Affinage

USP25

Ubiquitin carboxyl-terminal hydrolase 25 · UniProt Q9UHP3

Length
1055 aa
Mass
122.2 kDa
Annotated
2026-06-11
76 papers in source corpus 52 papers cited in narrative 51 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

USP25 is a cysteine deubiquitinating enzyme that acts through its catalytic cysteine C178 to edit ubiquitin chains on a broad set of substrates, thereby controlling their stability, localization, and downstream signaling across innate immunity, inflammation, metabolism, DNA repair, and neurodegeneration (PMID:23042150, PMID:36722348, PMID:41861519). A defining mechanistic feature is its self-regulation: USP25 partitions between a catalytically active dimer and an autoinhibited tetramer in which a USP25-specific coiled-coil insertion occludes the ubiquitin-binding pocket, and shifting this equilibrium toward the dimer increases substrate stabilization in cells (PMID:30926242, PMID:30926243, PMID:30478318). Activity is further tuned by post-translational competition at K99, where ubiquitination activates and SUMO conjugation inhibits the enzyme, and by non-covalent SUMO2 binding to its N-terminal ubiquitin-binding region that competitively blocks substrate engagement (PMID:19440361, PMID:28538147); VRK2 phosphorylation of C-terminal residues additionally suppresses catalytic activity (PMID:25755282). In innate antiviral and inflammatory signaling USP25 both stabilizes TRAF3 and TRAF6 by removing K48-linked chains to promote IRF3/NF-κB activation and type I IFN production, and restrains K63-linked signaling on adaptors such as TRAF5/TRAF6, TAB2, and RIPK1 to limit inflammation (PMID:26305951, PMID:23042150, PMID:37587766, PMID:41861519); its expression is induced by the type I IFN–IRF7 axis through direct IRF7 binding to the USP25 promoter (PMID:27129230). Beyond immunity, USP25 stabilizes substrates including SERCA2a, HIF-1α, tankyrases (activating Wnt/β-catenin), KEAP1, SHLD2 (promoting NHEJ DNA repair), MDM2, and KRAS, and regulates LATS1/YAP and FOXO3 and optineurin-dependent mitophagy (PMID:36722348, PMID:35440539, PMID:28619731, PMID:37339955, PMID:38803048, PMID:37480689, PMID:40473213, PMID:41882191, PMID:40370563, PMID:41499392). In disease contexts captured by the corpus, USP25 promotes microgliosis, amyloidogenic processing of APP/BACE1, and neuroinflammation linked to Alzheimer's pathology, and is required for optineurin-mediated mitophagy whose disruption drives dopaminergic neuron loss (PMID:33523861, PMID:35229730, PMID:41499392). Notably, USP25 can also act independently of its deubiquitinase activity, as it impedes RNF31-mediated linear ubiquitination of oncogenic KRAS to support membrane localization and signaling in lung cancer (PMID:39952242).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 Medium

    Established the first substrate context for USP25, showing it physically engages sarcomeric proteins and selectively rescues a short-lived proteasomal substrate, defining it as a stabilizing deubiquitinase.

    Evidence Yeast two-hybrid, Co-IP and proteasomal degradation assays of the muscle isoform with ACTA1, FLNC and MyBPC1

    PMID:16501887

    Open questions at the time
    • No catalytic-residue requirement demonstrated
    • Linkage specificity of removed chains not defined
    • Limited to overexpression in one cell context
  2. 2009 High

    Defined how USP25 activity is intrinsically regulated, showing a coiled-coil region is required for catalysis and that opposing ubiquitin versus SUMO modification at K99 toggles enzymatic output.

    Evidence Deletion mutagenesis, ubiquitination/SUMOylation assays and MyBPC1 rescue assay

    PMID:19440361

    Open questions at the time
    • Structural basis of K99 modification switch not resolved
    • Physiological enzymes mediating K99 modification not identified in this work
  3. 2012 High

    Placed USP25 in IL-17 innate signaling as a negative regulator, showing it counteracts Act1-driven K63 ubiquitination of TRAF adaptors.

    Evidence Reciprocal Co-IP, knockdown/overexpression and Usp25-/- mouse phenotyping

    PMID:23042150

    Open questions at the time
    • Catalytic-site dependence not formally tested here
    • Direct demonstration of chain removal on endogenous adaptors limited
  4. 2015 High

    Resolved a seemingly opposite role in antiviral immunity, showing USP25 stabilizes TRAF3/TRAF6 to promote IRF3/NF-κB activation and type I IFN, indicating substrate- and chain-context-dependent outcomes.

    Evidence Co-IP, Usp25-/- MEF reconstitution rescue and viral infection assays; VRK2 phosphorylation suppressing activity (separate study)

    PMID:25755282 PMID:26305951

    Open questions at the time
    • How the same TRAF6 can be both stabilized and K63-edited by USP25 in different contexts unresolved
    • Determinants of K48 versus K63 selectivity not defined
  5. 2016 High

    Explained how USP25 is induced during infection, identifying direct IRF7 binding to the USP25 promoter downstream of IFNAR1 signaling.

    Evidence IRF7 KO and IFNAR1 KO cells, promoter mutagenesis and reporter assays

    PMID:27129230

    Open questions at the time
    • Transcriptional regulation outside the IFN context not addressed
    • Tissue-specific promoter usage not explored
  6. 2017 High

    Provided structural and functional basis for substrate recognition and SUMO inhibition, and connected USP25 to Wnt signaling via tankyrase stabilization.

    Evidence NMR of the N-terminal ubiquitin-binding region with SUMO2/ubiquitin competition assays; crystal structure of the TNKS1-USP25 complex with KO validation

    PMID:28538147 PMID:28619731

    Open questions at the time
    • In vivo relevance of SUMO competition not established
    • Tankyrase-independent Wnt inputs not separated
  7. 2019 High

    Resolved the central activity switch, showing USP25 is autoinhibited as a tetramer through a coiled-coil insertion occluding the ubiquitin pocket while the dimer is active, and that the equilibrium controls substrate stabilization.

    Evidence Cryo-EM/X-ray structures, kinetic assays with dimer/tetramer/truncation constructs and cellular tankyrase-stabilization assays

    PMID:30478318 PMID:30926242 PMID:30926243

    Open questions at the time
    • Cellular signals that drive dimer-tetramer transitions not identified
    • Whether all substrates are governed by the same oligomeric control unknown
  8. 2022 High

    Extended USP25 into metabolic and neurodegenerative disease mechanisms, showing it stabilizes HIF-1α to drive glycolysis and promotes amyloidogenic APP/BACE1 processing.

    Evidence Activity-based proteomics and PDAC organoid/xenograft screens for HIF-1α; Usp25 KO/transgenic 5xFAD crosses with ubiquitination and lysosomal degradation assays for APP/BACE1

    PMID:35229730 PMID:35440539

    Open questions at the time
    • Direct chain-linkage editing on HIF-1α not fully defined
    • Cell-type specificity of APP/BACE1 effects in vivo incomplete
  9. 2023 High

    Demonstrated chain-type- and substrate-specific control across multiple organ systems, including K48-mediated SERCA2a stabilization in cardiomyocytes, KEAP1 stabilization restraining NRF2, and K63 editing of TAB2 limiting microglial inflammation.

    Evidence C178A active-site mutants, MS substrate identification, AAV9 in vivo rescue, KO mice and linkage-specific ubiquitination assays across cardiac, hepatic and stroke models

    PMID:36722348 PMID:37339955 PMID:37587766

    Open questions at the time
    • Unifying rules predicting K48 versus K63 substrate outcomes still lacking
    • Most substrate relationships from single labs in single disease contexts
  10. 2024 High

    Defined a structural inhibitor pocket and expanded USP25 into DNA repair and a non-catalytic mode of action, including K64-specific deubiquitination of SHLD2 to promote NHEJ and inhibition of RNF31-mediated linear ubiquitination of KRAS.

    Evidence Crystal structures of USP25/USP28 with AZ1/Vismodegib/FT206 and E373 mutagenesis; site-specific ubiquitination and NHEJ assays for SHLD2; USP25 C178A knockin and RNF31 double-KO epistasis for KRAS

    PMID:38803048 PMID:38816515 PMID:39952242

    Open questions at the time
    • Generality of catalytic-independent functions across substrates unknown
    • Selectivity of inhibitors between USP25 and USP28 incompletely separated
  11. 2025 High

    Connected USP25 to autophagy/mitophagy and additional growth/metabolic substrates, including K63 editing of optineurin required for mitophagy, deubiquitination of KRAS, PPARα, FOXO3 and STAT6.

    Evidence Co-IP, site- and linkage-specific ubiquitination assays, KO and AAV rescue across PD, cancer, MASLD and fibrosis models

    PMID:39781451 PMID:39827322 PMID:40473213 PMID:41499392

    Open questions at the time
    • Whether mitophagy and substrate-stabilization roles operate simultaneously in the same cells unresolved
    • Many substrate findings rest on single-lab disease-model evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what governs USP25's substrate and chain-linkage selectivity in vivo and which physiological signals toggle its dimer-tetramer autoinhibition to dictate stabilizing versus chain-restricting outcomes.
  • No predictive code for K48 versus K63 substrate fates
  • Endogenous regulators of oligomeric-state switching unidentified
  • Scope of deubiquitinase-independent functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 1
Partners
KEAP1RIPK1SERCA2ASHLD2TAB2TNKS1TRAF3TRAF6

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 USP25 deubiquitinates TRAF5 and TRAF6 by removing Lys63-linked ubiquitin chains, negatively regulating IL-17-mediated signaling. Upon IL-17 stimulation, USP25 associates with TRAF5 and TRAF6 adaptors, opposing Act1-mediated K63-ubiquitination of these adaptors. Co-immunoprecipitation, overexpression/knockdown assays, Usp25-/- mouse model, phosphorylation assays, mRNA stability assays Nature immunology High 23042150
2015 USP25 stabilizes TRAF3 and TRAF6 after viral infection by protecting them from proteasome-dependent or independent degradation, respectively, thereby promoting IRF3 and NF-κB activation and type I IFN and cytokine production. Co-immunoprecipitation, Usp25-/- mouse model, reconstitution of TRAF3/TRAF6 in KO MEFs, viral infection assays Proceedings of the National Academy of Sciences of the United States of America High 26305951
2023 USP25 binds SERCA2a directly via its USP domain and removes K48-linked ubiquitin chains at the catalytic cysteine C178, preventing proteasomal degradation of SERCA2a and maintaining calcium handling in cardiomyocytes. LC-MS/MS, Co-IP, USP25 mutant constructs (C178A), AAV9-mediated overexpression in KO mice, Western blotting Circulation research High 36722348
2022 USP25 deubiquitinates and stabilizes the HIF-1α transcription factor, promoting HIF-1α transcriptional activity and glycolysis in pancreatic ductal adenocarcinoma under hypoxic conditions. Activity-based proteomics, loss-of-function genetic screen in PDAC organoids, genetic and pharmacological USP25 inhibition, patient-derived xenografts Nature communications High 35440539
2017 USP25 directly interacts with tankyrases (TNKS1/2) to promote their deubiquitination and stabilization, thereby activating Wnt/β-catenin signaling. The interaction interface was characterized by X-ray crystal structure determination. Co-immunoprecipitation, ubiquitination assays, USP25-KO cell lines, X-ray crystal structure of TNKS1-USP25 complex Genes & development High 28619731
2019 USP25 forms autoinhibited tetramers where a USP25-specific coiled-coil insertion sequence blocks ubiquitin binding, while the catalytically active form is a dimer. Modulating the dimer-tetramer equilibrium affects substrate stabilization in cells. Cryo-EM/X-ray crystallography, biochemical activity assays with dimer/tetramer/truncation constructs, cellular oligomeric state confirmation, substrate stabilization assays Molecular cell High 30926242 30926243
2019 USP25 forms an autoinhibited tetramer via contacts between a coiled-coil insertion domain and the ubiquitin-binding pocket of the catalytic domain. A constitutively dimeric USP25 construct shows higher tankyrase-stabilizing activity in cells, confirming biological relevance of the tetramerization mechanism. X-ray crystallography, biochemical/kinetic assays with dimer, tetramer and truncation constructs, cell-based tankyrase stabilization assay Nature communications High 30478318
2009 USP25m catalytic activity requires a coiled-coil stretch (aa 679-769) but not the UBA/UIM ubiquitin-binding domains. USP25 is monoubiquitinated at K99 (activating) and can autodeubiquitinate. SUMO conjugation at the same K99 residue inhibits USP25 activity, while ubiquitination at K99 activates it; UBDs favor monoubiquitination at K99 and mutation of K99 reduces USP25-dependent rescue of MyBPC1 from proteasomal degradation. Deletion mutagenesis, ubiquitination assays, SUMO modification assays, substrate (MyBPC1) rescue assay PloS one High 19440361
2006 USP25m (muscle isoform) interacts with sarcomeric proteins ACTA1, FLNC, and MyBPC1. MyBPC1 is a short-lived proteasomal substrate whose degradation is prevented by USP25m overexpression; ACTA1 and FLNC are stable proteins not regulated by USP25m turnover. Yeast two-hybrid, Co-immunoprecipitation, proteasomal degradation assays, overexpression Cellular and molecular life sciences : CMLS Medium 16501887
2021 USP25 overexpression promotes microglial activation, synapse elimination, and proinflammatory cytokine production in 5×FAD Alzheimer's disease mouse brains. Genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function, establishing USP25 as a mediator of trisomy 21-related microgliosis. USP25 BAC transgenic mice, Usp25 genetic KO in 5×FAD mice, pharmacological USP25 inhibition, behavioral testing, synaptic and microglial assays Science advances High 33523861
2022 USP25 promotes β-cleavage of APP and Aβ generation by reducing ubiquitination and lysosomal degradation of both APP and BACE1, thereby increasing amyloid pathology. Usp25 KO and USP25 BAC transgenic mice crossed with 5×FAD, pharmacological USP25 inhibition, ubiquitination assays, lysosomal degradation assays The Journal of clinical investigation High 35229730
2015 Vaccinia-related kinase 2 (VRK2) phosphorylates USP25 at Thr680, Thr727, and Ser745, suppressing USP25 deubiquitinating activity. USP25 interacts with the chaperonin TRiC and deubiquitinates it to maintain its stability; VRK2-mediated phosphorylation of USP25 impairs this, leading to TRiC destabilization. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of phosphorylation sites, deubiquitination assay, polyglutamine aggregation assay Molecular and cellular biology High 25755282
2020 USP25 suppresses ubiquitin-mediated degradation of BCR-ABL protein in Philadelphia chromosome-positive leukemia cells. USP25 is found proximal to BCR-ABL; its depletion increases BCR-ABL ubiquitination, reduces BCR-ABL protein levels, and suppresses BCR-ABL-mediated signaling and cell proliferation. shRNA-mediated USP25 knockdown, ubiquitination assays, BCR-ABL signaling pathway assays, pharmacological USP25 inhibition Oncogene Medium 32203161
2023 USP25 directly binds to KEAP1 and prevents KEAP1's own ubiquitination and degradation. In the absence of USP25, KEAP1 is downregulated and NRF2 is stabilized, enhancing the anti-oxidation response. Co-immunoprecipitation, USP25 KO mice, pharmacological USP25 inhibition, ubiquitination assays, APAP-induced liver injury model Nature communications High 37339955
2018 USP25 interacts with TRAF3 and removes K48-linked ubiquitin chains from TRAF3, stabilizing it in Kupffer cells and promoting endotoxin tolerance. USP25 knockdown activates K48-linked ubiquitination of TRAF3 and downstream JNK/p38 signaling. Lentiviral USP25 knockdown, Co-immunoprecipitation, K48-specific ubiquitination assay, cytokine production assays Molecular immunology Medium 30579117
2023 USP25 removes K63-specific polyubiquitin chains from TAB2, restricting NF-κB and MAPK signaling and reducing neuroinflammation after ischemic stroke in microglia. AAV9-mediated TAB2 knockdown abolishes the effect of USP25 deletion. USP25 KO mouse ischemic stroke model, AAV9-mediated TAB2 knockdown, K63-specific ubiquitin assay, Co-immunoprecipitation Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 37587766
2018 USP25 associates with HDAC11 via co-immunoprecipitation and catalyzes deubiquitination of HDAC11, maintaining HDAC11 protein stability. Cigarette smoke extract promotes USP25 ubiquitination and degradation, which consequently destabilizes HDAC11. Co-immunoprecipitation, ubiquitination assay, cigarette smoke extract treatment of lung epithelial cells American journal of physiology. Lung cellular and molecular physiology Medium 31746627
2018 USP25 associates with HBO1 (histone acetyltransferase) via co-immunoprecipitation and promotes its stability by suppressing HBO1 ubiquitination during LPS stimulation, facilitating HBO1-mediated inflammatory gene transcription. Co-immunoprecipitation, ubiquitination assay, LPS treatment of THP-1 cells Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30745998
2018 Smurf1 E3 ubiquitin ligase promotes K48-linked polyubiquitination and proteasomal degradation of USP25. Smurf1 overexpression decreases USP25 protein levels and reduces USP25-mediated antiviral activity; Smurf1 knockdown enhances USP25-dependent restriction of VSV replication. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, VSV replication assay Biochemical and biophysical research communications Medium 29518389
2019 USP25 interacts with tankyrase and co-localizes with GLUT4 in insulin-sensitive adipocytes. USP25 depletion reduces GLUT4 protein levels and blunts insulin-stimulated glucose transport, linking USP25-tankyrase deubiquitination to GLUT4 trafficking. Co-immunoprecipitation, co-localization imaging, USP25 depletion in adipocytes, glucose transport assay Scientific reports Medium 30886164
2020 USP25 restrains EGFR degradation by assisting in the association of the E3 ubiquitin ligase c-Cbl with EGFR at early internalization steps, modulating the amplitude of EGFR ubiquitylation; USP25 depletion accelerates EGFR internalization and degradation. USP25 siRNA depletion, quantitative EGFR internalization and degradation assays, c-Cbl/EGFR association assay Biomolecules Medium 33202887
2021 USP25 deubiquitinates PTEN in granulosa cells; USP25 knockdown reduces PTEN levels, activates the PI3K/AKT pathway, and increases granulosa cell proliferation while reducing apoptosis. USP25 shRNA knockdown, ubiquitination assay, PI3K/AKT pathway analysis, USP25 KO mouse PCOS model Frontiers in cell and developmental biology Medium 34805185
2016 Viral infection-induced upregulation of USP25 requires de novo synthesis of IRF7 and signaling through IFNAR1. IRF7 directly binds to two conserved IRF binding sites on the USP25 promoter to drive Usp25 transcription; mutation of these sites abolishes virus-induced USP25 promoter activation. IRF7 KO and IFNAR1 KO cells, IRF7 ChIP/promoter binding assay, promoter mutation and reporter assay The Journal of biological chemistry High 27129230
2022 USP25 deficiency in macrophages enhances TBK1-NF-κB signaling, leading to increased inflammatory cytokine expression and worsening acute pancreatitis. Bone marrow Usp25-/- chimeric mice recapitulate the exacerbated AP phenotype, localizing the effect to macrophages. Usp25-/- mouse models of AP, bone marrow chimeric mice, in vitro BMDM assays, TBK1-NF-κB pathway analysis Cellular and molecular gastroenterology and hepatology Medium 35934222
2023 USP25 inhibits the TGF-β/SMAD pathway by reducing SMAD4 K63-linked polyubiquitination, suppressing SMAD2 nuclear translocation and renal fibrosis in hypertensive kidney disease. USP25 KO and AAV9-overexpression mice, ubiquitination assay (K63-specific), SMAD2 nuclear translocation assay Biochimica et biophysica acta. Molecular basis of disease Medium 37059312
2023 USP25 interacts with TRAF6 via co-immunoprecipitation and inhibits K63 polyubiquitination of TRAF6 induced by AGEs, suppressing NF-κB and MAPK pathways in mesangial cells and macrophages in diabetic nephropathy. USP25 KO mice, Co-immunoprecipitation, K63-specific ubiquitination assay, NF-κB/MAPK pathway analysis International immunopharmacology Medium 37657242
2024 USP25 directly binds to TAK1 and P62; the C178 cysteine of USP25 removes K63 ubiquitin chains from P62, which promotes autophagic-lysosomal degradation of TAK1, reducing TAK1-MAPK inflammatory signaling in obesity cardiomyopathy. Co-immunoprecipitation, USP25 C178A mutant, autophagy-lysosome pathway assays, USP25 KO and cardiomyocyte-specific overexpression in HFD mice JACC. Basic to translational science Medium 39619140
2024 USP25 deubiquitinates SHLD2 at K64, enhancing its binding with REV7 and promoting non-homologous end joining (NHEJ) DNA repair. TRIM25 E3 ligase is identified as the enzyme responsible for degrading USP25. A peptide disrupting the USP25-SHLD2 interaction impairs NHEJ and sensitizes tumors to chemotherapy. Co-immunoprecipitation, ubiquitination assay (K64-specific), NHEJ reporter assay, class switch recombination in USP25 KO mice, TRIM25 E3 ligase assay, PDX model Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 38803048
2025 USP25 stabilizes STAT6 by reducing its K48-linked ubiquitination, thereby promoting IL-4-induced M2 macrophage polarization and downstream fibrosis. USP25 KO mice (BLM and BDL fibrosis models), Co-immunoprecipitation, K48 ubiquitination assay, M2 macrophage polarization assay International journal of biological sciences Medium 39781451
2023 USP25 stabilizes KLF4 through deubiquitination; KLF4 transcriptionally represses miR-10a-5p expression, and miR-10a-5p targets GSDMD expression, establishing an USP25-KLF4-miR-10a-5p-GSDMD axis that promotes pyroptosis of acinar cells in acute pancreatitis. Co-immunoprecipitation, ubiquitination assay, miRNA/luciferase assays, KLF4 overexpression rescue experiments Shock (Augusta, Ga.) Medium 36155610
2025 USP25 promotes ERK signaling in macrophages by deubiquitinating and stabilizing B-Raf and C-Raf, enhancing the antimycobacterial immune response against M. tuberculosis infection. USP25 KO macrophages and mice, Co-immunoprecipitation, deubiquitination assay, ERK pathway analysis, M. tuberculosis infection model The Journal of infectious diseases Medium 39110031
2025 Tim-3 inhibits USP25 expression via STAT1 and physically interacts with USP25. As a result, Tim-3 inhibits USP25-mediated deubiquitination of TRAF3, promotes K48-linked ubiquitination and degradation of TRAF3, inhibits IRF7 phosphorylation, and suppresses the type I interferon response against VSV. Tim-3 myeloid-specific KO mice, VSV infection model, Co-immunoprecipitation, K48-ubiquitination assay, IRF7 phosphorylation assay Cellular immunology Medium 39946759
2024 USP25 directly interacts with FOXO3 and removes K63-linked ubiquitin chains at K258 of FOXO3, increasing FOXO3 binding to LC3B and autophagosomic-lysosomal degradation of FOXO3, thereby ameliorating Ang II-induced vascular remodeling. Co-immunoprecipitation, K63-specific ubiquitination assay, LC3B binding assay, USP25 KO and AAV9-overexpression in mouse aorta, Ang II model Acta pharmaceutica Sinica. B Medium 40370563
2025 USP25 physically interacts with optineurin autophagy receptor and removes K63-linked polyubiquitin chains from it, which is required for mitophagy. USP25 disruption impairs mitophagy and leads to accumulation of damaged mitochondria and dopaminergic neuronal loss in PD models. Co-immunoprecipitation, K63 ubiquitination assay, mitophagy assays, USP25 KO and pharmacological inhibition in PD mouse models Proceedings of the National Academy of Sciences of the United States of America High 41499392
2025 USP25 impedes RNF31-mediated linear ubiquitination of KRAS oncogenic mutants independently of its deubiquitinase activity, facilitating plasma membrane localization and downstream oncogenic signaling of KRAS mutants in NSCLC. USP25 C178A knockin fails to suppress NSCLC progression, but additional RNF31 deletion/inhibition restores suppression in USP25 KO models. USP25 KO and C178A knockin mouse models, RNF31 KO, KRAS ubiquitination assay, plasma membrane localization assay, autochthonous NSCLC models, xenograft models Developmental cell High 39952242
2025 USP25 deubiquitinates KRAS (including oncogenic mutants) to prevent its proteasomal degradation. USP25 depletion increases KRAS ubiquitination and leads to its proteasomal degradation, suppressing oncogenic KRAS signaling in cancer cells. siRNA-based DUB screen, KRAS ubiquitination assay, USP25 depletion, USP25 inhibitor treatment, xenograft tumor model The Journal of biological chemistry Medium 40473213
2026 USP25 interacts with RIPK1 and removes K63 ubiquitin chains from RIPK1 via its C178 active site, attenuating RIPK1-mediated NF-κB inflammatory signaling in macrophages and suppressing atherosclerosis. Mass spectrometry substrate identification, Co-immunoprecipitation, K63 ubiquitination assay (C178A mutation), macrophage-specific USP25 KO in ApoE-/- mice EBioMedicine Medium 41861519
2026 USP25 regulates LATS1 kinase activity by removing K63-linked ubiquitin at K688 of LATS1, disrupting LATS1-MOB1 complex formation and promoting YAP-mediated transcriptional activation in hepatocellular carcinoma; this is independent of LATS1 protein stability. Co-immunoprecipitation, K63-specific ubiquitination assay (K688 site), LATS1-MOB1 interaction assay, YAP activity assay, USP25 KO, cell-penetrating peptide disruption, PDX models EMBO reports Medium 41882191
2025 USP25 deubiquitinates cytosolic METTL3 by cleaving K48-linked polyubiquitin chains, preventing proteasomal degradation. This specifically stabilizes cytosolic (but not nuclear) METTL3 without affecting global m6A abundance, and USP25 promotes EGFR expression through cytosolic METTL3 in glioma cells. Co-immunoprecipitation, K48 ubiquitination assay, subcellular fractionation, m6A measurement, USP25 depletion, EGFR expression assay, clinical glioma sample analysis iScience Medium 41321637
2025 USP25 binds to and stabilizes PPARα by removing K48-linked ubiquitin chains at PPARα K429 via the H608 catalytic residue of USP25's USP domain, reducing lipid accumulation in hepatocytes and protecting against MASLD. Pulldown-LC-MS/MS substrate identification, Co-immunoprecipitation, site-specific mutagenesis (H608, K429), K48 ubiquitination assay, USP25 KO and hepatocyte-specific rescue, Ppara KO epistasis Cell death and differentiation High 39827322
2026 USP25 mediates deubiquitination of talin-1 to stabilize it in platelets, promoting platelet hyperreactivity. USP25 deficiency impairs platelet function and delays arterial thrombus formation; pharmacological USP25/28 inhibition (AZ1) suppresses age-dependent platelet hyperactivity. Ubiquitin-modified proteomics, mass spectrometry, USP25 KO mouse platelet functional assays, pharmacological inhibition with AZ1, arterial thrombosis model Blood Medium 40997299
2017 NMR solution structure of the USP25 N-terminal ubiquitin-binding region (aa 1-146) was determined; key residues for recognition of ubiquitin and SUMO2 were identified. Non-covalent SUMO2 binding to the SUMO-interacting motif of USP25 inhibits its catalytic activity and competitively blocks interaction of the UBR with ubiquitin substrates. NMR structure determination, binding assays, catalytic activity assay with SUMO2 binding Biophysical journal High 28538147
2024 Crystal structures of USP25 and USP28 in the presence of inhibitors (AZ1, Vismodegib, FT206) revealed a common inhibitor-binding pocket. A glutamate residue at position 373 in USP25 (366 in USP28) plays a central structural role for pocket stability and for inhibitor binding and enzymatic activity. X-ray crystallography of USP28/USP25 with inhibitors, site-directed mutagenesis of E373/E366, enzymatic activity assays EMBO reports High 38816515
2023 USP25 interacts with TRIM21 E3 ligase via co-immunoprecipitation and mass spectrometry; USP25 regulates the Wnt/β-catenin pathway and EMT-related proteins through this interaction to promote HCC cell proliferation, migration, and invasion. Mass spectrometry, Co-immunoprecipitation, USP25 overexpression/knockdown in HCC cells, mouse liver cancer KO model, Wnt pathway protein analysis Chinese medical journal Medium 37439386
2023 USP25 interacts with MDM2 via Co-immunoprecipitation and maintains MDM2 protein stability through deubiquitination (C178A mutation abolishes this). USP25 promotes DLBCL progression by stabilizing MDM2 and consequently decreasing p53 expression via the MDM2-p53 signaling pathway. Co-immunoprecipitation, deubiquitination assay, C178A USP25 mutant, p53/MDM2 pathway analysis, in vitro and in vivo tumor models Biochemical and biophysical research communications Medium 37480689
2025 USP25 deubiquitinates SMAD7 to stabilize it in podocytes; ADSC-derived exosomes transfer USP25 protein to podocytes, elevating SMAD7 levels and protecting against diabetic nephropathy-induced apoptosis and inflammation. Exosome transfer assay, Co-immunoprecipitation, cellular ubiquitination assay, in vitro and in vivo DN models Chemical biology & drug design Medium 40317686
2024 USP25 prevents ubiquitination and degradation of RAC1, maintaining RAC1 protein levels. Reduced USP25 in IgG4-RD leads to RAC1 ubiquitination/degradation, decreased aldolase A release from the actin cytoskeleton, and reduced glycolysis. Additionally, LYN expression is reduced in USP25-deficient B cells. USP25 KO mice, ubiquitination assay for RAC1, aldolase A fractionation from actin cytoskeleton, glycolysis assay, IgG4-RD patient PBMCs Nature communications Medium 38521787
2026 USP25 interacts with TRAF6 and stabilizes its protein level by reducing TRAF6 ubiquitination in severe acute pancreatitis; USP25 inhibition alleviates pancreatic microcirculatory disturbance in SAP rats. Co-immunoprecipitation, TRAF6 ubiquitination assay with MG132, sh-USP25 adenoviral delivery, SAP rat model Scientific reports Medium 41771990
2026 USP25 binds to and stabilizes PARP1 through deubiquitination; PARP1 in turn facilitates preadipocyte differentiation by regulating ELOVL3 (elongation of very long-chain fatty acids protein 3), establishing a USP25-PARP1-ELOVL3 axis in adipogenesis. Co-immunoprecipitation, deubiquitination assay, RNA-seq, USP25 KO mice on HFD, 3T3-L1 differentiation assay Journal of lipid research Medium 41692245
2023 USP25 overexpression impairs cell cycle regulation during embryonic neurogenesis by altering the cyclin D1/cyclin D2 balance, promoting neural stem cell-to-glial fates over neuronal fates in hippocampus and suppressing neurogenesis. USP25-Tg mice, embryonic neurogenesis analysis, cyclin D1/D2 expression, hippocampal NSC fate assays, behavioral testing FASEB journal Medium 37171286
2024 USP25 deficiency in T cells causes impaired mitochondrial mass and cristae condensation. USP25 interacts with ATP5A and ATP5B mitochondrial ATP synthase subunits to promote their stability, and this contributes to mitochondrial homeostasis and T cell functional competence. MHC-mismatched transplant models with USP25 KO mice, Co-IP of USP25 with ATP5A/ATP5B, Western blotting, mitochondrial morphology analysis International immunopharmacology Medium 36822087

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nature immunology 174 23042150
2015 Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6. Proceedings of the National Academy of Sciences of the United States of America 117 26305951
2023 USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes. Circulation research 112 36722348
2022 USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nature communications 93 35440539
2019 The miR-27a-3p/USP25 axis participates in the pathogenesis of recurrent miscarriage by inhibiting trophoblast migration and invasion. Journal of cellular physiology 74 30953360
2021 Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer's brains is mediated by USP25. Science advances 71 33523861
2017 Identification and Characterization of Dual Inhibitors of the USP25/28 Deubiquitinating Enzyme Subfamily. ACS chemical biology 71 29131570
2017 USP25 regulates Wnt signaling by controlling the stability of tankyrases. Genes & development 63 28619731
2021 USP25 Regulates the Proliferation and Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome by Modulating the PI3K/AKT Pathway via Deubiquitinating PTEN. Frontiers in cell and developmental biology 61 34805185
2009 The UBA-UIM domains of the USP25 regulate the enzyme ubiquitination state and modulate substrate recognition. PloS one 61 19440361
2022 USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation. The Journal of clinical investigation 58 35229730
2019 Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity. Molecular cell 58 30926242
2023 USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. Nature communications 56 37339955
2001 Characterization of alternatively spliced products and tissue-specific isoforms of USP28 and USP25. Genome biology 55 11597335
1999 USP25, a novel gene encoding a deubiquitinating enzyme, is located in the gene-poor region 21q11.2. Genomics 54 10644437
2019 Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities. Molecular cell 52 30926243
2006 The ubiquitin-specific protease USP25 interacts with three sarcomeric proteins. Cellular and molecular life sciences : CMLS 47 16501887
2023 USP25 Inhibits Neuroinflammatory Responses After Cerebral Ischemic Stroke by Deubiquitinating TAB2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 38 37587766
2016 The Type I Interferon-IRF7 Axis Mediates Transcriptional Expression of Usp25 Gene. The Journal of biological chemistry 37 27129230
2020 Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells. Oncogene 36 32203161
2022 USP25 Deficiency Exacerbates Acute Pancreatitis via Up-Regulating TBK1-NF-κB Signaling in Macrophages. Cellular and molecular gastroenterology and hepatology 32 35934222
2020 USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines. The FEBS journal 32 32578360
2018 A quaternary tetramer assembly inhibits the deubiquitinating activity of USP25. Nature communications 29 30478318
2015 Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25. Molecular and cellular biology 27 25755282
2023 USP25 promotes hepatocellular carcinoma progression by interacting with TRIM21 via the Wnt/β-catenin signaling pathway. Chinese medical journal 26 37439386
2023 USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses. International immunopharmacology 23 37657242
2018 LPS promotes HBO1 stability via USP25 to modulate inflammatory gene transcription in THP-1 cells. Biochimica et biophysica acta. Gene regulatory mechanisms 23 30745998
2023 USP25-PKM2-glycolysis axis contributes to ischemia reperfusion-induced acute kidney injury by promoting M1-like macrophage polarization and proinflammatory response. Clinical immunology (Orlando, Fla.) 22 36894047
2019 The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes. Scientific reports 21 30886164
2019 Cigarette smoke extract modulates Pseudomonas aeruginosa bacterial load via USP25/HDAC11 axis in lung epithelial cells. American journal of physiology. Lung cellular and molecular physiology 20 31746627
2018 USP25 promotes endotoxin tolerance via suppressing K48-linked ubiquitination and degradation of TRAF3 in Kupffer cells. Molecular immunology 20 30579117
2023 USP25 inhibits renal fibrosis by regulating TGFβ-SMAD signaling pathway in Ang II-induced hypertensive mice. Biochimica et biophysica acta. Molecular basis of disease 19 37059312
2024 Heterozygous variants in USP25 cause genetic generalized epilepsy. Brain : a journal of neurology 16 38875478
2018 Smurf1 restricts the antiviral function mediated by USP25 through promoting its ubiquitination and degradation. Biochemical and biophysical research communications 16 29518389
2025 USP25 stabilizes STAT6 to promote IL-4-induced macrophage M2 polarization and fibrosis. International journal of biological sciences 15 39781451
2024 Deubiquitinase USP25 Alleviates Obesity-Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation. JACC. Basic to translational science 13 39619140
2016 Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25. Canadian journal of physiology and pharmacology 13 28134560
2024 USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 38803048
2024 Structural basis for the bi-specificity of USP25 and USP28 inhibitors. EMBO reports 12 38816515
2023 USP25 contributes to defective neurogenesis and cognitive impairments. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 37171286
2022 USP25 UPREGULATION BOOSTS GSDMD -MEDIATED PYROPTOSIS OF ACINAR CELLS IN ACUTE PANCREATITIS. Shock (Augusta, Ga.) 12 36155610
2020 USP25 Regulates EGFR Fate by Modulating EGF-Induced Ubiquitylation Dynamics. Biomolecules 12 33202887
2024 Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease. Nature communications 11 38521787
2023 USP25 deficiency promotes T cell dysfunction and transplant acceptance via mitochondrial dynamics. International immunopharmacology 10 36822087
2025 USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice. Cell death and differentiation 9 39827322
2023 A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer. Acta pharmaceutica Sinica. B 9 38261825
2013 ¹H, ¹³C and ¹⁵N backbone and side-chain resonance assignments of the N-terminal ubiquitin-binding domains of USP25. Biomolecular NMR assignments 9 23754700
2017 Structural and Functional Investigations of the N-Terminal Ubiquitin Binding Region of Usp25. Biophysical journal 7 28538147
2025 The Transfer of USP25 by Exosomes of Adipose Tissue-Derived Mesenchymal Stem Cells Ameliorates Diabetic Nephropathy Through Stabilizing SMAD7 Expression. Chemical biology & drug design 6 40317686
2024 A New Modulator of Neuroinflammation in Diabetic Retinopathy: USP25. Inflammation 6 38436811
2022 USP25 Expression in Peripheral Blood Mononuclear Cells Is Associated With Bone Mineral Density in Women. Frontiers in cell and developmental biology 6 35141233
2025 Ophiopogonin D from Ophiopogon japonicas-induced USP25 Activity to Reduce Ferroptosis of Macrophage in Acute Lung Injury by the Inhibition of Bound Rac1 and Nox1 Complex. The American journal of Chinese medicine 5 40099394
2022 USP25 inhibits DNA damage by stabilizing BARD1 protein in a house dust mite-induced asthmatic model in vitro and in vivo. Cell biology international 5 35143098
2022 Deubiquitination of TNKS1 Regulates Wnt/β-Catenin to Affect the Expression of USP25 to Promote the Progression of Glioma. Disease markers 5 35450028
2025 Engineered MEVs for photoreceptor-targeted delivery of USP25 to alleviate diabetic retinopathy. Journal of nanobiotechnology 4 40830790
2025 USP25 Promotes the Antimycobacterial Response of Macrophages Through Stabilizing B-Raf and C-Raf. The Journal of infectious diseases 3 39110031
2025 Tim-3 promotes viral infection by suppressing the USP25-TRAF3-IRF7 signaling pathway. Cellular immunology 3 39946759
2025 Effects of USP25 knockout on the gut microbial diversity and composition in mice. BMC microbiology 3 40405076
2023 Regulation of USP25 by SP1 Associates with Amyloidogenesis. Journal of Alzheimer's disease : JAD 3 36938736
2023 Upregulation of USP25 promotes progression of human diffuse large B-cell lymphoma through blocking the ubiquitinated degradation of MDM2. Biochemical and biophysical research communications 3 37480689
2022 Downregulation of deubiquitinating enzyme USP25 promotes the development of allergic rhinitis by enhancing TSLP signaling in the nasal epithelium. Molecular medicine reports 3 36177892
2025 KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31. Developmental cell 2 39952242
2024 USP25 attenuates anti-GBM nephritis in mice by negative feedback regulation of Th17 cell differentiation. Renal failure 2 38616174
2024 USP25 ameliorates vascular remodeling by deubiquitinating FOXO3 and promoting autophagic degradation of FOXO3. Acta pharmaceutica Sinica. B 2 40370563
2026 USP25-mediated talin-1 stabilization in platelets: a novel mechanism of hyperreactivity and thrombosis risk during aging. Blood 1 40997299
2026 USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses. EBioMedicine 1 41861519
2025 USP25 maintains KRAS expression and inhibiting the deubiquitinase suppresses KRAS signaling in human cancer. The Journal of biological chemistry 1 40473213
2022 A Novel USP25::PDGFRA Gene Fusion in a 78 Year Old Patient with a Myeloid Neoplasm. Laboratory medicine 1 35217871
2026 USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy. Proceedings of the National Academy of Sciences of the United States of America 0 41499392
2026 USP25 deficiency suppresses diet-induced obesity via ubiquitination and degradation of PARP1 and Elovl3 downregulation. Journal of lipid research 0 41692245
2026 Ophiopogonin D Reduced Ferroptosis of Skin Epithelial Cells to Thermal Injury by USP25/ TAB2. The international journal of lower extremity wounds 0 41729829
2026 The role and regulatory mechanism of USP25 in pancreatic microcirculatory disturbance in severe acute pancreatitis. Scientific reports 0 41771990
2026 USP25 aggravates liver cancer development and impairs chemosensitivity by limiting LATS1 activation. EMBO reports 0 41882191
2025 USP25-driven KIFC1 regulates MYCBP expression and promotes the progression of cervical cancer. Cell death & disease 0 40379626
2025 USP25 deubiquitinates cytosolic METTL3 to impede glioma proliferation via an m6A-independent pathway. iScience 0 41321637
2025 USP25 attenuates the immunosuppressive tumor microenvironment via the deubiquitination of TAB2 in head and neck squamous cell carcinoma. Cell death discovery 0 41326342

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