2 vs other factors not benchmarked
  7. 2021 High

    Showed an in vivo dental developmental requirement, with USP34 stabilizing NFIC to drive odontogenic differentiation and prevent short root anomaly.

    Evidence Conditional KO mice, siRNA, NFIC overexpression rescue, ubiquitylation assay, histomorphometry

    PMID:33686052

    Open questions at the time
    • Direct deubiquitylation of NFIC not reconstituted in vitro
    • Upstream regulators directing USP34 to NFIC unknown
  8. 2022 Medium

    Defined the DNA-repair role more precisely by showing Usp34 is indispensable specifically for homologous recombination at induced DSBs in Drosophila.

    Evidence siRNA knockdown, DR-white HR reporter, survival after UV/X-ray

    PMID:35393473

    Open questions at the time
    • Molecular substrate of Usp34 in HR not identified in this system
    • Conservation of the exact mechanism to human cells not shown here
  9. 2023 Medium

    Connected USP34 to GPCR signaling by identifying it as a regulator of thrombin-PAR1-driven p38 MAPK activation and IL-6 production.

    Evidence siRNA DUB screen in endothelial/HeLa cells, p38 phosphorylation assay, IL-6 ELISA, permeability assay

    PMID:37865315

    Open questions at the time
    • Direct USP34 substrate in the PAR1-p38 pathway not identified
    • Mechanism of selectivity for p38 vs barrier function unexplained
  10. 2024 Medium

    Resolved part of the PAR1 mechanism by showing USP34 acts via transcriptional control of F2R rather than receptor ubiquitination or trafficking.

    Evidence siRNA, flow cytometry, RT-PCR, internalization/degradation assays, p38 phosphorylation assay

    PMID:39705380

    Open questions at the time
    • Molecular link between USP34 and F2R transcription undefined
    • Whether this reflects a deubiquitylase-dependent activity unknown
  11. 2024 High

    Defined a PTM-gated cancer mechanism in which USP34 stabilizes Pin1 (facilitated by Plk1 phosphorylation), driving Ubc9 isomerization and SUMO1 hypersumoylation in glioma stem cells.

    Evidence Reciprocal Co-IP, ubiquitylation assays, Plk1/CDK1 inhibition, in vitro isomerization, orthotopic xenograft

    PMID:38167292

    Open questions at the time
    • How Plk1 phosphorylation licenses USP34-Pin1 binding mechanistically not fully detailed
    • Generality of the hypersumoylation axis beyond glioma stem cells unknown
  12. 2024 Medium

    Added FOXC1 to the USP34 substrate set, placing USP34 downstream of BPTF in controlling FOXC1 stability in glioma.

    Evidence Co-IP, ubiquitylation assay, western blot, lentiviral knockdown/overexpression, functional rescue

    PMID:38686761

    Open questions at the time
    • Single-lab evidence without reciprocal validation
    • How BPTF directs USP34 to FOXC1 not defined
  13. 2025 Medium

    Implicated USP34 in tumor metabolism by showing it stabilizes c-Myc and sustains aerobic glycolysis in hepatocellular carcinoma.

    Evidence Co-IP, ubiquitylation assay, siRNA, glycolysis assays, c-Myc overexpression rescue

    PMID:40260316

    Open questions at the time
    • Direct deubiquitylation of c-Myc not reconstituted
    • Single-lab evidence
  14. 2026 High

    Demonstrated an in vivo mitochondrial-quality-control role, with USP34 stabilizing ANT1 to enable PINK1-Parkin mitophagy and protect against TMJ osteoarthritis.

    Evidence Chondrocyte-specific conditional KO mice, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy and overexpression studies

    PMID:41631201

    Open questions at the time
    • Direct in vitro deubiquitylation of ANT1 not shown
    • How ANT1 levels gate PINK1-Parkin initiation not mechanistically detailed
  15. 2026 Medium

    Extended the substrate repertoire to translation/mitochondrial maintenance by showing USP34 stabilizes eIF3m, which binds MTCH2 5'UTR to support TNBC proliferation.

    Evidence Co-IP, GST pulldown, RIP, RNA pulldown, ubiquitylation assay, siRNA, mitochondrial function assays

    PMID:42023842

    Open questions at the time
    • Single-lab evidence without reciprocal validation
    • Direct deubiquitylation of eIF3m not reconstituted

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical determinants of USP34 substrate selectivity, polyubiquitin chain-type specificity, and structural basis for its broad substrate range remain undefined.
  • No structural model of the USP34 catalytic domain in the timeline
  • No defined recognition motif explaining its diverse substrate set
  • Whether non-catalytic/scaffolding activities account for transcriptional and NF-κB effects unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 4
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-73894 DNA Repair 2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 USP34 was identified in purified axin-containing protein complexes by LC-MS/MS and shown to stabilize axin by opposing its tankyrase-dependent ubiquitination, thereby functioning downstream of the β-catenin destruction complex to regulate Wnt/β-catenin signaling; RNAi knockdown of USP34 led to axin degradation and inhibition of β-catenin-mediated transcription. LC-MS/MS of purified axin complexes, RNA interference, Wnt/β-catenin reporter assays Molecular and cellular biology High 21383061
2013 USP34 stabilizes the E3 ubiquitin ligase RNF168 by deubiquitylation in response to DNA double-strand breaks; loss of USP34 causes rapid RNF168 degradation, attenuated DSB-associated ubiquitylation, defective recruitment of BRCA1 and 53BP1, and compromised cell survival after ionizing radiation. siRNA knockdown, immunofluorescence for DSB repair factors (BRCA1, 53BP1), clonogenic survival assay, ubiquitylation assays Nucleic acids research High 23863847
2013 In a genome-wide siRNA DUB screen in T lymphocytes, knockdown of USP34 selectively enhanced TCR-driven NF-κB activation, led to more pronounced degradation of the NF-κB inhibitor IκBα, and increased NF-κB DNA-binding activity, positioning USP34 as a negative regulator of NF-κB signaling downstream of TCR engagement. siRNA library screen, NF-κB reporter assay, IκBα degradation analysis, NF-κB DNA binding assay Cell communication and signaling : CCS Medium 23590831
2018 USP34 stabilizes both Smad1 and RUNX2 by deubiquitylation in mesenchymal stem cells; USP34 depletion inhibits osteogenic differentiation and BMP2 signaling responses, and depletion of Smurf1 (an E3 ligase for Smad1) restores the osteogenic potential of Usp34-deficient MSCs in vitro, placing USP34 in opposition to Smurf1-mediated degradation of Smad1/RUNX2. Conditional knockout in mice, siRNA knockdown, ubiquitylation assays, epistasis (Smurf1 co-depletion rescue), bone phenotype analysis (micro-CT, histology) The EMBO journal High 30181118
2018 USP34 was identified as an interaction partner of the E3 ligase gp78 by Co-IP/LC-MS/MS; USP34 knockdown facilitates proteasomal degradation of gp78 and consequently impairs gp78-mediated lipid droplet formation. Co-IP coupled to LC-MS/MS, siRNA knockdown, lipid droplet formation assay Biochemical and biophysical research communications Medium 30585151
2024 USP34 deubiquitinates and stabilizes the peptidyl-prolyl isomerase Pin1; this interaction is facilitated by Plk1-mediated phosphorylation of Pin1, and stabilized Pin1 promotes isomerization of the SUMO E2 enzyme Ubc9 (requiring CDK1-mediated phosphorylation of Ubc9), leading to elevated SUMO1-modified protein hypersumoylation that supports glioma stem cell maintenance. Co-immunoprecipitation, ubiquitylation assays, pharmacological inhibition (Plk1 inhibitor, CDK1 inhibitor), in vitro isomerization assay, orthotopic tumor xenograft Nature communications High 38167292
2020 USP34 interacts with SOX2, reduces its polyubiquitination, and stabilizes SOX2 protein (without affecting SOX2 mRNA), thereby promoting cell survival and cisplatin resistance in laryngeal squamous cell carcinoma cells. Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, overexpression rescue, cell viability assay The Kaohsiung journal of medical sciences Medium 32783291
2021 USP34 stabilizes the transcription factor NFIC by deubiquitylation in dental pulp cells; conditional deletion of Usp34 in dental mesenchymal cells reduces NFIC levels and impairs odontogenic differentiation, resulting in short root anomaly, and overexpression of NFIC partially restores the differentiation defect. Conditional knockout in mice, siRNA knockdown, overexpression rescue, ubiquitylation assay, histomorphometry International journal of oral science High 33686052
2022 In Drosophila, loss of Usp34 by siRNA abolishes homologous recombination at I-SceI-induced DSBs (DR-white assay), demonstrating an indispensable role for Usp34 specifically in homologous recombination-mediated DSB repair. siRNA knockdown, DR-white homologous recombination reporter assay, survival assay after UV/X-ray irradiation Scientific reports Medium 35393473
2023 An siRNA screen of 96 DUBs in endothelial and HeLa cells identified USP34 as a regulator of thrombin-GPCR (PAR1)-driven p38 MAPK signaling; USP34 knockdown decreased thrombin-stimulated p38 phosphorylation and reduced IL-6 cytokine expression, but had no effect on endothelial barrier permeability. siRNA library screen, p38 phosphorylation assay, IL-6 ELISA, endothelial permeability assay The Journal of biological chemistry Medium 37865315
2024 USP34 knockdown in endothelial cells increases PAR1 (F2R) mRNA transcript levels, leading to elevated PAR1 cell surface abundance and altered thrombin-stimulated p38 activation; this effect is not due to altered PAR1 ubiquitination, internalization, or degradation, but to transcriptional regulation of the F2R gene. siRNA knockdown, flow cytometry, RT-PCR, receptor internalization and degradation assays, p38 phosphorylation assay Molecular biology of the cell Medium 39705380
2024 USP34 mediates BPTF-regulated stabilization of FOXC1 via deubiquitylation; immunoprecipitation experiments showed that BPTF affects FOXC1 protein stability through USP34-dependent de-ubiquitylation, and FOXC1 overexpression rescues the phenotype of BPTF knockdown in glioma cells. Co-immunoprecipitation, ubiquitylation assay, western blot, lentiviral overexpression/knockdown, functional rescue Histology and histopathology Medium 38686761
2025 USP34 interacts with c-Myc, reduces its ubiquitination, and stabilizes the c-Myc protein; USP34 knockdown enhances c-Myc ubiquitination and degradation, and reduces aerobic glycolysis in hepatocellular carcinoma cells; overexpression of c-Myc reverses si-USP34-mediated phenotypic effects. Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown, CCK-8, glycolysis assays, overexpression rescue The Turkish journal of gastroenterology Medium 40260316
2026 USP34 deubiquitinates and stabilizes ANT1 (adenine nucleotide translocase 1) in TMJ chondrocytes; USP34 deficiency in chondrocyte-specific Usp34 KO mice leads to impaired ANT1-dependent initiation of PINK1-Parkin mitophagy and age-dependent TMJ osteoarthritis; USP34 overexpression protects chondrocytes against cellular injury. Chondrocyte-specific conditional KO mouse model, micro-CT/histomorphometry, Co-IP, ubiquitylation assay, mitophagy assays, overexpression studies JBMR plus High 41631201
2026 USP34 stabilizes eIF3m protein through deubiquitylation in triple-negative breast cancer cells; stabilized eIF3m binds the 5'UTR of MTCH2 mRNA to upregulate MTCH2 expression, thereby maintaining mitochondrial function and promoting TNBC proliferation. Co-immunoprecipitation, GST pulldown, RNA immunoprecipitation, RNA pulldown, ubiquitylation assay, siRNA knockdown, mitochondrial function assays Journal of histotechnology Medium 42023842

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The ubiquitin-specific protease USP34 regulates axin stability and Wnt/β-catenin signaling. Molecular and cellular biology 115 21383061
2018 Ubiquitin-specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling. The EMBO journal 69 30181118
2013 The ubiquitin specific protease USP34 promotes ubiquitin signaling at DNA double-strand breaks. Nucleic acids research 60 23863847
2024 Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells. Nature communications 37 38167292
2013 Negative regulation of NF-κB signaling in T lymphocytes by the ubiquitin-specific protease USP34. Cell communication and signaling : CCS 27 23590831
2017 Inhibition of ubiquitin-specific protease 34 (USP34) induces epithelial-mesenchymal transition and promotes stemness in mammary epithelial cells. Cellular signalling 22 28499884
2020 The deubiquitinase USP34 stabilizes SOX2 and induces cell survival and drug resistance in laryngeal squamous cell carcinoma. The Kaohsiung journal of medical sciences 17 32783291
2019 USP34 Regulated Human Pancreatic Cancer Cell Survival via AKT and PKC Pathways. Biological & pharmaceutical bulletin 17 30686807
2020 Downregulation of USP34 Inhibits the Growth and Migration of Pancreatic Cancer Cells via Inhibiting the PRR11. OncoTargets and therapy 16 32110045
2021 USP34 regulates tooth root morphogenesis by stabilizing NFIC. International journal of oral science 15 33686052
2025 USP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation. International immunopharmacology 12 39752760
2015 An association study between USP34 and polycystic ovary syndrome. Journal of ovarian research 9 25975428
2023 An siRNA library screen identifies CYLD and USP34 as deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses. The Journal of biological chemistry 7 37865315
2022 Usp5, Usp34, and Otu1 deubiquitylases mediate DNA repair in Drosophila melanogaster. Scientific reports 6 35393473
2022 Whole-Exome Sequencing Implicates the USP34 rs777591A > G Intron Variant in Chronic Obstructive Pulmonary Disease in a Kashi Cohort. Frontiers in cell and developmental biology 5 35198563
2020 The role of USP34 in the fixation of titanium implants in murine models. European journal of oral sciences 5 32363724
2018 The ubiquitin specific protease USP34 protects the ubiquitin ligase gp78 from proteasomal degradation. Biochemical and biophysical research communications 5 30585151
2024 USP34 regulates endothelial PAR1 mRNA transcript expression and cellular signaling. Molecular biology of the cell 2 39705380
2026 USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy. JBMR plus 1 41631201
2024 BPTF promotes glioma development through USP34-mediated de-ubiquitination of FOXC1. Histology and histopathology 1 38686761
2024 Rare Case of de Novo 2p15 Microdeletion Syndrome with Deletion Covering XPO1 and USP34 Genes Diagnosed in a Child - A Case Report. The application of clinical genetics 1 39050773
2026 USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis. Journal of histotechnology 0 42023842
2025 The Knockdown of USP34 Inhibits the Progression of Hepatocellular Carcinoma by Accelerating c-Myc Degradation. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 0 40260316

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