Affinage

UCHL3

Ubiquitin carboxyl-terminal hydrolase isozyme L3 · UniProt P15374

Length
230 aa
Mass
26.2 kDa
Annotated
2026-06-10
85 papers in source corpus 45 papers cited in narrative 44 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

UCHL3 is a papain-like cysteine deubiquitylase whose active site is built on a Cys95-His169-Asp184 catalytic triad with an oxyanion-hole glutamine (Gln89), and which hydrolyzes the C-terminus of both ubiquitin and the ubiquitin-like protein NEDD8, distinguishing it from its paralog UCHL1 (PMID:9233788, PMID:9790970). Substrate access is governed by an active-site crossover loop that sterically restricts cleavage of bulky polyubiquitin adducts, such that wild-type UCHL3 favors small ubiquitin substrates while loop enlargement confers gain-of-function polyubiquitin chain cleavage (PMID:15531586, PMID:19047059); this gating is modulated by phosphorylation at Ser75, which enhances activity and permits cleavage of K48-linked tetra-ubiquitin, and by allosteric inhibition from non-covalently bound K48-linked ubiquitin dimers (PMID:36142702, PMID:19154770). The dominant cellular function emerging from the corpus is substrate stabilization: UCHL3 removes K48-linked degradative ubiquitin chains from a broad panel of client proteins, protecting them from proteasomal turnover in a catalysis-dependent manner. Through this activity UCHL3 stabilizes DNA-repair factors including TDP1, Ku80, and RAD51 to support topoisomerase-lesion repair, non-homologous end joining, and homologous recombination (PMID:29898404, PMID:30559450, PMID:31113933). The same deubiquitylase logic drives its role in cancer, where it stabilizes oncogenic clients such as AhR, YAP, FOXM1, β-catenin/CTNNB1, ENO1, and TRAF2 to sustain proliferation, stemness, and survival signaling (PMID:32546741, PMID:32738097, PMID:36813921, PMID:38092274, PMID:37740194, PMID:41271634). UCHL3 also regulates physiological homeostasis across tissues, controlling ENaC recycling in renal epithelium, meiotic spindle function in oocytes, and neuronal maintenance, where loss in mice causes axonal and dorsal root ganglia degeneration and accumulation of polyubiquitinated proteins (PMID:17967898, PMID:21751213, PMID:21678411, PMID:11555633, PMID:20380862). Its activity is itself redox-sensitive, being impaired by oxidation of catalytic cysteine (PMID:21762696).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Established the structural and catalytic basis of UCHL3 as a cysteine protease, defining the active-site architecture before any substrate was known.

    Evidence X-ray crystallography of human UCH-L3 at 1.8 Å resolving the Cys95-His169-Asp184 triad and a masked active-site cleft

    PMID:9233788

    Open questions at the time
    • Unliganded structure did not capture the substrate-bound conformation
    • Did not define physiological substrates
  2. 1998 High

    Showed UCHL3 is a dual-specificity C-terminal hydrolase for ubiquitin and NEDD8, distinguishing it functionally from UCHL1.

    Evidence Yeast two-hybrid, GST pull-down, and in vitro cleavage assay with recombinant enzyme

    PMID:9790970

    Open questions at the time
    • Did not establish cellular NEDD8 substrates
    • In vitro context only
  3. 2004 High

    Confirmed the catalytic mechanism with a covalent ubiquitin-suicide-substrate complex and revealed the active-site crossover loop plus tolerance for sizable leaving groups.

    Evidence X-ray crystallography at 1.45 Å of the ubiquitin-vinylmethylester adduct with in vitro isopeptide hydrolysis

    PMID:15531586

    Open questions at the time
    • Did not address chain-linkage selectivity in cells
  4. 2008 High

    Defined the crossover loop as the determinant restricting polyubiquitin chain cleavage, explaining why wild-type UCHL3 prefers small substrates.

    Evidence Sortagging-based cleavage assays with crossover-loop mutagenesis and in vitro DUB activity tests

    PMID:19047059

    Open questions at the time
    • Loop dynamics in the presence of physiological substrates not resolved
  5. 2008 Medium

    Identified an allosteric brake: K48-linked ubiquitin dimers inhibit UCHL3 specifically, providing a feedback mechanism on its activity.

    Evidence In vitro binding, cell-based Co-IP, and enzymatic activity assays

    PMID:19154770

    Open questions at the time
    • Single lab; structural basis of the allosteric site not determined
    • In vivo relevance of dimer inhibition unestablished
  6. 2007 High

    Provided early in vivo function, showing UCHL3 controls ENaC deubiquitination and recycling in renal epithelium.

    Evidence Activity-based probe labeling, knockdown, surface biotinylation, and electrophysiology in CCD cells

    PMID:17967898

    Open questions at the time
    • Direct deubiquitylation of ENaC not reconstituted in vitro
  7. 2010 High

    Demonstrated genuine in vivo deubiquitinating function required for proteostasis, since catalytically active enzyme is needed to clear polyubiquitin accumulation.

    Evidence Uchl3-/- mice, MEF rescue with wild-type vs catalytic/ubiquitin-binding mutants, and in vitro DUB assay

    PMID:20380862

    Open questions at the time
    • Individual physiological substrates in muscle not identified
  8. 2006 Medium

    Linked UCHL3 loss to tissue-specific degeneration, implicating it in protection against oxidative-stress-driven apoptosis.

    Evidence Knockout mouse retina with IHC, EM, and apoptosis-marker westerns

    PMID:16816367

    Open questions at the time
    • Mechanistic substrate linking UCHL3 to mitochondrial stress not defined
  9. 2018 High

    Initiated the substrate-stabilization paradigm by showing UCHL3 deubiquitylates DNA-repair factors to control their proteostasis and the DNA damage response.

    Evidence Reciprocal gain/loss-of-function with catalytic mutant controls, ubiquitylation assays, and TOP1-poison/NHEJ readouts for TDP1 and Ku80

    PMID:29898404 PMID:30559450

    Open questions at the time
    • Direct cellular E3 ligases opposing UCHL3 on these substrates not fully mapped
  10. 2019 Medium

    Extended UCHL3 to homologous recombination and to oncogenic client stabilization, framing it as a druggable cancer dependency.

    Evidence In vitro DUB and ubiquitination assays, Co-IP, HR/NF-κB reporters and xenografts for RAD51, TRAF2, FOXM1, and LSH

    PMID:31113933 PMID:31417184 PMID:31477831 PMID:31598398

    Open questions at the time
    • Most are single-lab studies
    • Direct vs indirect deubiquitylation not uniformly distinguished
  11. 2022 Medium

    Showed that Ser75 phosphorylation reprograms chain-length preference, providing a regulatory switch enabling K48 tetra-ubiquitin cleavage.

    Evidence Phosphomimetic S75E modeling, crystal structure of the S75E-Ub-PA complex, and in vitro DUB assays on di/tri/tetra-ubiquitin

    PMID:36142702

    Open questions at the time
    • The physiological kinase for Ser75 not identified
    • Cellular consequences of S75 phosphorylation untested
  12. 2020 High

    Broadened UCHL3 substrates to mitotic and oncogenic regulators, reinforcing catalysis-dependent stabilization across pathways.

    Evidence Co-IP, DUB assays, catalytic-mutant controls, ChIP and localization for AhR and Aurora B

    PMID:32546741 PMID:32738097

    Open questions at the time
    • Aurora B finding is single-lab
    • Linkage specificity on each substrate not always defined
  13. 2023 Medium

    Identified small molecules that directly modulate UCHL3 (activator farrerol) and consolidated its broad oncogenic and tissue-homeostasis substrate network.

    Evidence Direct binding/activity assays with KO rescue (farrerol/RAD51) plus Co-IP/DUB assays for YAP, Vimentin, β-catenin, SMAD1, p300, with in vivo models

    PMID:36813921 PMID:36915132 PMID:36969045 PMID:37012254 PMID:37524875 PMID:38092274

    Open questions at the time
    • Many substrate studies are single-lab
    • Whether all clients are direct catalytic substrates not uniformly verified
  14. 2024 Medium

    Established site-specific deubiquitylation and upstream control of UCHL3, with K48-chain removal at defined substrate lysines and regulation of UCHL3 by phosphorylation and E3 ligases.

    Evidence Site-specific substrate mutagenesis (RIPK4-K469, SIPA1-K805), active-site mutants, and Co-IP across CTNNB1, POLD4, EEF1A1, RIPK4, SIPA1

    PMID:37740194 PMID:38664501 PMID:38829550 PMID:38965582 PMID:41412211

    Open questions at the time
    • Single-lab substrate studies
    • Integration of competing E3 ligases into a unified regulatory model incomplete
  15. 2025 Medium

    Expanded UCHL3 into metabolism, ferroptosis/cuproptosis, antiviral defense, and disease models, and identified selective peptide and small-molecule modulators.

    Evidence Active-site mutant (C95A) and site-specific assays for PKM2/ENO1, ubiquitination/autophagy assays for HMGB1/TFEB/TRPV1/PACRG/GOPC, sfRNA interactome capture, and RaPID peptide inhibitors

    PMID:38739798 PMID:40451468 PMID:40784473 PMID:40916238 PMID:41058558 PMID:41271634 PMID:41864857 PMID:42169250 PMID:42231789

    Open questions at the time
    • Mostly single-lab mechanistic claims
    • Direct vs scaffold roles in antiviral sfRNA protection not fully resolved
  16. 2026 Medium

    Linked UCHL3 activity to neurodegenerative proteostasis, showing its inhibition is neuroprotective in Huntington's disease models via enhanced autophagic clearance.

    Evidence Genetic and pharmacological loss-of-function in patient-derived neurons with aggregate and autophagy-flux readouts

    PMID:41578740

    Open questions at the time
    • Direct UCHL3 substrate controlling autophagosome-lysosome fusion not identified
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how UCHL3's intrinsic small-substrate preference is reconciled with its many reported K48-polyubiquitin substrate-stabilization events, and which cellular signals (kinases, redox, allosteric ligands) select among its dozens of clients in a given tissue.
  • No unified model of substrate selectivity
  • Crossover-loop gating vs in-cell polyubiquitin cleavage not reconciled
  • Endogenous regulators of chain-length switching incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 6 R-HSA-73894 DNA Repair 4 R-HSA-392499 Metabolism of proteins 2
Partners
AHRCTNNB1ENO1KU80RAD51TDP1TRAF2YAP

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Crystal structure of human UCH-L3 at 1.8 Å resolution revealed a papain-like cysteine protease fold with catalytic triad Cys95, His169, Asp184 and oxyanion hole residue Gln89. The active site cleft is masked by two segments (residues 9-12 and 90-94) in the unliganded structure, implying a conformational change upon substrate binding. X-ray crystallography The EMBO journal High 9233788
2004 Crystal structure of human UCH-L3 in complex with ubiquitin vinylmethylester (a suicide substrate) at 1.45 Å resolution confirmed the catalytic mechanism and revealed an active site crossover loop. UCH-L3 efficiently hydrolyzed a 13-residue peptide in isopeptide linkage with ubiquitin, demonstrating flexibility in substrate size acceptance. X-ray crystallography (1.45 Å), in vitro hydrolysis assay The Journal of biological chemistry High 15531586
1998 UCH-L3 binds NEDD8 (as well as ubiquitin) and cleaves the C-terminus of NEDD8 in vitro, functioning as a C-terminal hydrolase for both ubiquitin and the ubiquitin-like protein NEDD8. UCH-L1 did not show this NEDD8 cleavage activity. Yeast two-hybrid, GST pull-down, in vitro cleavage assay with recombinant UCH-L3 Biochemical and biophysical research communications High 9790970
1999 NMR and site-directed mutagenesis identified the binding site on ubiquitin for UCH-L3: basic residues K6, K11, R72, and R74 on ubiquitin contact acidic residues E10, E14, D33, E219 on UCH-L3. Solution NMR, site-directed mutagenesis, X-ray crystallography-based modeling Journal of molecular biology High 10518943
2007 UCH-L3 is the predominant active deubiquitinating enzyme in endosomal compartments of cortical collecting duct (CCD) epithelial cells. Blocking UCH-L3 activity or knockdown increased ENaC ubiquitination, removed ENaC from apical membranes, and reduced transepithelial Na+ currents, establishing UCH-L3 as a regulator of ENaC recycling. Activity-based chemical probe labeling, selective knockdown, surface biotinylation, whole-cell immunoprecipitation, electrophysiology The Journal of biological chemistry High 17967898
2008 The active site crossover loop of UCH-L3 restricts access of bulky ubiquitin adducts to the active site. Physical integrity of the crossover loop is dispensable for catalysis per se, but enlarging it by mutation creates gain-of-function variants capable of cleaving polyubiquitin chains of various linkages that the wild-type enzyme cannot. Sortagging protein cleavage/tagging, active-site crossover loop mutagenesis, in vitro DUB activity assays The Journal of biological chemistry High 19047059
2001 Mice doubly homozygous for Uch-L1gad and Uch-L3Δ3-7 deletions show earlier lethality, dysphagia, and more severe axonal degeneration than either single mutant, demonstrating that UCH-L1 and UCH-L3 have both separate and overlapping (redundant) functions in neuronal maintenance. Uch-L3 single knockouts also show dorsal root ganglia degeneration. Genetic epistasis — double knockout mouse model, histological analysis Human molecular genetics High 11555633
2006 In Uchl3-deficient mice, UCH-L3 is normally enriched in photoreceptor inner segments. Loss of UCH-L3 leads to mitochondrial oxidative stress (increased MnSOD, cytochrome c oxidase I, AIF immunoreactivity) and caspase-independent photoreceptor apoptosis via endonuclease G nuclear translocation. Knockout mouse model, immunohistochemistry, electron microscopy, western blot for apoptosis markers The American journal of pathology Medium 16816367
2008 K48-linked ubiquitin dimers non-covalently interact with UCH-L3 in vitro and in cells, and these dimers potently inhibit UCH-L3 hydrolase activity; this regulatory interaction was not observed with UCH-L1, demonstrating a specific allosteric regulatory mechanism for UCH-L3. In vitro binding assay, cell-based co-immunoprecipitation, enzymatic activity assay Neurochemistry international Medium 19154770
2009 UCH-L3 can fold and unfold reversibly in vitro without molecular chaperones, despite possessing the most complex knotted (5₂) topology known. Folding proceeds through two hyperfluorescent intermediates with a slow phase limited by proline isomerization. In vitro folding/unfolding equilibrium and kinetic experiments, fluorescence spectroscopy The FEBS journal Medium 19476499
2010 Skeletal muscles of Uchl3-/- mice accumulate polyubiquitinated proteins and display ER stress and heat shock responses. Re-expression of wild-type but not hydrolase-inactive or ubiquitin-binding-deficient UCH-L3 rescued polyubiquitin accumulation in knockout MEFs, and wild-type UCH-L3 cleaved ubiquitin from polyubiquitinated lysozyme in vitro, confirming in vivo deubiquitinating function. Knockout mouse model, MEF rescue with wild-type vs. mutant UCH-L3, in vitro deubiquitination assay, western blot Neurochemistry international High 20380862
2011 UCH-L3 (and yeast ortholog YUH1) hydrolyzes the C-terminal extension of mutant ubiquitin UBB+1, yielding UB(G76Y); in vitro oxidation of recombinant UCH-L3 impairs its deubiquitinating activity, suggesting oxidative inactivation may contribute to UBB+1 accumulation in neurodegenerative disease. In vitro hydrolysis assay with recombinant enzyme, oxidation treatment of recombinant UCH-L3 FEBS letters Medium 21762696
2012 UCHL3 associates with the meiotic spindle in oocytes (distinct from UCHL1 at the cortex). Microinjection of anti-UCHL3 antibodies disrupted oocyte maturation, caused abnormally long meiotic spindles, and blocked fertilization, establishing UCHL3 as required for proper meiotic spindle function and oocyte maturation. Microinjection of antibodies/inhibitors into GV oocytes, live-cell imaging, spindle morphology analysis Journal of cellular physiology Medium 21678411 21751213
2018 UCHL3 deubiquitylates TDP1 (tyrosyl DNA phosphodiesterase 1), controlling its proteostasis. UCHL3 depletion increases TDP1 ubiquitylation and turnover, sensitizing cells to TOP1 poisons. Overexpression of catalytically active (but not inactive) UCHL3 suppresses TDP1 ubiquitylation. UCHL3 is downregulated in SCAN1, correlating with elevated TDP1 ubiquitylation. Knockdown and overexpression with catalytically inactive mutant controls, ubiquitylation assays, TOP1 poison sensitivity assays Cell reports High 29898404
2018 UCHL3 interacts with and directly deubiquitylates Ku80, promoting Ku80 retention at DNA double-strand break sites. UCHL3 depletion reduces Ku80 foci and chromatin binding after DSB induction and decreases NHEJ efficiency. DNA damage induces ATM-dependent phosphorylation of UCHL3 (which destabilizes UCHL3 but does not affect its catalytic activity). Co-immunoprecipitation, in vitro deubiquitylation assay, laser micro-irradiation/ChIP, NHEJ reporter assay, kinase inhibitor studies Scientific reports High 30559450
2019 UCHL3 deubiquitinates and stabilizes TRAF2 protein, activating NF-κB signaling to promote ovarian cancer tumorigenesis. Genetic ablation of UCHL3 blocked NF-κB activation and cancer cell proliferation/migration. Co-immunoprecipitation, in vitro deubiquitination assay, luciferase NF-κB reporter, knockdown/knockout, xenograft Oncogene Medium 31477831
2019 UCHL3 deubiquitinates and stabilizes FOXM1 in pancreatic cancer cells, promoting proliferation, migration, invasion, and gemcitabine resistance. UCHL3 knockdown increased FOXM1 ubiquitination and turnover. Co-immunoprecipitation, in vitro deubiquitination assay, cycloheximide chase, xenograft mouse model American journal of cancer research Medium 31598398
2019 UCHL3 deubiquitinates RAD51 to promote its recruitment to DNA damage sites and augment homologous recombination repair. Perifosine (an Akt inhibitor) inhibits UCHL3 deubiquitination activity at low dose, induces RAD51 ubiquitination, blocks RAD51-BRCA2 interaction, and reduces IRIF of RAD51. In vitro DUB assay, ubiquitination assay, Co-IP, IRIF foci analysis, HR reporter, xenograft Cell death & disease Medium 31113933
2019 UCHL3 deubiquitinates and stabilizes LSH (lymphoid-specific helicase chromatin remodeler) in non-small cell lung cancer cells; the lncRNA GIAT4RA counteracts this interaction by binding LSH and competing with UCHL3. Co-immunoprecipitation, ubiquitination assay, protein stability assay, knockdown/rescue Oncogene Medium 31417184
2020 UCHL3 interacts with, deubiquitylates, and stabilizes AhR (aryl hydrocarbon receptor) in NSCLC cells in a deubiquitylation activity-dependent manner, promoting stem-like gene expression (ABCG2, KLF4, c-Myc) and tumorigenic capacity. Co-immunoprecipitation, in vitro deubiquitylation assay, catalytic mutant controls, chromatin IP, knockdown/overexpression Signal transduction and targeted therapy High 32546741
2020 UCHL3 deubiquitylates Aurora B (catalytic subunit of the chromosome passenger complex) and promotes Aurora B localization to kinetochores during mitosis. Downregulation or inhibition of UCHL3 causes chromosome alignment defects and segregation errors during metaphase/anaphase. Co-immunoprecipitation, deubiquitylation assay, immunofluorescence for kinetochore localization, siRNA knockdown, UCHL3 inhibition FASEB journal Medium 32738097
2022 Structural modeling and in vitro biochemistry showed that phosphorylation of UCHL3 at Ser75 (mimicked by S75E mutation) enhances deubiquitinating activity toward Ub-AMC and enables cleavage of K48-linked tetra-ubiquitin chains, which the wild-type enzyme cannot cleave at lower chain lengths. Structural simulation of phosphomimetic UCHL3S75E, crystal structure of UCHL3S75E-Ub-PA complex, in vitro DUB activity assay with di/tri/tetra-ubiquitin chains International journal of molecular sciences Medium 36142702
2023 UCHL3 deubiquitylates and stabilizes YAP in anaplastic thyroid cancer cells in a deubiquitylation activity-dependent manner. YAP/TEAD4 in turn transcriptionally activates UCHL3 expression, forming a positive feedback loop. Co-immunoprecipitation, deubiquitylation assay, UCHL3 promoter analysis, ChIP, knockdown/rescue Cell death and differentiation Medium 36813921
2023 Mechanical force-stimulated macrophage-derived exosomes enriched in UCHL3 promote BMSC osteogenesis. Mechanistically, UCHL3 interacts with and stabilizes SMAD1 in BMSCs; UCHL3 inhibition downregulates SMAD1 and overexpression of SMAD1 rescues UCHL3-inhibition effects on osteogenesis. Proteomic analysis of exosomes, Co-immunoprecipitation, knockdown/rescue, in vivo orthodontic tooth movement model Journal of nanobiotechnology Medium 36915132
2023 UCHL3 interacts with and deubiquitylates p300, leading to transcriptional activation of chemokines Ccl2, Ccl7, Ccl12 cooperatively with C/EBPβ, promoting M2 macrophage polarization and pulmonary fibrosis in alveolar type II cells. Co-immunoprecipitation, deubiquitination assay, ATII cell-specific knockout, transcriptional analysis Experimental & molecular medicine Medium 37524875
2023 Farrerol directly activates UCHL3 deubiquitinase activity, enhancing RAD51 deubiquitination and promoting homologous recombination repair. UCHL3 ablation significantly attenuates farrerol-mediated HR stimulation, identifying UCHL3 as the direct target of farrerol. Direct binding assay, in vitro DUB activity assay, HR reporter, UCHL3 knockout rescue experiment Nature communications High 37012254
2023 UCHL3 interacts with and deubiquitylates Vimentin (via K48-linked chains), enhancing its stability and promoting HCC cell migration; siRNA or TCID inhibitor-mediated suppression of UCHL3 upregulated ubiquitinated Vimentin. Co-immunoprecipitation, immunofluorescence, ubiquitination assay, siRNA knockdown, wound healing/Transwell assays Frontiers in oncology Medium 36969045
2023 UCHL3 interacts with and removes K48-linked poly-ubiquitin chains from β-catenin (ARM domain required), stabilizing β-catenin and activating Wnt/TCF target gene expression to promote HCC stem-like properties. UCHL3 depletion induces ferroptosis in HCC cells that is rescued by β-catenin overexpression. Co-immunoprecipitation, ubiquitination assay, TOP-luciferase reporter, domain mapping, knockdown/rescue Free radical biology & medicine Medium 38092274
2024 UCHL3 deubiquitylates POLD4 (DNA polymerase delta subunit 4) in glioma stem cells, stabilizing it and promoting proneural-to-mesenchymal transition and radiation resistance via maintenance of HR and NHEJ repair. Co-immunoprecipitation, GST pull-down, deubiquitylation assay, in vitro/in vivo radiation assays, xenograft Cellular and molecular life sciences Medium 38829550
2024 UCHL3 stabilizes CTNNB1 (β-catenin) through deubiquitination, activating Wnt signaling in bladder cancer in a deubiquitylation activity-dependent manner. Uchl3-deficient mice are less susceptible to bladder tumorigenesis. CRISPR-Cas9 knockout/overexpression, Co-IP, RNA-seq, dual-luciferase Wnt reporter, conditional knockout mice Journal of translational medicine Medium 37740194
2024 UCHL3 deubiquitinates RIPK4 at the K469 site, removing K48-linked ubiquitin chains and stabilizing RIPK4. GSK3β-mediated phosphorylation of RIPK4 at Ser420 enhances its interaction with UCHL3, facilitating further deubiquitination and stabilization to promote ovarian cancer metastasis. Co-immunoprecipitation, ubiquitination assay, site-specific mutagenesis (K469, S420), TCID inhibitor treatment Oncogene Medium 38664501
2024 UCHL3 directly binds EEF1A1 at its lysine site and reduces EEF1A1 ubiquitination, stabilizing it; the UCHL3/EEF1A1 axis promotes HCC migration, stemness, and drug resistance. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, immunofluorescence, xenograft Biology direct Medium 38965582
2024 Chemically constrained peptides identified by RaPID mRNA display bind PfUCHL3 with nanomolar affinity and selectively inhibit its deubiquitinase activity versus human UCHL3. NMR spectroscopy showed the peptides block ubiquitin substrate binding rather than occupying the active site. mRNA display (RaPID), NMR spectroscopy, in vitro DUB activity assay, selectivity profiling Proceedings of the National Academy of Sciences High 38739798
2025 UCHL3 removes K48-linked polyubiquitin chains from SIPA1 at lysine 805, protecting it from proteasomal degradation; ITCH E3 ligase antagonistically promotes SIPA1 ubiquitination. TRIM21 post-translationally targets UCHL3 for proteasomal degradation. Co-immunoprecipitation, ubiquitination assay, site-specific mutagenesis (K805), knockdown/rescue Cancer letters Medium 41412211
2025 UCHL3 deubiquitinates and stabilizes PKM2 at K206 (C95A active-site mutant cannot do so), promoting pyruvate biosynthesis and augmenting cuproptosis in hepatocellular carcinoma. siRNA library screen, Co-IP, active-site mutagenesis (C95A), ubiquitinome profiling, site-specific mutagenesis (K206R), in vitro and in vivo cuproptosis assays Free radical biology & medicine Medium 40451468
2025 UCHL3 binds PACRG and stabilizes it via deubiquitination; DNAH10 exerts a bridging effect that enhances UCHL3-PACRG complex interaction to facilitate manchette function during spermiogenesis. Co-immunoprecipitation, deubiquitination assay, knockout mouse/cell models, localization studies Development Medium 41058558
2025 MC-LR directly binds the catalytic domain of UCHL3, blocking its interaction with GOPC and inhibiting its enzymatic activity, leading to excessive GOPC ubiquitination and proteasomal degradation, disrupting acrosome biogenesis. Direct binding assay, ubiquitination assay, proteasomal degradation assay, knockdown Environmental pollution Medium 40784473
2025 UCHL3 deubiquitinates and stabilizes HMGB1 by cleaving Lys48-linked polyubiquitin chains, promoting cytoplasmic HMGB1 accumulation, NCOA4-mediated ferritinophagy, and ferroptosis in nucleus pulposus cells. Co-immunoprecipitation, ubiquitination assay, transcriptomics, siRNA knockdown, in vivo disc degeneration model Autophagy Medium 42169250
2025 UCHL3 deubiquitinates TFEB, preventing its proteasomal degradation. DOX suppresses TFEB via UCHL3 downregulation, and 20-DOI counteracts DIC by restoring autophagic flux through UCHL3-mediated TFEB deubiquitination. Co-immunoprecipitation, siRNA knockdown, western blot, autophagic flux assays, in vivo MI/R model Phytomedicine Medium 40916238
2025 Redox regulation: in S. cerevisiae, accumulated ROS during the diauxic shift inactivate Yuh1 (UCHL3 ortholog) via a thiol-based redox switch, reducing NEDD8/Rub1 maturation and affecting mitochondrial integrity. Yeast genetic model, redox biochemistry, mitochondrial function assays Redox biology Medium 40347692
2025 UCHL3 is activated upon flavivirus (ZIKV/DENV) infection; catalytically inactive UCHL3 C95A fails to rescue viral replication in UCHL3-KO cells. UCHL3 physically associates with sfRNA complexes and its loss accelerates RNase L-dependent sfRNA degradation from P-bodies to RLBs. CRISPR-Cas9 KO, reconstitution with WT vs. C95A mutant, proximity-biotinylation sfRNA-interactome capture, RNase L knockdown epistasis Advanced science Medium 42231789
2025 c/EBPβ transcriptionally upregulates Uchl3; UCHL3 then deubiquitinates TRPV1 and inhibits its proteasomal degradation in dorsal root ganglion neurons, stabilizing TRPV1 and promoting mitochondrial fission and neuropathic pain. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, luciferase assay, ChIP, CCI rat model with intrathecal siRNA Neuropharmacology Medium 41864857
2025 UCHL3 deubiquitinates and stabilizes ENO1 by removing K48-linked polyubiquitin chains at lysine 92; a C95A point mutation abolishes this activity. ENO1 stabilization activates the AKT/CCND1 pathway to drive gastric cancer progression. Co-immunoprecipitation, GST pull-down, site-specific mutagenesis (C95A, K92), cycloheximide chase, ubiquitination assay, molecular docking, PDX model Cell death & disease High 41271634
2026 Genetic lowering of UCHL3 in Huntington's disease neuronal models (primary mouse neurons, patient fibroblasts, patient-derived medium spiny neurons) decreased polyQ aggregates and increased autophagosome-lysosome fusion, accompanied by STAT3 induction. A small-molecule UCHL3 inhibitor recapitulated these neuroprotective effects. siRNA/genetic knockdown, small-molecule inhibitor treatment, autophagy flux assays, aggregate quantification in patient-derived neurons Brain Medium 41578740

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8 A resolution. The EMBO journal 217 9233788
2004 Structure of the ubiquitin hydrolase UCH-L3 complexed with a suicide substrate. The Journal of biological chemistry 166 15531586
1998 Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochemical and biophysical research communications 137 9790970
2007 The deubiquitinating enzyme UCH-L3 regulates the apical membrane recycling of the epithelial sodium channel. The Journal of biological chemistry 87 17967898
2001 Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Human molecular genetics 81 11555633
2007 Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution. Cellular microbiology 78 17371404
2020 The deubiquitylase UCHL3 maintains cancer stem-like properties by stabilizing the aryl hydrocarbon receptor. Signal transduction and targeted therapy 77 32546741
2000 Expression and functional analysis of Uch-L3 during mouse development. Molecular and cellular biology 65 10713173
2003 An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina. Human molecular genetics 62 12761045
2005 Ubiquitin C-terminal hydrolase L3 (Uchl3) is involved in working memory. Hippocampus 56 15884048
2019 UCHL3 promotes ovarian cancer progression by stabilizing TRAF2 to activate the NF-κB pathway. Oncogene 54 31477831
2008 Substrate filtering by the active site crossover loop in UCHL3 revealed by sortagging and gain-of-function mutations. The Journal of biological chemistry 54 19047059
2006 Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice. The American journal of pathology 54 16816367
2009 Characterization and structural studies of the Plasmodium falciparum ubiquitin and Nedd8 hydrolase UCHL3. The Journal of biological chemistry 53 20042598
2019 UCHL3 promotes pancreatic cancer progression and chemo-resistance through FOXM1 stabilization. American journal of cancer research 52 31598398
2012 Essential role of ubiquitin C-terminal hydrolases UCHL1 and UCHL3 in mammalian oocyte maturation. Journal of cellular physiology 52 21751213
2018 UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis. Cell reports 51 29898404
2012 Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development. Journal of cellular physiology 51 21678411
2009 Untangling the folding mechanism of the 5(2)-knotted protein UCH-L3. The FEBS journal 50 19476499
2023 The deubiquitinating enzyme UCHL3 promotes anaplastic thyroid cancer progression and metastasis through Hippo signaling pathway. Cell death and differentiation 49 36813921
2005 Synthesis and characterization of fluorescent ubiquitin derivatives as highly sensitive substrates for the deubiquitinating enzymes UCH-L3 and USP-2. Analytical biochemistry 47 15963938
2018 The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage. Scientific reports 46 30559450
2023 Mechanical force induces macrophage-derived exosomal UCHL3 promoting bone marrow mesenchymal stem cell osteogenesis by targeting SMAD1. Journal of nanobiotechnology 44 36915132
2019 GIAT4RA functions as a tumor suppressor in non-small cell lung cancer by counteracting Uchl3-mediated deubiquitination of LSH. Oncogene 42 31417184
2019 A novel UCHL3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair. Cell death & disease 41 31113933
2011 Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3). FEBS letters 40 21762696
1999 The binding site for UCH-L3 on ubiquitin: mutagenesis and NMR studies on the complex between ubiquitin and UCH-L3. Journal of molecular biology 33 10518943
2020 UCHL3 promotes proliferation of colorectal cancer cells by regulating SOX12 via AKT/mTOR signaling pathway. American journal of translational research 31 33194042
2008 Ubiquitin dimers control the hydrolase activity of UCH-L3. Neurochemistry international 28 19154770
2021 UCHL3 promotes aerobic glycolysis of pancreatic cancer through upregulating LDHA expression. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 26 33616859
2008 The hippocampal proteomic analysis of senescence-accelerated mouse: implications of Uchl3 and mitofilin in cognitive disorder and mitochondria dysfunction in SAMP8. Neurochemical research 26 18307031
2023 Farrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer. Nature communications 21 37012254
2022 LINC00665 knockdown confers sensitivity in irradiated non-small cell lung cancer cells through the miR-582-5p/UCHL3/AhR axis. Journal of translational medicine 21 35918714
2010 Skeletal muscles of Uchl3 knockout mice show polyubiquitinated protein accumulation and stress responses. Neurochemistry international 21 20380862
2023 UCHL3 inhibits ferroptosis by stabilizing β-catenin and maintains stem-like properties of hepatocellular carcinoma cells. Free radical biology & medicine 19 38092274
2021 UCH-L1 and UCH-L3 regulate the cancer stem cell-like properties through PI3 K/Akt signaling pathway in prostate cancer cells. Animal cells and systems 18 34745437
2023 The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis. Experimental & molecular medicine 17 37524875
2021 UCH-L3 structure and function: Insights about a promising drug target. European journal of medicinal chemistry 16 34752952
2001 Cloning, expression, and mapping of a mouse gene, Uchl4, highly homologous to human and mouse Uchl3. Biochemical and biophysical research communications 16 11341770
2023 UCHL3 promotes hepatocellular carcinoma cell migration by de-ubiquitinating and stabilizing Vimentin. Frontiers in oncology 15 36969045
2021 Silencing UCHL3 enhances radio-sensitivity of non-small cell lung cancer cells by inhibiting DNA repair. Aging 15 34016790
2023 Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression. Journal of translational medicine 14 37740194
2025 Targeting the JAK2-STAT3-UCHL3-ENO1 axis suppresses glycolysis and enhances the sensitivity to 5-FU chemotherapy in TP53-mutant colorectal cancer. Acta pharmaceutica Sinica. B 13 40487654
2020 UCH-L3 promotes non-small cell lung cancer proliferation via accelerating cell cycle and inhibiting cell apoptosis. Biotechnology and applied biochemistry 11 32180254
2024 UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells. Cellular and molecular life sciences : CMLS 10 38829550
2024 UCHL3 promotes hepatocellular carcinoma progression by stabilizing EEF1A1 through deubiquitination. Biology direct 10 38965582
2022 Structural Insights into the Phosphorylation-Enhanced Deubiquitinating Activity of UCHL3 and Ubiquitin Chain Cleavage Preference Analysis. International journal of molecular sciences 10 36142702
2021 UCHL3 plays an important role in the occurrence and development of melanoma. Oncology letters 10 34539860
2023 Porphyromonas gingivalis induced UCHL3 to promote colon cancer progression. American journal of cancer research 9 38187053
2022 Knockdown of UCHL3 inhibits esophageal squamous cell carcinoma progression by reducing CRY2 methylation. Human cell 9 35088238
2022 UCHL3 promotes cervical cancer development and metastasis by stabilizing NRF2 via deubiquitination. Biochemical and biophysical research communications 9 36527747
2020 Deubiquitylase UCHL3 regulates bi-orientation and segregation of chromosomes during mitosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 32738097
2024 UCHL-3 as a potential biomarker of ovarian cancer. Gynecologic oncology 8 38266402
2007 Ubiquitin binds to a short peptide segment of hydrolase UCH-L3: a study by FCS, RIfS, ITC and NMR. Chembiochem : a European journal of chemical biology 7 17211910
1999 Molecular cloning of chick UCH-6 which shares high similarity with human UCH-L3: its unusual substrate specificity and tissue distribution. Biochemical and biophysical research communications 7 10527871
2025 The peptide from C- Phycocyanin alleviates myocardial ischemia-reperfusion injury by suppressing ferroptosis via upregulating UCHL3. Free radical biology & medicine 6 40451467
2024 CircMTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3. International journal of molecular sciences 6 38474064
2021 Friend or Foe: UCHL3 Mediated Carcinogenesis and Current Approaches in Small Molecule Inhibitors' Development. Current medicinal chemistry 6 34238144
2024 GSK3β and UCHL3 govern RIPK4 homeostasis via deubiquitination to enhance tumor metastasis in ovarian cancer. Oncogene 5 38664501
2024 Role of UCHL3 in health and disease. Biochemical and biophysical research communications 5 39226739
2020 Targeting homologous recombination (HR) repair mechanism for cancer treatment: discovery of new potential UCHL-3 inhibitors via virtual screening, molecular dynamics and binding mode analysis. Journal of biomolecular structure & dynamics 5 32851933
2008 cDNA cloning, sequence identification and tissue expression distribution of three novel porcine genes: UCHL3, RIT1 and CCND3. Molecular biology reports 5 18202904
2025 Morin induces autophagy-dependent ferroptosis in colorectal cancer cells by inhibiting the AURKB-UCHL3 interactions. Cellular signalling 4 40389047
2024 Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides. Proceedings of the National Academy of Sciences of the United States of America 4 38739798
2019 [UCH-L3 Expression in Epithelial Ovarian Cancer and Its Clinical Significance]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 4 31642235
2025 UCHL3 augments cuproptosis via PKM2 deubiquitination in hepatocellular carcinoma. Free radical biology & medicine 3 40451468
2025 UCHL3: a crucial deubiquitinase in DNA damage repair and tumor progression. Cancer cell international 3 40691601
2007 Backbone 1H, 13C, and 15N resonance assignments for the 26-kD human de-ubiquitinating enzyme UCH-L3. Biomolecular NMR assignments 3 19636824
2025 Investigation of UCHL3 and HNMT Gene Polymorphisms in Greek Patients with Type 2 Diabetes Mellitus and Diabetic Retinopathy. Biomedicines 1 40002753
2025 UCHL3-mediated proteasomal degradation of GOPC drives microcystin-LR-induced acrosomal dysgenesis. Environmental pollution (Barking, Essex : 1987) 1 40784473
2025 20-Deoxyingenol attenuated doxorubicin-induced cardiotoxicity by promoting autolysosome degradation through the UCHL3-TFEB pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 40916238
2025 A TRIM21-UCHL3-ITCH-SIPA1 axis promotes colorectal cancer growth and metastasis. Cancer letters 1 41412211
2024 Screening Traditional Chinese Medicine Compounds for Inhibiting UCHL3 Activity Based on Molecular Docking and Deubiquitinating Enzyme Probe Technology. Journal of visualized experiments : JoVE 1 39651760
2026 ACTG1 promotes breast cancer aggressiveness and confers ribociclib resistance by deubiquitinating HSPA8 through UCHL3. Cellular oncology (Dordrecht, Netherlands) 0 41492038
2026 Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease. Brain : a journal of neurology 0 41578740
2026 c/EBPβ-driven Uchl3-mediated deubiquitination of TRPV1 promotes neuropathic pain by inducing mitochondrial fission in male rats. Neuropharmacology 0 41864557
2026 UCHL3 Promotes Triple-Negative Breast Cancer Metastatic Potential Through Enhancing Cell Migration and Invasion. Applied biochemistry and biotechnology 0 41945287
2026 UCHL3 drives ferroptosis in nucleus pulposus cells by deubiquitinating HMGB1 to activate NCOA4-mediated ferritinophagy. Autophagy 0 42169250
2026 UCHL3 Regulates Subgenomic Flaviviral RNA Condensates to Promote Virus Propagation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42231789
2025 Redox-driven regulation of UCHL3/Yuh1 influences mitochondrial health via the NEDD8/Rub1 pathway. Redox biology 0 40347692
2025 Exploring the mechanism by which UCHL3 alleviates diabetic foot ulcers: FOXM1/NLRP3 inflammasome-mediated angiogenesis and endothelial cell pyroptosis. Journal of orthopaedic surgery and research 0 40394598
2025 UCHL3 regulates snail stability and promotes epithelial-mesenchymal transition in ovarian cancer. Cytotechnology 0 40689350
2025 DNAH10 interacts with UCHL3-PACRG complex to coordinate sperm head and flagella development during spermiogenesis. Development (Cambridge, England) 0 41058558
2025 UCHL3 depletion inhibits gastric cancer progression and enhances palbociclib sensitivity by regulating the AKT/CCND1 signaling axis via ENO1 ubiquitination. Cell death & disease 0 41271634
2018 [Autophagy and Expression of UCH-L3 Induced by Rapamycin in HL-60 Cells]. Zhongguo shi yan xue ye xue za zhi 0 30111405

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