Affinage

UCHL1

Ubiquitin carboxyl-terminal hydrolase isozyme L1 · UniProt P09936

Length
223 aa
Mass
24.8 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UCHL1 is a neuronally enriched cysteine deubiquitinase that maintains ubiquitin homeostasis and protects diverse substrates from proteasomal or lysosomal degradation, functioning broadly in neuronal survival, synaptic plasticity, receptor trafficking, metabolic regulation, and cell death signaling. Its catalytic activity at the active-site Cys90 cleaves ubiquitin from substrates including HIF-1α, EGFR, TrkB (at K460), TGFβRI/SMAD2, CD36, TAZ, POM121, AKT1, Sox17, and PFKFB3, while a second reactive cysteine (Cys152) serves as a sensor for cyclopentenone prostaglandin adduction that inactivates the enzyme and promotes its aggregation (PMID:30760601, PMID:33159930, PMID:25615526, PMID:32494592, PMID:28500221, PMID:26539913). UCHL1 is itself regulated by reversible monoubiquitination near the active site (with intramolecular auto-deubiquitination restoring activity), S-nitrosylation at multiple cysteines, and C-terminal farnesylation that directs a membrane-associated pool implicated in α-synuclein metabolism (PMID:17259170, PMID:28300150, PMID:19261853). Translation of UCHL1 is post-transcriptionally enhanced by a nuclear antisense lncRNA (AS Uchl1) that shuttles to the cytoplasm upon mTORC1 inhibition to load sense mRNA onto polysomes, while UCHL1 itself destabilizes mTORC1 by disrupting DDB1-CUL4-mediated raptor ubiquitination, creating a reciprocal regulatory circuit (PMID:23064229, PMID:23297343).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2006 High

    Establishing that UCHL1 is required for synaptic and cognitive function addressed the question of whether this abundant neuronal DUB has an active role beyond ubiquitin recycling, revealing a UCH-L1→PKA→CREB signaling axis that is disrupted by Aβ oligomers.

    Evidence TAT-UCHL1 protein transduction restored LTP in hippocampal slices and memory in APP/PS1 mice

    PMID:16923396

    Open questions at the time
    • Direct deubiquitination substrate linking UCHL1 to PKA-RIIα regulation was not identified
    • Whether UCHL1 enzymatic activity or scaffold function underlies the rescue was not resolved
  2. 2006 High

    Systematic kinetic analysis of UCHL1 versus UCHL3 defined how the UCH family achieves substrate selectivity despite sharing a common fold, identifying ubiquitin side chains critical for Michaelis complex formation.

    Evidence In vitro kinetics with ubiquitin-fusion substrates and mutant ubiquitins

    PMID:17144664

    Open questions at the time
    • Structural basis for the kinetic differences was not resolved at atomic level at this time
  3. 2007 High

    Discovery of reversible monoubiquitination as an auto-regulatory switch resolved how UCHL1 activity is toggled on and off, showing that monoubiquitin attachment near the active site blocks substrate access and that UCHL1 catalyzes its own deubiquitination.

    Evidence In vitro ubiquitination/deubiquitination assay with permanent ubiquitin-fusion mimics and active-site mutants

    PMID:17259170

    Open questions at the time
    • The E3 ligase(s) responsible for UCHL1 monoubiquitination were not identified
    • In vivo dynamics of this switch were not measured
  4. 2009 High

    Identification of a farnesylation-dependent membrane-associated pool of UCHL1 explained how a soluble DUB influences α-synuclein turnover at the ER/lysosome interface, linking a post-translational lipid modification to Parkinson's-relevant biology.

    Evidence Cell fractionation and farnesyltransferase inhibitor treatment in neuronal cells

    PMID:19261853

    Open questions at the time
    • Direct farnesylation site mapping was not performed
    • Whether membrane-associated UCHL1 retains DUB activity was unclear
  5. 2010 High

    Mapping CyPG adduction to Cys152 by NMR/MS established a molecular mechanism by which neuroinflammatory lipids inactivate UCHL1 and trigger its aggregation, directly connecting oxidative stress to loss of DUB function.

    Evidence NMR spectroscopy and tandem MS after 15d-PGJ2 treatment in vitro

    PMID:20231490

    Open questions at the time
    • In vivo relevance of Cys152 adduction in disease models was not yet tested
  6. 2011 High

    Structural characterization of PD-associated variants (S18Y, I93M) revealed that I93M exposes hydrophobic surface predisposing to aggregation while S18Y is structurally benign, providing a biophysical rationale for opposing disease-risk associations.

    Evidence Multi-technique structural analysis (NMR, CD, fluorescence, equilibrium unfolding)

    PMID:21251915

    Open questions at the time
    • Functional consequence of I93M on DUB activity toward specific substrates was not measured
  7. 2012 High

    Discovery that the antisense lncRNA AS Uchl1 post-transcriptionally boosts UCHL1 protein via mTOR-regulated nuclear-cytoplasmic shuttling introduced a new paradigm for translational regulation by embedded SINEB2 elements.

    Evidence Polysome fractionation, RNA fractionation, rapamycin treatment, SINEB2-deletion reporters

    PMID:23064229

    Open questions at the time
    • Generality of the SINEB2-dependent mechanism to other lncRNAs was not established
    • Direct RNA–ribosome interaction was not reconstituted
  8. 2013 High

    Demonstrating that UCHL1 destabilizes mTORC1 by disrupting DDB1-CUL4-mediated raptor ubiquitination positioned UCHL1 as a signaling node that reciprocally regulates mTORC1/mTORC2 balance, explaining secondary Akt activation.

    Evidence Reciprocal Co-IP, raptor ubiquitination assay, phosphorylation readouts, Uchl1 KO and transgenic mice

    PMID:23297343

    Open questions at the time
    • Whether UCHL1 directly deubiquitinates raptor or acts indirectly through the DDB1-CUL4 complex was not resolved
  9. 2015 High

    Genetic validation that UCHL1 stabilizes HIF-1α by counteracting VHL-mediated ubiquitination expanded UCHL1's role beyond the nervous system into hypoxia-driven tumor metastasis.

    Evidence Ubiquitination assays and murine pulmonary metastasis models with UCHL1 manipulation

    PMID:25615526

    Open questions at the time
    • Whether UCHL1 directly binds VHL or HIF-1α was not structurally resolved
  10. 2015 High

    C152A knock-in mice confirmed that Cys152 adduction by CyPGs is the in vivo mechanism of UCHL1 inactivation in neurons, validating the NMR/MS findings from 2010 in a genetic model.

    Evidence C152A knock-in primary neurons with CyPG treatment; viability, ubiquitin accumulation, and aggregation readouts

    PMID:26539913

    Open questions at the time
    • Whether Cys152 has an independent catalytic role beyond being a CyPG sensor was not yet tested
  11. 2017 High

    Identification of TrkB K460 as a direct deubiquitination site established UCHL1's role in maintaining surface receptor levels critical for BDNF signaling and hippocampal memory.

    Evidence Deubiquitination assay, K460R mutagenesis, TrkB surface trafficking, in vivo behavioral rescue with inhibitory peptide

    PMID:28500221

    Open questions at the time
    • Structural basis of UCHL1-TrkB recognition was not determined
  12. 2019 High

    C152A knock-in mice subjected to stroke demonstrated that preventing CyPG adduction at Cys152 preserves UCHL1 hydrolase function and protects neurons after ischemia, separating Cys152-dependent and Cys90-dependent activities in vivo.

    Evidence MCAO model in C152A knock-in mice with electrophysiology, ubiquitin-linkage analysis, and behavioral recovery

    PMID:30760601

    Open questions at the time
    • Cys152 hydrolase activity toward specific substrates was not reconstituted in vitro
  13. 2019 High

    Showing that UCHL1 deubiquitinates TGFβRI and SMAD2 to facilitate metastatic TGFβ signaling, and that UCHL1-enriched exosomes act in a paracrine manner, broadened the enzyme's oncogenic substrate repertoire and introduced an extracellular signaling dimension.

    Evidence Activity-based DUB profiling, ubiquitination assays, specific inhibitor 6RK73, zebrafish and murine xenograft models

    PMID:31857432

    Open questions at the time
    • Mechanism of UCHL1 loading into exosomes was not determined
  14. 2020 High

    Multiple concurrent studies expanded the substrate catalog to EGFR (cardiac hypertrophy and breast cancer), CD36 (foam cell formation), and Mfn2 (mitochondrial dynamics), establishing UCHL1 as a promiscuous DUB with context-dependent substrate selection.

    Evidence Co-IP and deubiquitination assays for each substrate, in vivo models (pressure-overload, xenograft), farnesylation-mutant dissection for Mfn2

    PMID:32042339 PMID:32494592 PMID:32801299 PMID:32956978

    Open questions at the time
    • How UCHL1 selects among its many substrates in different cell types is unknown
    • Direct deubiquitination of Mfn2 was not reconstituted
  15. 2020 High

    C90A knock-in mice after TBI demonstrated that Cys90-dependent hydrolase activity is required for ubiquitin-proteasome function and suppression of autophagy in injured brain, mechanistically separating the two catalytic cysteines in vivo.

    Evidence C90A knock-in mice, controlled cortical impact, polyubiquitin and Beclin-1 western blots, behavioral testing

    PMID:33159930

    Open questions at the time
    • Specific substrates of Cys90-dependent activity in TBI were not identified
  16. 2021 High

    Discovery that UCHL1 loss destabilizes PKM and triggers AMPK-FUNDC1/ULK1-dependent mitophagy linked the DUB to glycolytic metabolism and provided a PINK1/Parkin-independent mitophagy rescue pathway relevant to Parkinson's disease.

    Evidence UCHL1 KO cells, epistasis with TRIM63, AMPK/mitophagy assays, Drosophila genetic rescue

    PMID:34244144

    Open questions at the time
    • Direct deubiquitination of PKM by UCHL1 versus indirect stabilization was not definitively distinguished
  17. 2022 High

    The crystal structure of UCHL1 with the GK13S activity-based probe captured a hybrid apo/Ub-bound conformation, explaining the probe's family-member selectivity and providing a structural basis for inhibitor design.

    Evidence X-ray crystallography, stereoselective inhibition assay, cellular monoubiquitin level measurement

    PMID:36216817

    Open questions at the time
    • Structure of UCHL1 bound to a full ubiquitinated substrate is still lacking
  18. 2023 Medium

    Identification of TAZ K46 deubiquitination and the downstream TAZ-calcineurin A competition for NFATC1 revealed how UCHL1 suppresses osteoclastogenesis through a non-neuronal signaling axis.

    Evidence Conditional KO mice, K46 ubiquitination mapping, Co-IP of TAZ-CNA-NFATC1 complex, in vivo bone loss model

    PMID:37215988

    Open questions at the time
    • Whether UCHL1-TAZ interaction is direct or scaffolded was not resolved
    • Generalizability beyond osteoclast lineage not tested
  19. 2024 Medium

    Multiple 2024 studies identified POM121, AKT1 (with ubiquitin-linkage switching), NLRP3, and CD13 as additional UCHL1 substrates or interactors, extending the enzyme's reach to nuclear transport, inflammasome activation, pulmonary vascular biology, and bone remodeling.

    Evidence BioID/Co-IP for NLRP3, linkage-specific IP for AKT1 in KO rats and conditional KO mice, deubiquitination assays for POM121 and CD13

    PMID:38244540 PMID:38669140 PMID:38695173 PMID:39389988

    Open questions at the time
    • How UCHL1 achieves substrate selectivity across such diverse clients remains unknown
    • NLRP3 deubiquitination by UCHL1 was not directly reconstituted
    • AKT1 linkage-switching mechanism is not structurally explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is how a single small DUB achieves substrate selectivity across dozens of structurally unrelated clients in a tissue- and context-dependent manner, and whether its two catalytic cysteines serve genuinely independent substrate pools.
  • No structural model of UCHL1 bound to a full ubiquitinated protein substrate exists
  • Systematic substrate-specificity profiling across cell types has not been performed
  • Relative contributions of Cys90 versus Cys152 hydrolase activities toward specific substrates are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 3 GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 13 R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
EGFRHIF1ANLRP3NTRK2PKMRPTORSMAD2TGFBR1

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 A nuclear-enriched lncRNA antisense to Uchl1 (AS Uchl1) increases UCHL1 protein synthesis post-transcriptionally. This activity depends on a 5' overlapping sequence and an embedded inverted SINEB2 element. mTORC1 inhibition by rapamycin causes AS Uchl1 to shuttle from nucleus to cytoplasm, where it promotes association of the sense Uchl1 mRNA with active polysomes for translation. Polysome fractionation, RNA localization (nuclear/cytoplasmic fractionation), rapamycin treatment, reporter assays with SINEB2 deletion mutants Nature High 23064229
2006 UCH-L1 is required for normal synaptic and cognitive function. TAT-fused UCH-L1 protein restores enzymatic activity and synaptic function in hippocampal slices treated with oligomeric Aβ and in APP/PS1 mice. The beneficial effect is associated with restoration of normal PKA-regulatory subunit IIα levels, PKA activity, and CREB phosphorylation. TAT-fusion protein transduction, hippocampal slice electrophysiology, contextual fear conditioning, PKA activity assay, CREB phosphorylation western blot Cell High 16923396
2015 UCHL1 abrogates von Hippel-Lindau (VHL)-mediated ubiquitination of HIF-1α, thereby stabilizing HIF-1α and promoting tumor metastasis in a HIF-1-dependent manner. Co-immunoprecipitation, ubiquitination assays, murine pulmonary metastasis models, UCHL1 overexpression/knockdown Nature communications High 25615526
2009 UCH-L1 exists in a membrane-associated form (UCH-L1M) in addition to the soluble form. C-terminal farnesylation promotes association of UCH-L1 with cellular membranes including the ER. The amount of UCH-L1M correlates with intracellular α-synuclein levels, and farnesyltransferase inhibitor (FTI-277) reduces UCH-L1M, lowers α-synuclein levels, and increases cell viability, suggesting UCH-L1M negatively regulates lysosomal degradation of α-synuclein. Cell fractionation, farnesyltransferase inhibitor treatment, α-synuclein quantification, cell viability assay Proceedings of the National Academy of Sciences of the United States of America High 19261853
2007 UCH-L1 is post-translationally modified by monoubiquitin at lysine residues near the active site. This monoubiquitination restricts enzyme activity by preventing binding to ubiquitinated targets. UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, providing a reversible regulatory mechanism for its own DUB activity. In vitro ubiquitination assay, ubiquitin-UCH-L1 fusion (permanent monoubiquitination mimic), free ubiquitin level measurements in cells, active-site mutagenesis The Journal of biological chemistry High 17259170
2013 UCH-L1 destabilizes mTORC1 by disrupting the complex between the DDB1-CUL4 ubiquitin ligase and raptor, counteracting DDB1-CUL4-mediated raptor ubiquitination. This leads to mTORC1 dissolution and a secondary increase in mTORC2/Akt signaling. UCH-L1 thus impairs S6K and 4EBP1 phosphorylation while increasing Akt phosphorylation. Co-immunoprecipitation, raptor ubiquitination assay, phosphorylation western blots (S6K, 4EBP1, Akt), Uchl1 KO and transgenic mice Molecular and cellular biology High 23297343
2020 UCHL1 binds, deubiquitinates, and stabilizes EGFR, thereby activating downstream mediators and promoting pathological cardiac hypertrophy. UCHL1 knockdown in cardiomyocytes and mouse hearts ameliorates hypertrophy; overexpression has the opposite effect. Co-immunoprecipitation, deubiquitination assay, cardiomyocyte knockdown/overexpression, rAAV9 delivery in mice, pressure-overload model, pharmacological inhibition (LDN-57444) Science advances High 32494592
2019 UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination and degradation. UCHL1-enriched exosomes also stimulate breast cancer migration and extravasation in a paracrine manner. DUB activity profiling with activity-based probes, in vivo zebrafish and murine xenograft models, ubiquitination assays for TGFβR1 and SMAD2, specific inhibitor (6RK73), patient sera UCHL1 measurement Clinical cancer research : an official journal of the American Association for Cancer Research High 31857432
2019 UCHL1 hydrolase activity at Cys152 is critical for neuronal protection after cerebral ischemia. A C152A knock-in mouse (preventing reactive lipid/CyPG adduction) shows decreased K63- and K48-linked polyubiquitinated protein accumulation in the ischemic penumbra, preserved excitatory synaptic drive, recovered axonal conduction, and improved sensorimotor recovery after MCAO. Knock-in mouse model (C152A), middle cerebral artery occlusion, ubiquitin linkage-specific western blots, electrophysiology, histology, behavioral testing Proceedings of the National Academy of Sciences of the United States of America High 30760601
2010 Cyclopentenone prostaglandins (CyPGs) covalently adduct UCH-L1 at Cys152 via Michael addition to the α,β-unsaturated carbonyl, causing protein unfolding and aggregation. The PD-associated I93M mutant, though structurally similar to wild-type, also aggregates upon CyPG conjugation. NMR spectroscopy, mass spectrometry (tandem MS for adduct site), fluorescence and CD spectroscopy, in vitro aggregation assay Proceedings of the National Academy of Sciences of the United States of America High 20231490
2006 UCH-L1 shows distinct substrate recognition from UCH-L3. Specific ubiquitin side chains critical for Michaelis complex formation and catalysis were identified using a panel of ubiquitin fusion substrates. Differences in substrate specificity between UCH-L1 and UCH-L3 were revealed through kinetic analysis. In vitro enzymatic assay with ubiquitin fusion substrates, kinetic measurements (kcat, KM), activation parameter determination Biochemistry High 17144664
2017 UCH-L1 directly deubiquitinates TrkB at K460 in its juxtamembrane domain. This deubiquitination prevents BDNF-induced TrkB internalization and lysosomal degradation, maintaining surface TrkB levels and downstream signaling. Inhibiting the UCH-L1/TrkB interaction in vivo impairs hippocampus-dependent contextual fear memory. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K460R), competitive inhibitory peptide, TrkB surface trafficking assay, in vivo DG injection and behavioral testing The Journal of neuroscience : the official journal of the Society for Neuroscience High 28500221
2014 UCHL1 interacts with APP and promotes its lysosomal degradation by increasing free ubiquitin and APP ubiquitination. UCHL1 overexpression via rAAV reduces Aβ production, inhibits neuritic plaque formation, and improves memory in AD transgenic mice. Co-immunoprecipitation (UCHL1-APP interaction), free ubiquitin measurement, lysosomal degradation assay, rAAV intracranial injection, Aβ ELISA, behavioral testing in transgenic mice Scientific reports Medium 25466238
2017 S-nitrosylation of UCHL1 at Cys90, Cys152, and Cys220 alters its catalytic activity and structural stability in a rotenone-induced PD mouse model, inducing amorphous aggregation that acts as a nucleation seed to accelerate native α-synuclein aggregation. S-nitrosylation assay (biotin-switch), mass spectrometry for site identification, CD and fluorescence spectroscopy (structural analysis), in vitro α-synuclein aggregation assay, rotenone mouse model Scientific reports Medium 28300150
2016 UCH-L1 contains a trefoil knot topology and folds through two parallel kinetic pathways involving transient intermediates. Under native conditions, partially unfolded forms (PUFs) share structural features (stable central β-sheet core, partially formed α-helix 3) with kinetic intermediates, as established by NMR hydrogen-deuterium exchange. Fluorescence-based kinetic folding measurements, NMR hydrogen-deuterium exchange (HDX), pulse-labelled HDX NMR Journal of molecular biology High 27067109
2011 The S18Y mutation (associated with decreased PD risk) causes minimal structural perturbation, while the I93M mutation (associated with increased PD risk) causes local structural rearrangements near the mutation site that likely expose hydrophobic surface area, predisposing to aggregation and aberrant interactions. Fluorescence spectroscopy, far-UV CD, NMR, equilibrium unfolding analysis Journal of molecular biology High 21251915
2015 UCH-L1 C152A point mutation prevents CyPG adduction and preserves hydrolase activity after 15dPGJ2 treatment. Neurons from C152A knock-in mice are resistant to CyPG-induced cytotoxicity, showing less ubiquitinated protein accumulation and less UCH-L1 aggregation, and less axonal injury. Tandem mass spectrometry (adduct site mapping), C152A knock-in mouse generation, primary neuron viability assay, caspase-3/PARP cleavage, ubiquitinated protein accumulation Cell death & disease High 26539913
2020 UCHL1 hydrolase activity (at Cys90, distinct from Cys152) contributes to normal ubiquitin proteasome pathway function and suppresses autophagy after traumatic brain injury. C90A knock-in mice devoid of hydrolase activity show greater axonal injury, greater neuron loss, elevated polyubiquitinated proteins, elevated Beclin-1, and poorer motor recovery after controlled cortical impact. C90A knock-in mouse, controlled cortical impact TBI model, immunohistochemistry (APP, SMI-32), western blot (poly-Ub proteins, Beclin-1), beam balance behavioral test Experimental neurology High 33159930
2022 Crystal structure of UCHL1 in complex with the activity-based probe GK13S reveals the enzyme locked in a hybrid conformation of apo and ubiquitin-bound states, explaining the probe's UCHL1-specificity within the UCH DUB family. GK13S reduces monoubiquitin levels in a human glioblastoma cell line, phenocopying an inactivating UCHL1 mutation. Crystal structure determination, stereoselective inhibition biochemical assay, cellular monoubiquitin level measurement, activity-based protein profiling Nature communications High 36216817
2013 UCHL1 regulates ubiquitination and lysosomal trafficking of NCAM180 and NCAM140. UCHL1 physically interacts with NCAM180 (identified by protein macroarray) and NCAM140. Overexpression of UCHL1 decreases constitutive ubiquitination of both NCAM isoforms and reduces their lysosomal localization. Protein macroarray pulldown (NCAM180 cytosolic domain bait), co-immunoprecipitation, immunofluorescence colocalization in primary neurons and B35 cells, UCHL1 overexpression/inhibition ubiquitination assay The FEBS journal Medium 23061666
2021 Loss of UCHL1 destabilizes pyruvate kinase (PKM), reducing pyruvate/ATP production and activating AMPK, which promotes FUNDC1/ULK1-dependent mitophagy. UCHL1 thus antagonizes TRIM63 (an E3 ligase of PKM) to regulate PKM stability. This pathway links UCHL1 to glycolysis and rescues Parkinson's-related PINK1/Parkin phenotypes in Drosophila and mammalian cells. UCHL1 KO cells, epistasis rescue experiments, AMPK activity assay, mitophagy assay (FUNDC1/ULK1), E3 ligase identification (TRIM63) by co-immunoprecipitation, Drosophila genetics Science advances High 34244144
2019 UCHL1 promotes podocyte necroptosis by regulating the ubiquitination state of RIPK1 and RIPK3; UCHL1 knockdown reduces the protein levels and half-life of RIPK1 and RIPK3, thereby decreasing necroptotic signaling (MLKL). UCHL1 siRNA knockdown in podocytes, RIPK1/RIPK3/MLKL protein level and half-life measurement, in vivo diabetic nephropathy model, caspase activity assay Experimental cell research Medium 31247189
2013 HtrA2/Omi, a serine protease, induces monoubiquitination of UCH-L1 (activating it) during TNF-induced necroptosis. UCH-L1 functions downstream of HtrA2/Omi as a mediator of caspase-independent necroptotic cell death, and its inhibition protects from TNF-induced necroptosis in multiple cell systems. Pharmacological inhibition and genetic deletion of HtrA2/Omi, UCH-L1 siRNA knockdown, PARP-1 cleavage assay, cell death measurements, monoubiquitination assay Cell communication and signaling : CCS Medium 24090154
2020 UCHL1 deubiquitinates CD36, protecting it from K48-polyubiquitination and proteasomal degradation. UCHL1 deletion or inhibition increases K48-polyubiquitin on CD36, decreases CD36 protein, and significantly inhibits lipid accumulation and foam cell formation. UCHL1 siRNA knockdown/inhibitor, K48-ubiquitin immunoprecipitation of CD36, CD36 protein level measurement, lipid uptake assay (foam cell formation) Cell death & disease Medium 32801299
2020 UCHL1 deubiquitinates and stabilizes EGFR, which in turn suppresses ERα transcription, mediating insensitivity to endocrine therapy in ERα-negative breast cancer. UCH-L1 inhibition restores ERα expression and sensitizes ER-negative breast cancer cells to tamoxifen and fulvestrant in vivo and in vitro. Immunoprecipitation, ubiquitination assay, ChIP assay (ERα promoter), luciferase reporter assay, in vivo xenograft model, UCHL1 inhibition (pharmacological and siRNA) Theranostics Medium 32042339
2020 UCH-L1 knockdown reduces Mitofusin-2 (Mfn2) levels but not Mfn1, causing mitochondrial enlargement, loss of tubular network, reduced ER-mitochondria tethering, altered mitochondrial calcium uptake, and higher proton leak. Overexpression of UCH-L1 (especially the non-farnesylated C220S mutant) increases Mfn2 levels, establishing that the soluble cytosolic form of UCH-L1 regulates Mfn2 and mitochondrial function. siRNA knockdown, UCH-L1 overexpression, C220S farnesylation mutant, mitochondrial morphology imaging, Seahorse respirometry, mitochondrial calcium uptake measurement, Drosophila ortholog KD validation Redox biology Medium 32956978
2020 UCHL1 regulates post-myocardial infarction cardiac fibrosis through interaction with and promotion of degradation of GRP78 via ubiquitination. GRP78 was identified as a UCHL1 interactor by immunoprecipitation-mass spectrometry, and GRP78 inhibition abrogates the anti-fibrotic effects of UCHL1 knockdown. Immunoprecipitation-mass spectrometry, Co-IP, UCHL1 siRNA/LDN57444 inhibition, TGF-β1 fibrosis model, GRP78 protein level measurement, in vivo MI model Scientific reports Medium 32606430
2024 UCHL1 interacts with the NACHT domain of NLRP3 and regulates NLRP3 inflammasome activation. UCH-L1 downregulation decreases pro-IL-1β levels, and UCHL1 chemical inhibition interferes with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia. Proximity labeling (BioID), affinity purification, RNAi screening, NLRP3 Co-IP, ASC oligomerization assay, IL-1β ELISA, UCHL1-specific inhibitor treatment Cell reports Medium 38669140
2024 UCHL1 binds, deubiquitinates, and stabilizes POM121 (nucleoporin), regulating POM121-associated nuclear transport of E2F1 and c-MYC to maintain neuroendocrine differentiation and promote cancer progression. Co-immunoprecipitation, deubiquitination assay, nuclear transport assay (E2F1/c-MYC), loss-of-function in vivo xenograft, LDN-57444 inhibitor treatment Cell reports. Medicine Medium 38244540
2024 RANKL stimulates UCHL1 expression in osteoclast precursors; UCHL1 then stabilizes CD13 by deubiquitination, augmenting soluble CD13 (sCD13) release, which triggers an autocrine inhibitory effect on the MAPK pathway to suppress osteoclast formation, constituting a RANKL-UCHL1-sCD13 negative feedback loop. Conditional UCHL1 knockout in osteoclast precursors, AAV9-mediated UCHL1 overexpression, UCHL1-CD13 Co-IP, ubiquitination assay, MAPK phosphorylation assay, OA mouse model Nature communications Medium 39389988
2023 UCHL1 deubiquitinates and stabilizes TAZ at K46 (removing K48-linked polyubiquitin), and stabilized TAZ inhibits NFATC1 dephosphorylation and nuclear transport by competing with calcineurin A for NFATC1 binding, thereby suppressing osteoclastogenesis. Osteoclast-specific UCHL1 conditional KO mice, ubiquitination site mapping (K46), Co-IP (TAZ-CNA-NFATC1), NFATC1 nuclear transport assay, UCHL1 AAV overexpression in bone loss model International journal of biological sciences Medium 37215988
2024 UCHL1 reduces K63-linked ubiquitination and increases K48-linked ubiquitination of AKT1 in pulmonary artery endothelial cells, stabilizing AKT1. UCHL1 deficiency reduces total and activated AKT1, attenuating pulmonary arterial hypertension in three preclinical models. Uchl1 KO rats, Tie2Cre-Uchl1 conditional KO mice, AKT1 ubiquitin linkage-specific IP, UCHL1-silenced human pulmonary artery endothelial cells, LDN57444 pharmacological inhibition, in vivo hemodynamic measurements Circulation High 38695173
2025 UCHL1 stabilizes PFKFB3 by cleaving K48-linked ubiquitin chains from it, promoting astrocytic glycolysis. The resulting lactate production increases histone lactylation (H4K8la), which further transcriptionally upregulates Uchl1 and glycolysis genes, forming a positive feedback loop that supports neuronal survival after spinal cord injury. UCHL1-PFKFB3 Co-IP, K48-ubiquitin chain cleavage assay, genetic deletion of Uchl1 in mice (SCI model), histone lactylation ChIP, scRNA-seq analysis Cell death and differentiation Medium 40016338
2024 UCHL1 interacts with Sox17 (identified by IP-mass spectrometry) in endothelial cells and stabilizes it by deubiquitination, promoting angiogenesis and blood-spinal cord barrier repair after SCI. Immunoprecipitation-mass spectrometry (UCHL1-Sox17 interaction), conditional UCHL1 KO mice, Sox17 ubiquitination assay, in vivo SCI model with endothelial-cell angiogenesis and BSCB permeability readouts Cellular and molecular life sciences : CMLS Medium 38478109
2020 UCH-L1 interacts with Akt2 preferentially over Akt1, and overexpression of UCH-L1 leads to activation (phosphorylation) of Akt, promoting breast cancer cell invasion. BioID proximity ligation followed by streptavidin pulldown, His-tagged recombinant UCH-L1 pulldown from cell lysate, phospho-Akt western blot, invasion assay Journal of cellular biochemistry Low 28636190
2010 UCH-L1 localizes to the inside of the plasma membrane of DRG neurons and binds to phosphatidic acid in a manner dependent on redox status and mono-ubiquitin. UCH-L1 deficiency (gad mice) leads to vulnerability to lipid peroxidation and increased neuronal death. Immunolocalization in DRG neurons (membrane fractionation), phosphatidic acid binding assay, gad (UCH-L1 deficient) mouse phenotype analysis, vitamin E-deficient diet Neurochemistry international Medium 20447430
2012 UCHL1 is expressed asymmetrically in type A spermatogonia: cells retaining high UCH-L1 co-express PLZF (undifferentiated stem cell marker) while cells with low/absent UCH-L1 express differentiation markers (DAZL, DDX4, c-KIT). This asymmetric segregation provides direct evidence for asymmetric division of mammalian spermatogonial stem cells. Immunofluorescence co-localization in vivo and in vitro, live imaging of gonocyte division, co-staining with differentiation/self-renewal markers Journal of cellular physiology Medium 19388011
2022 UCHL1 promotes M1 macrophage polarization by promoting autophagic degradation of the PI3K catalytic subunit p110α while paradoxically increasing Akt activity, shifting macrophages toward a pro-inflammatory state. UCHL1-deficient mice, LPS stimulation, flow cytometry (CD80, CD86, CD206), cytokine ELISA, p110α protein level and autophagy flux measurement, Akt phosphorylation assay Journal of inflammation research Low 35153498
2021 UCHL1 interacts with IκBα protein and inhibits its degradation through the ubiquitin-proteasome system, thereby suppressing LPS-induced NF-κB nuclear translocation and ERK1/2 phosphorylation, reducing pro-inflammatory cytokine production. Co-immunoprecipitation (UCHL1-IκBα), IκBα ubiquitination and degradation assay, NF-κB nuclear translocation assay, cytokine ELISA, in vivo LPS endotoxemia model Cell biology international Medium 34288216
2020 UCHL1 inhibition (via LDN-57444) suppresses UCHL1 DUB activity, inhibits exosome secretion, reduces pro-metastatic LMP1 factor in exosomal fractions, and suppresses motility, adhesion, and extracellular vesicle-mediated transfer of the viral invasive factor LMP1 in nasopharyngeal and oral carcinoma cells. LDN-57444 inhibitor and nanoparticle formulation (LDN-POx), exosome isolation and western blot, cell motility assay, adhesion assay, ECV transfer assay International journal of molecular sciences Low 31370144

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 786 23064229
2018 Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. The Lancet. Neurology 447 30054151
2016 Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury. JAMA neurology 388 27018834
2006 Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 366 16923396
2007 The functions of UCH-L1 and its relation to neurodegenerative diseases. Neurochemistry international 239 17586089
2004 UCHL1 is a Parkinson's disease susceptibility gene. Annals of neurology 200 15048890
2015 UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α. Nature communications 187 25615526
2009 Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 119 19261853
2019 Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research 115 31857432
2014 Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo. Scientific reports 105 25466238
2015 NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. Human molecular genetics 104 25687137
2016 Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients. Scientific reports 92 27074724
2020 The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor. Science advances 91 32494592
2006 Silencing of the UCHL1 gene in human colorectal and ovarian cancers. International journal of cancer 90 16642472
2016 It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease. Oxidative medicine and cellular longevity 89 26881020
2009 Asymmetric distribution of UCH-L1 in spermatogonia is associated with maintenance and differentiation of spermatogonial stem cells. Journal of cellular physiology 86 19388011
2007 Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1. The Journal of biological chemistry 85 17259170
2006 UCHL-1 is not a Parkinson's disease susceptibility gene. Annals of neurology 83 16450370
2023 Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury. Ageing research reviews 74 36681249
2019 Role of UCHL1 in axonal injury and functional recovery after cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 69 30760601
2010 Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1. Proceedings of the National Academy of Sciences of the United States of America 69 20231490
2013 Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor. Molecular and cellular biology 68 23297343
2021 UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology. British journal of cancer 65 34497382
2013 eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 23637180
2019 High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway. Experimental cell research 64 31247189
2017 S-nitrosylation of UCHL1 induces its structural instability and promotes α-synuclein aggregation. Scientific reports 64 28300150
2011 The effect of Parkinson's-disease-associated mutations on the deubiquitinating enzyme UCH-L1. Journal of molecular biology 60 21251915
2020 Small-Molecule Activity-Based Probe for Monitoring Ubiquitin C-Terminal Hydrolase L1 (UCHL1) Activity in Live Cells and Zebrafish Embryos. Journal of the American Chemical Society 57 32886496
2013 The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis. Cell communication and signaling : CCS 56 24090154
2012 Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation. Aging cell 56 22726800
2009 Effects of UCH-L1 on alpha-synuclein over-expression mouse model of Parkinson's disease. Journal of neurochemistry 55 19141079
2008 The role of PGP9.5 as a tumor suppressor gene in human cancer. International journal of cancer 54 18512240
2020 Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients. Resuscitation 51 32445783
2012 Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development. Journal of cellular physiology 51 21678411
2015 The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 50 26018507
2021 Loss of UCHL1 rescues the defects related to Parkinson's disease by suppressing glycolysis. Science advances 49 34244144
2003 PGP9.5 overexpression in esophageal squamous cell carcinoma. Hepato-gastroenterology 48 14571718
2013 Could dysregulation of UPS be a common underlying mechanism for cancer and neurodegeneration? Lessons from UCHL1. Cell biochemistry and biophysics 47 23695785
2020 The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics 45 32483437
2017 UCH-L1 promotes invasion of breast cancer cells through activating Akt signaling pathway. Journal of cellular biochemistry 45 28636190
1992 cDNA cloning and tissue distribution of a rat ubiquitin carboxyl-terminal hydrolase PGP9.5. Journal of biochemistry 44 1331034
1991 The immunolocalisation of the neuroendocrine specific protein PGP9.5 during neurogenesis in the rat. Brain research. Developmental brain research 44 1826643
2016 The Knotted Protein UCH-L1 Exhibits Partially Unfolded Forms under Native Conditions that Share Common Structural Features with Its Kinetic Folding Intermediates. Journal of molecular biology 42 27067109
2020 UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer. Theranostics 41 32042339
2020 Deubiquitination of CD36 by UCHL1 promotes foam cell formation. Cell death & disease 41 32801299
2018 The deubiquitinating enzyme UCHL1 negatively regulates the immunosuppressive capacity and survival of multipotent mesenchymal stromal cells. Cell death & disease 40 29686406
2016 Are UCH-L1 and GFAP promising biomarkers for children with mild traumatic brain injury? Brain injury 40 27416022
2005 Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proceedings of the National Academy of Sciences of the United States of America 39 15911766
2022 UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis. Journal of dental research 37 36112902
2008 Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. Molecular and cellular biochemistry 36 18622688
2024 The game changer: UCH-L1 and GFAP-based blood test as the first marketed in vitro diagnostic test for mild traumatic brain injury. Expert review of molecular diagnostics 35 38275158
2013 Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression. PloS one 35 24086249
1989 Increased proportion of CD4+CDw29+CD45R-UCHL-1+ lymphocytes in the cerebrospinal fluid of both multiple sclerosis patients and healthy individuals. Cellular immunology 35 2562931
2022 UCHL1 protects against ischemic heart injury via activating HIF-1α signal pathway. Redox biology 34 35339825
2016 Absence of UCHL 1 function leads to selective motor neuropathy. Annals of clinical and translational neurology 34 27231703
2004 Genetic causes of Parkinson's disease: UCHL-1. Cell and tissue research 34 15221445
2017 The diagnostic values of UCH-L1 in traumatic brain injury: A meta-analysis. Brain injury 33 29087740
2016 Wnt/β-Catenin Signaling Mediated-UCH-L1 Expression in Podocytes of Diabetic Nephropathy. International journal of molecular sciences 33 27571062
2022 Structural basis for specific inhibition of the deubiquitinase UCHL1. Nature communications 32 36216817
2020 Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78). Scientific reports 32 32606430
2015 UCH-L1 involved in regulating the degradation of EGFR and promoting malignant properties in drug-resistant breast cancer. International journal of clinical and experimental pathology 32 26722437
2006 Substrate recognition and catalysis by UCH-L1. Biochemistry 31 17144664
1991 Reduction in the number of UCHL-1+ cells and IL-2 production in the peripheral blood of patients with visceral leishmaniasis. Journal of immunology (Baltimore, Md. : 1950) 31 1824848
1997 Low specificity of PGP9.5 expression for detection of micrometastatic neuroblastoma. British journal of cancer 30 9192981
2020 A new target for an old DUB: UCH-L1 regulates mitofusin-2 levels, altering mitochondrial morphology, function and calcium uptake. Redox biology 28 32956978
2024 UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas. Cell reports. Medicine 27 38244540
2017 Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma. PloS one 27 28472177
2015 The point mutation UCH-L1 C152A protects primary neurons against cyclopentenone prostaglandin-induced cytotoxicity: implications for post-ischemic neuronal injury. Cell death & disease 27 26539913
2021 Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7-APEH-Proteasome Axis in High-grade Serous Ovarian Carcinoma. Molecular cancer research : MCR 26 33753553
2019 Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells. International journal of molecular sciences 26 31370144
2016 UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. Journal of Alzheimer's disease : JAD 26 26444754
2021 The Epstein-Barr virus noncoding RNA EBER2 transactivates the UCHL1 deubiquitinase to accelerate cell growth. Proceedings of the National Academy of Sciences of the United States of America 24 34686609
2020 Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 24 32120844
2017 Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 28500221
2013 The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes. Cellular signalling 24 23567262
2010 Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening. Neurochemistry international 24 20144674
2014 N-terminal truncated UCH-L1 prevents Parkinson's disease associated damage. PloS one 23 24959670
2024 Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1β production in human macrophages and microglia. Cell reports 22 38669140
2024 A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression. Nature communications 22 39389988
2022 UCHL1 Promoted Polarization of M1 Macrophages by Regulating the PI3K/AKT Signaling Pathway. Journal of inflammation research 21 35153498
2019 UCHL1 regulates muscle fibers and mTORC1 activity in skeletal muscle. Life sciences 20 31356902
2015 Potential of UCHL1 as biomarker for destruction of pancreatic beta cells. Journal of proteomics 20 25638021
2025 Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop. Cell death and differentiation 19 40016338
2021 UCHL1 regulates inflammation via MAPK and NF-κB pathways in LPS-activated macrophages. Cell biology international 19 34288216
2019 UCHL1 loss alters the cell-cycle in metastatic pancreatic neuroendocrine tumors. Endocrine-related cancer 19 30689542
2016 α-Chymotrypsin regulates free fatty acids and UCHL-1 to ameliorate N-methyl nitrosourea induced mammary gland carcinoma in albino wistar rats. Inflammopharmacology 19 27671329
2010 Silencing of the UCHL1 gene in giant cell tumors of bone. International journal of cancer 19 20104524
2023 UCHL1 facilitates protein aggregates clearance to enhance neural stem cell activation in spinal cord injury. Cell death & disease 18 37507386
2020 Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice. Experimental neurology 18 33159930
2012 UCHL1 regulates ubiquitination and recycling of the neural cell adhesion molecule NCAM. The FEBS journal 18 23061666
2024 Deubiquitinase UCHL1 promotes angiogenesis and blood-spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17. Cellular and molecular life sciences : CMLS 17 38478109
2023 The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ/NFATC1 signalling. International journal of biological sciences 17 37215988
2020 Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats. Hypertension research : official journal of the Japanese Society of Hypertension 17 32541849
2010 Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease. Molecular neurodegeneration 17 20302621
2010 Modelling the role of UCH-L1 on protein aggregation in age-related neurodegeneration. PloS one 17 20949132
2024 Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension. Circulation 16 38695173
2022 Ubiquitin C-terminal hydrolase L1 (UCHL1), a double-edged sword in mammalian oocyte maturation and spermatogenesis. Cell proliferation 16 36218038
2010 Deficiency of ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) leads to vulnerability to lipid peroxidation. Neurochemistry international 16 20447430
2023 UCHL1 aggravates skin fibrosis through an IGF-1-induced Akt/mTOR/HIF-1α pathway in keloid. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 37256780
2022 Combined GFAP, NFL, Tau, and UCH-L1 panel increases prediction of outcomes in neonatal encephalopathy. Pediatric research 15 35273370