Affinage

USP5

Ubiquitin carboxyl-terminal hydrolase 5 · UniProt P45974

Length
858 aa
Mass
95.8 kDa
Annotated
2026-06-14
100 papers in source corpus 61 papers cited in narrative 62 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP5 (isopeptidase T) is a multidomain deubiquitinase that maintains cellular ubiquitin homeostasis and proteostasis by disassembling free, unanchored Lys48-linked polyubiquitin chains, the accumulation of which competitively inhibits proteasomal recognition of substrates such as ubiquitinated p53 (PMID:19098288). Its catalytic competence depends on a cryptic N-terminal ZnF-UBP domain that is tightly bound to the catalytic core and indispensable for activity, while a second ZnF-UBP domain targets substrates by engaging the free diglycine ubiquitin tail and allosterically activates hydrolysis upon binding free monoubiquitin (PMID:22283393). Genetic loss of the USP5 ortholog establishes its conserved role: depletion causes accumulation of free and conjugated polyubiquitin chains and disrupts proteasome function and tissue development (PMID:25152394), and in mammalian cardiomyocytes USP5 loss drives polyubiquitin and protein-aggregate accumulation, dysregulated proteostasis via its interaction with the proteasomal subunit PSMD14, and dilated cardiomyopathy (PMID:39841822). Beyond chain catabolism, USP5 acts as a substrate-specific deubiquitinase that stabilizes a broad set of proteins by reversing K48- (and in some cases K11-) linked polyubiquitination, including the m6A methyltransferase components METTL3/WTAP downstream of ERK phosphorylation (PMID:33217317), c-Myc (PMID:36602428), c-Maf (PMID:28933784), SLUG (PMID:30809294), CyclinD1 (PMID:34858787), and the immune checkpoint proteins PD-1 and PD-L1 (PMID:37208329, PMID:34741014), thereby influencing cancer progression and immune regulation. A distinct, catalysis-independent function operates in nociception, where the cryptic ZnF-UBP domain binds the domain III-IV linker of Cav3.2 T-type calcium channels to deubiquitinate and stabilize the channel at the plasma membrane, promoting pain signaling (PMID:25189210, PMID:27130589). USP5 activity is itself tuned by post-translational regulation, including ERK/KRAS-driven C195 disulfide homodimerization that stabilizes and activates the enzyme (PMID:36528652) and Smurf1-mediated ubiquitination that targets it for degradation (PMID:27133717). A de novo R24W mutation in USP5 causes hereditary pain insensitivity in humans, with the mutant acting as a dominant-negative regulator of Cav3.2 (PMID:40377597).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Established USP5's core cellular function by showing it is the principal enzyme disassembling Lys48-linked polyubiquitin, and that failure to do so produces free chains that jam proteasomal substrate recognition.

    Evidence shRNA knockdown plus in vitro chain hydrolysis and a ubiquitin G75A/G76A mutant in mammalian cells

    PMID:19098288

    Open questions at the time
    • Did not resolve which structural element confers free-chain specificity
    • p53 stabilization shown but breadth of affected substrates undefined
  2. 2012 High

    Resolved the structural basis of catalysis and substrate targeting, defining the cryptic N-terminal ZnF-UBP as essential for activity and the second ZnF-UBP as the unanchored-chain sensor.

    Evidence Crystal structure of full-length USP5 with deletion mutagenesis, ubiquitin-AMC assay and SAXS

    PMID:22283393

    Open questions at the time
    • Conformational dynamics in solution not addressed by static structure
    • How domain occupancy translates to substrate selection in cells unclear
  3. 2014 High

    Identified the first specific protein substrate beyond free chains—the Cav3.2 calcium channel—defining a deubiquitination axis controlling channel surface levels and pain.

    Evidence Proteomic screen, reciprocal Co-IP, patch-clamp and in vivo pain models with intrathecal Tat-peptides

    PMID:25189210

    Open questions at the time
    • Which USP5 domain mediates Cav3.2 binding not yet mapped
    • Endogenous regulation of the interaction in disease undefined
  4. 2014 High

    Confirmed in vivo that USP5 is the evolutionarily conserved guardian of ubiquitin homeostasis whose loss disrupts proteasome function and development.

    Evidence Drosophila leon loss-of-function mutants with ubiquitin chain and proteasome activity assays

    PMID:25152394

    Open questions at the time
    • Mechanism linking free-chain accumulation to elevated proteasome subunits not resolved
    • Mammalian developmental requirement not directly tested here
  5. 2016 High

    Localized the Cav3.2-binding activity to the cryptic ZnF-UBP domain and demonstrated therapeutic analgesia, separating substrate recruitment from catalysis.

    Evidence USP5 peptide competition mapping, Co-IP, and multiple pain models with Cav3.2-null controls

    PMID:27130589

    Open questions at the time
    • Whether catalytic activity is dispensable for the analgesic mechanism not fully isolated
    • Structural detail of the cUBP–Cav3.2 interface unknown
  6. 2017 High

    Defined upstream control of the USP5–Cav3.2 axis by neuronal activity and inflammatory signaling, establishing how injury and cytokines amplify pain through USP5.

    Evidence Optogenetic TRPV1 activation, intrathecal IL-1β, in vivo Co-IP and electrophysiology

    PMID:27974205 PMID:28741432

    Open questions at the time
    • Transcriptional mechanism of activity-driven USP5 upregulation not defined
    • Direct link between cytokine signaling and USP5 enzymatic state unclear
  7. 2017 High

    Expanded USP5's substrate repertoire to oncogenic transcription factors, showing it deubiquitinates specific lysines to extend protein half-life with paralog selectivity.

    Evidence Co-IP, domain mapping, c-Maf K308/K347 mutagenesis, CHX chase with MafA negative control (also FoxM1, WT1)

    PMID:28807830 PMID:28933784 PMID:31845546

    Open questions at the time
    • Determinants of substrate-lysine selectivity not generalized
    • Whether these substrates compete for a common USP5 binding mode unknown
  8. 2018 High

    Demonstrated that USP5 governs cytoplasmic stress-granule dynamics through clearance of unanchored chains, extending its proteostasis role to membraneless organelles.

    Evidence shRNA depletion, ubiquitin chain immunoblotting, ubiquitin diglycine mutant, and time-course imaging

    PMID:29567855

    Open questions at the time
    • How unanchored chains promote SG persistence mechanistically not resolved
    • Specific SG substrates not identified
  9. 2020 High

    Connected USP5 to RNA epitranscriptomic regulation, showing ERK phosphorylation primes METTL3/WTAP for USP5-mediated deubiquitination and m6A complex stabilization.

    Evidence Genome-wide CRISPR screen, phosphosite mutagenesis, ubiquitination assay and m6A sequencing in ESCs

    PMID:33217317

    Open questions at the time
    • How phosphorylation increases USP5 affinity structurally unclear
    • Whether ERK acts on USP5 directly versus on substrates only partly addressed
  10. 2022 High

    Revealed that USP5 itself is activated by oncogenic signaling through C195 disulfide-mediated homodimerization, linking KRAS/ROS to USP5-driven tumorigenesis via Beclin 1 and p53.

    Evidence CRISPR KO, C195 disulfide mutagenesis, dimerization assay and KrasG12D/Becn1 mouse models

    PMID:35393473 PMID:36528652

    Open questions at the time
    • Whether dimerization alters domain conformation or substrate access not structurally defined
    • Generality of redox activation across other contexts unknown
  11. 2023 High

    Established USP5 as a controller of immune-checkpoint protein stability, stabilizing PD-1 and PD-L1 in a phosphorylation-regulated manner relevant to anti-tumor immunity.

    Evidence Co-IP, ubiquitination assays, Thr234 mutagenesis and conditional T-cell Usp5 knockout mice (also c-Myc)

    PMID:24980819 PMID:36602428 PMID:37208329

    Open questions at the time
    • Relative contribution of PD-1 versus PD-L1 stabilization to immune phenotype unresolved
    • Whether USP5 inhibition synergizes with checkpoint blockade not fully defined here
  12. 2024 High

    Provided developable structural and pharmacological tools, defining ZnF-UBD ligand binding sites and selective inhibitors that competitively block catalysis.

    Evidence X-ray crystallography of ZnF-UBD–ligand complexes, di-ubiquitin cleavage assay and selectivity profiling

    PMID:31663737 PMID:34648286

    Open questions at the time
    • Cellular and in vivo efficacy of ZnF-UBD inhibitors not established in these studies
    • Effect on substrate-specific versus free-chain activity not dissected
  13. 2025 High

    Validated USP5 as a human pain gene and an in vivo proteostasis safeguard, with a de novo R24W mutation causing pain insensitivity and cardiomyocyte loss causing dilated cardiomyopathy.

    Evidence Human genetics with CRISPR knock-in mice, enzymatic and Cav3.2 binding assays; cardiac-specific KO/overexpression with PSMD14 Co-IP

    PMID:39841822 PMID:40377597

    Open questions at the time
    • How R24W simultaneously loses catalysis yet binds Cav3.2 more strongly not structurally explained
    • Tissue-specific substrate dependence of cardiac phenotype not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP5 balances its housekeeping free-chain disassembly against its many substrate-specific deubiquitination events—and what selects a given mode in a given cell—remains unresolved.
  • No unified model reconciling free-chain catabolism with the expanding catalog of stabilized substrates
  • Structural basis for phospho-/redox-/palmitoyl-dependent substrate switching undefined
  • In vivo physiological hierarchy among the many reported substrates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 2
Partners
BECN1CACNA1HCD274METTL3PD-1PSMD14SMURF1WTAP

Evidence

Reading pass · 62 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 USP5 (isopeptidase T) is the major enzyme responsible for Lys-48-linked polyubiquitin disassembly in mammalian cells; knockdown of USP5 causes accumulation of unanchored polyubiquitin chains, which competitively inhibit proteasomal recognition of ubiquitinated p53, selectively stabilizing p53 without affecting Mdm2 stability. shRNA knockdown, in vitro ubiquitin chain hydrolysis assay, cell-based ubiquitination assays, ectopic expression of ubiquitin C-terminal mutant (G75A/G76A) The Journal of biological chemistry High 19098288
2012 Full-length USP5 contains two ZnF-UBP domains: a cryptic N-terminal ZnF-UBP (residues 1–156) that is tightly bound to the catalytic core and is indispensable for catalytic activity, and a second ZnF-UBP (residues 163–291) that primarily functions in substrate targeting and specificity by binding the unanchored diglycine carboxyl tail. Free monoubiquitin allosterically activates hydrolysis of ubiquitin-AMC through the ZnF-UBP domain. Crystal structure of full-length USP5, deletion mutagenesis, fluorogenic substrate hydrolysis assay (ubiquitin-AMC), small-angle X-ray scattering Biochemistry High 22283393
2014 USP5 interacts with the intracellular domain III-IV linker region of Cav3.2 T-type calcium channels; WWP1 ubiquitinates Cav3.2 at specific lysines in this region, while USP5 deubiquitinates Cav3.2 to increase its plasma membrane levels and whole-cell currents. shRNA knockdown of USP5 increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces currents; in vivo disruption mediates analgesia. Proteomic screen, Co-IP, shRNA knockdown, whole-cell patch-clamp electrophysiology, intrathecal delivery of Tat-peptides in mouse pain models Neuron High 25189210
2014 In BRAF-mutant melanoma, BRAF signaling activates USP5 activity; USP5 suppresses p53 (and p73) levels and FAS expression. Knockdown or small-molecule inhibition (EOAI3402143) of USP5 restores p53/p73 and FAS induction and sensitizes cells to apoptosis. shRNA knockdown, overexpression, small-molecule DUB inhibitor, cell growth/cell cycle assays, mouse tumor xenograft Oncotarget Medium 24980819
2014 Drosophila USP5 ortholog Leon is essential for ubiquitin homeostasis during development; loss of Leon causes accumulation of both free and substrate-conjugated polyubiquitin chains, elevation of proteasomal subunit levels and enzymatic activity, and impaired proteasomal degradation, leading to lethality and tissue disorder. Genetic loss-of-function (leon mutants), immunoblotting for ubiquitin chain types and proteasomal subunits, proteasome activity assays Biochemical and biophysical research communications High 25152394
2015 USP5 exists in at least two distinct conformational states (compact and extended) that are detectable in solution, consistent with significant domain flexibility; molecular dynamics simulations of the crystal structure and SAXS-based extended form match measured gas-phase collisional cross sections. Ion mobility-mass spectrometry (IM-MS), native ESI-MS, molecular dynamics simulation, SAXS Proteomics Medium 25641936
2016 The cUBP (cryptic ZnF-UBP) domain of USP5 is responsible for binding to the III-IV linker of Cav3.2 channels; a TAT-cUBP1-USP5 cell-permeant peptide disrupts this interaction in vitro and reverses mechanical and thermal hyperalgesia in CFA, partial sciatic nerve injury, and diabetic neuropathy mouse models. Effects are absent in Cav3.2 null mice, confirming Cav3.2 dependence. Competition peptide mapping with USP5-derived peptides, Co-IP, intrathecal peptide delivery, behavioral pain assays in multiple mouse models, Cav3.2 knockout controls Molecular pain High 27130589
2016 TRPV1-expressing nociceptor activity drives upregulation of USP5 expression in dorsal root ganglia and spinal dorsal horn, increasing USP5–Cav3.2 association and T-type channel-mediated pain sensitization; interfering with USP5-Cav3.2 binding or pharmacological TRPV1 block prevents this sensitization. Optogenetic activation of TRPV1 nociceptors, Co-IP in spinal tissue, interfering peptide delivery, pharmacological blockade, behavioral assays, spinal cord slice electrophysiology Cell reports High 27974205
2016 The E3 ligase Smurf1 interacts with USP5, mediates its polyubiquitination and proteasomal degradation, thereby down-regulating USP5 protein levels and consequently suppressing TNF-α production. Co-IP, overexpression/knockdown, proteasome inhibitor (MG132) rescue, TNF-α ELISA Biochemical and biophysical research communications Medium 27133717
2017 USP5 interacts with c-Maf via its cryptic ZnF and C-box domains; UBA1/UBA2 domains partly increase c-Maf stability. USP5 removes polyubiquitin from c-Maf at K308 and K347, preventing proteasomal degradation. USP5 promotes c-Maf transcriptional activity. USP5 does not deubiquitinate the paralog MafA, demonstrating substrate specificity. Co-IP, domain-deletion mapping, site-directed mutagenesis of c-Maf lysines (K308R/K347R), ubiquitination assay, CHX chase, shRNA knockdown, luciferase reporter Cell death & disease High 28933784
2017 USP5 co-immunoprecipitates with FoxM1 in pancreatic cancer cells; overexpression of USP5 extends FoxM1 half-life and prevents proteasomal degradation (MG-132 restores FoxM1 after USP5 knockdown), establishing FoxM1 as a deubiquitination substrate of USP5. Reciprocal Co-IP, CHX chase assay, proteasome inhibitor rescue, shRNA knockdown, xenograft mouse model Biochemical and biophysical research communications Medium 28807830
2017 USP5 interacts with and deubiquitinates WT1 to stabilize its protein levels; the deubiquitinase inhibitor degrasyn inhibits USP5 activity toward WT1, leading to WT1 ubiquitination and degradation, and subsequent upregulation of E-cadherin to inhibit metastasis in pancreatic cancer. Co-IP, ubiquitination assay, shRNA/overexpression rescue, xenograft mouse model, USP5 inhibitor (degrasyn) Journal of cellular and molecular medicine Medium 31845546
2017 Drosophila USP5 (Leon) controls postsynaptic growth at NMJs by maintaining ubiquitin homeostasis; loss of Leon causes accumulation of free ubiquitin chains and ubiquitinated substrates, leading to dramatic expansion of postsynaptic specializations. This is partly mediated by accumulation of Ubiquilin (Ubqn). Genetic loss-of-function (leon mutants), immunofluorescence, electron microscopy, genetic interaction studies with Ubqn eLife High 28489002
2017 Interleukin-1β administered intrathecally increases the interaction between USP5 and Cav3.2 in spinal dorsal horn (detected by Co-IP); disruption of USP5–Cav3.2 interaction with TAT peptides suppresses IL-1β-induced nocifensive responses. This upregulation requires neuronal activity and is blocked by tetrodotoxin or IL-1Ra. Intrathecal IL-1β injection, Co-IP from spinal tissue, TAT-peptide interference, pharmacological blockers (TTX, IL-1Ra, mibefradil, TTA-A2), behavioral pain assays, DRG neuron cultures Molecular pain High 28741432
2018 USP5 and USP13 are recruited to heat-induced stress granules (SGs); depletion of USP5 elevates K48- and K63-linked ubiquitin chain levels, accelerates SG assembly, and markedly represses SG disassembly after heat removal. Overexpression of a ubiquitin mutant lacking the diglycine motif (which accumulates unanchored chains) similarly represses SG disassembly, consistent with unanchored chains being the key USP5 substrate in this context. shRNA depletion, immunofluorescence for SG markers, ubiquitin chain-type immunoblotting, ubiquitin C-terminal mutant overexpression, time-course disassembly assay Journal of cell science High 29567855
2018 USP5 deubiquitinates β-catenin, prevents its proteasomal degradation, promotes β-catenin nuclear accumulation, and activates Wnt/β-catenin signaling in NSCLC cells. Co-IP, ubiquitination assay, shRNA knockdown, overexpression, nuclear fractionation, Western blot, xenograft mouse model American journal of cancer research Medium 30555744
2018 Disrupting USP5–Cav3.2 interaction with intrathecal TAT-UBPc peptide fully reverses mechanical hypersensitivity in female mice with CFA-induced inflammation, showing that USP5-mediated Cav3.2 dysregulation does not exhibit sex differences. Intrathecal TAT-peptide delivery, behavioral mechanical threshold testing in female mice with synchronized estrous cycle Molecular brain Medium 30340616
2019 USP5 interacts with SLUG and stabilizes it through deubiquitination activity, promoting EMT in hepatocellular carcinoma. The natural compound Formononetin binds USP5 (verified by SPR and molecular docking) and inhibits USP5 deubiquitination of SLUG. Affinity purification/mass spectrometry, Co-IP, CHX chase, deubiquitination assay, dual-luciferase/ChIP for E-cadherin regulation, SPR, molecular docking, xenograft Theranostics High 30809294
2019 SUMOylation of USP5 at lysine K113 by SUMO2/3 reduces USP5's affinity for Cav3.2 calcium channels; peripheral nerve injury decreases USP5 SUMOylation in DRG, thereby enhancing USP5–Cav3.2 interaction and increasing channel activity during neuropathic pain. SUMO prediction software, single-lysine mutagenesis (K113R), Co-IP with Cav3.2, expression in tsA-201 cells, endogenous DRG SUMOylation assay Molecular brain Medium 31455361
2019 TRAIL treatment reduces USP5 activity and induces USP5 cleavage in TRAIL-sensitive cancer cells; caspase-8 mediates this cleavage/regulation of USP5. USP5 knockdown in TRAIL-resistant cells restores apoptotic responsiveness to TRAIL. TRAIL treatment, DUB activity assays, caspase-8 specific inhibitors, shRNA knockdown, colony formation assay Oncotarget Medium 31645897
2019 USP5 ZnF-UBD small-molecule antagonists bind the C-terminal ubiquitin-binding site of the ZnF-UBP domain and competitively inhibit catalytic activity in vitro; crystal structures of ZnF-UBD bound to multiple ligands were determined. Chemical library screen, X-ray crystallography of ZnF-UBD–ligand complexes, in vitro di-ubiquitin cleavage assay, binding affinity measurement Journal of medicinal chemistry Medium 31663737
2020 ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341; phosphorylation is followed by USP5-mediated deubiquitination of METTL3 and WTAP, stabilizing the m6A methyltransferase complex and increasing m6A mRNA modification. Loss of METTL3/WTAP phosphorylation reduces m6A on pluripotent factor transcripts. Genome-wide CRISPR screen, phosphosite mutagenesis, Co-IP, ubiquitination assay, m6A sequencing, mouse embryonic stem cell pluripotency assays Molecular cell High 33217317
2020 USP5 interacts with TRAF6 and removes its K48-linked polyubiquitin chains, stabilizing TRAF6 protein and thereby promoting NF-κB signaling and pro-inflammatory cytokine production in rheumatoid arthritis fibroblast-like synoviocytes. Co-IP, ubiquitination assay (K48-specific), overexpression/knockdown, NF-κB reporter, cytokine ELISA Mediators of inflammation Medium 32214906
2021 USP5 promotes autophagic degradation of NLRP3 inflammasome; knockdown of USP5 attenuates NLRP3 inflammasome activation and IL-1β secretion, while USP5 overexpression enhances NLRP3 autophagic turnover. Co-IP, autophagic flux assays (3-MA, BafA1, CQ), NLRP3 stability assay, caspase-1 activity, IL-1β ELISA, genetic knockdown/overexpression Autophagy Medium 34486483
2021 USP5 directly interacts with PD-L1 (CD274) and deubiquitinates it, stabilizing PD-L1 protein in NSCLC cells; USP5 knockdown reduces PD-L1 levels and retards tumor growth in the Lewis lung carcinoma mouse model. Co-IP, ubiquitination assay, CHX chase, shRNA knockdown, mouse tumor model Cell death & disease Medium 34741014
2021 USP5 directly interacts with CyclinD1, decreases its K48-linked polyubiquitination, and stabilizes CyclinD1 protein, promoting G1/S progression in NSCLC cells; knockdown causes CyclinD1 degradation and cell cycle arrest reversible by MG-132. Co-IP, K48-specific ubiquitination assay, CHX chase, MG-132 rescue, shRNA knockdown, xenograft Translational lung cancer research Medium 34858787
2021 USP5 interacts with and stabilizes CyclinD1 via deubiquitination in GBM cells; USP5 knockdown reduces CyclinD1 K48-linked ubiquitination, induces G1/S arrest, and inhibits tumor growth in vivo. Co-IP, K48-ubiquitination assay, MG-132 rescue, CHX chase, shRNA knockdown, xenograft Frontiers in pharmacology Medium 34483932
2021 USP5 stabilizes HIF2α by directly interacting with it and protecting it from ubiquitin-proteasome degradation, promoting transcription of HIF2α target genes (SLC2A1, PLOD2, P4HA1, VEGFA) in breast cancer cells. Co-IP, ubiquitination assay, CHX chase, shRNA knockdown/overexpression, gene expression analysis Journal of cellular physiology Medium 35102545
2021 DC-UbP/UBTD2 interacts with both the tandem UBA domains of USP5 and the UFD domain of UbE1; overexpression of DC-UbP enhances the association of USP5 and UbE1, increasing cellular ubiquitination levels, establishing DC-UbP as a ubiquitin shuttle linking ubiquitination and deubiquitination. Co-IP from HEK293T cells, domain-specific pull-down, overexpression/knockdown with ubiquitination level measurement PloS one Medium 25207809
2022 KRAS elevates ROS to induce USP5 homodimer formation via a C195 disulfide bond, resulting in stabilization and activation of USP5. Activated USP5 stabilizes nuclear Beclin 1, which promotes MDM2-mediated p53 instability to override senescence and drive Kras-mediated lung tumorigenesis. CRISPR KO, biochemical dimerization assay, disulfide bond mutagenesis (C195), Co-IP, xenograft and KrasG12D mouse models with Becn1 KO, senescence markers Nature communications High 36528652
2022 A rhodanine compound (II-1) inhibits biochemical interactions between USP5 and the Cav3.2 domain III-IV linker in a dose-dependent manner without affecting USP5 enzymatic activity; molecular docking identifies two binding pockets at the USP5–Cav3.2 interface distinct from the WP1130 binding site. Intrathecal II-1 mediates analgesia in formalin, CFA, and sciatic nerve injury models in a Cav3.2-dependent manner. Biochemical competition binding assay, molecular docking, in vitro orthogonal assays, behavioral pain assays in wild-type and Cav3.2 null mice ACS chemical neuroscience Medium 35113527
2022 USP5 depletion or Beclin 1 knockout leads to increased senescence and reduced autophagy; knockdown of USP5 in GBM cells causes accumulation of nuclear Beclin 1 and increased p53-dependent senescence. shRNA/CRISPR KO, senescence assays (SA-β-gal), autophagy flux assays, Co-IP Nature communications Medium 36528652
2022 In Drosophila, Usp5 loss impairs DNA damage-induced cellular response and non-homologous end joining (NHEJ) pathway; siRNA screening identified Usp5 as required for survival after UV and X-ray exposure, and DR-white reporter assay shows Usp5 loss causes strong position effect variegation after I-SceI–induced DSBs. Systematic siRNA screen for survival after radiation, direct repeat (DR)-white reporter system with I-SceI–induced DSBs in Drosophila, NHEJ pathway analysis Scientific reports Medium 35393473
2022 USP5 forms a complex with SGTA; this association is increased in the presence of a mislocalised membrane protein (MLP). USP5 is required for SGTA-mediated deubiquitination and accumulation of MLPs—overexpression of USP5 increases MLP steady-state levels, and knockdown of USP5 reduces them, impairing SGTA-dependent MLP quality control. Co-IP, MLP steady-state level assays, shRNA knockdown, overexpression, proteasomal degradation assays PloS one Medium 35895711
2021 USP5 ZnF-UBD inhibitors with sub-3 μM binding affinity were identified; crystallographic structures of multiple ligands bound to the ZnF-UBD domain were solved; compound 64 competitively inhibits USP5 catalytic cleavage of di-ubiquitin in vitro and is selective over nine structurally similar ZnF-UBD proteins. X-ray crystallography of multiple ligand–ZnF-UBD complexes, in vitro di-ubiquitin cleavage assay, selectivity panel against nine ZnF-UBD proteins Journal of medicinal chemistry High 34648286
2023 USP5 interacts with PD-1, deubiquitinates it, and stabilizes PD-1 protein on T cells. ERK phosphorylates PD-1 at Thr234, which promotes PD-1 interaction with USP5. Conditional T-cell knockout of Usp5 increases effector cytokine production and retards tumor growth in mice. Co-IP, ubiquitination assay, site-directed mutagenesis (Thr234), conditional T-cell Usp5 KO mouse, tumor growth assays, cytokine measurement Nature communications High 37208329
2023 USP5 interacts with c-Myc via its C-box and UBA domains and inhibits K48-linked polyubiquitination of c-Myc, stabilizing c-Myc protein. METTL5 controls USP5 translation, thereby regulating c-Myc ubiquitination and downstream glycolytic gene expression in HCC. GST pulldown, Co-IP, ubiquitination assay (K48-specific), polysome profiling, luciferase reporter, RNA-seq, non-targeted metabolomics, xenograft PDX model Cancer communications High 36602428
2023 USP5 interacts with YBX1 and stabilizes YBX1 through deubiquitination in cholangiocarcinoma cells; USP5 also promotes phosphorylation of YBX1 at S102 and its nuclear translocation. Co-IP, immunofluorescence co-localization, ubiquitination assay, CHX chase, shRNA knockdown/overexpression, xenograft Life sciences Medium 38692507
2023 miR-23a-3p targets USP5 mRNA to repress its expression; USP5 stabilizes HDAC2 via deubiquitination, promoting HDAC2 expression while inhibiting NRF2, thereby modulating inflammatory pain. Bioinformatics target prediction, luciferase reporter for miR-23a-3p targeting, Co-IP, ubiquitination assay for HDAC2, in vivo CFA mouse model FASEB journal Medium 34423867
2023 USP5 interacts with TXNIP and stabilizes it through deubiquitination; USP5 knockdown in LPS-treated hepatocytes reduces NLRP3 inflammasome activation (NLRP3, IL-1β, IL-18, ASC, procaspase-1 expression) and apoptosis, an effect reversed by TXNIP overexpression. Co-IP, deubiquitination assay, shRNA knockdown, TXNIP overexpression rescue, LPS inflammatory model, flow cytometry for apoptosis Hepatology communications Medium 37534934
2023 Leon/USP5 interacts with the autophagy-initiating kinase Atg1/ULK1; depletion of Leon increases Atg1/ULK1 levels and autophagosomes; Leon overexpression suppresses Atg1-induced cell death in Drosophila, establishing USP5 as a negative regulator of autophagy through Atg1/ULK1. Immunoblotting for Atg1/ULK1 levels, autophagosome formation assay, genetic epistasis (Atg1 overexpression + Leon overexpression in Drosophila), Co-IP Cell death & disease Medium 37607937
2024 USP5 interacts with IMPDH2 via its N-terminal cryptic ZnF-UBP and ZnF-UBP domains (binding IMPDH2 aa 251–514), removes Lys48-linked ubiquitin chains from IMPDH2, and stabilizes IMPDH2 to promote HCC proliferation and EMT; GTP biosynthesis pathway is involved in USP5-driven HCC progression. Co-IP, domain-deletion mutagenesis, K48-specific ubiquitination assay, CHX chase, shRNA knockdown, xenograft in zebrafish and nude mice, USP5 inhibitor (WP1130) Oncogene High 40164869
2024 USP5 interacts with c-Jun and stabilizes it by inhibiting its ubiquitination, activating JNK signaling and promoting bladder cancer progression; catalytically inactive USP5-C335A mutant fails to stabilize c-Jun, confirming enzymatic activity requirement. CRISPR KO, Co-IP, immunofluorescence, CHX chase, ubiquitination assay, catalytic mutant (C335A), RNA-seq, dual-luciferase reporter, xenograft Cancer cell international High 38229092
2024 USP5 interacts with and stabilizes EphA2 via the ubiquitin-proteasome pathway in nasopharyngeal carcinoma cells; mebendazole transcriptionally inhibits USP5 expression, leading to EphA2 ubiquitin degradation and reduced radioresistance. Co-IP, ubiquitin-proteasome pathway assay, CHX chase, mebendazole treatment, in vitro and in vivo radioresistance assays International journal of biological sciences Medium 39897046
2024 BRD7 competitively inhibits binding of USP5 to METTL3, thereby reducing METTL3 protein stability through the ubiquitin-proteasome pathway; loss of USP5-mediated METTL3 stabilization decreases BRCA1/RAD51-dependent homologous recombination repair and increases NPC radiosensitivity. Co-IP (competitive interaction assay), ubiquitination/proteasome pathway assay, CHX chase, METTL3 knockdown/overexpression, HR reporter, in vivo radiosensitivity model International journal of biological sciences Medium 39664566
2024 TRIM21 governs USP5 expression via K48-linked ubiquitination (acting as an E3 ligase for USP5); USP5 in turn deubiquitinates MDH2 to stabilize it. ZDHHC18 palmitoylates MDH2 to further increase its stability, collectively promoting ripretinib resistance in GIST. Proteome-ubiquitinome sequencing, mass spectrometry validation of TRIM21–USP5 and USP5–MDH2 interactions, ubiquitination assays, palmitoylation assay Advanced science Medium 38973363
2024 USP5 interacts with and deubiquitinates ROBO4, stabilizing its protein levels; USP5 knockdown decreases ROBO4 and mitigates high-glucose-induced proliferation suppression, inflammation, apoptosis, and oxidative stress in retinal pigment epithelium cells. Co-IP, deubiquitination assay, shRNA knockdown, overexpression, CCK-8, flow cytometry, ELISA Cellular signalling Medium 38735506
2024 USP5 is identified as the deubiquitylase for MLH1 (DNA mismatch repair protein); USP5 deficiency promotes MLH1 degradation and affects the cellular response to the nucleotide analog 6-TG. The E3 ligase UBR4 opposes USP5 by ubiquitinating MLH1. Co-IP, ubiquitination assay, MLH1 stability assay, 6-TG sensitivity assay, domain-mapping of MLH1 degradation determinants The Journal of biological chemistry Medium 39032648
2024 PDK1 binds and phosphorylates USP5; PDK1-mediated phosphorylation activates USP5 deubiquitinating activity, leading to stabilization of IKKγ and activation of NF-κB signaling in osteosarcoma cells, promoting tumor growth. Molecular docking, pull-down assay, Co-IP, USP5 deubiquitinase activity assay post-phosphorylation, IKKγ stability assay, NF-κB reporter, xenograft, PDK1 inhibitor (arctigenin) International journal of biological macromolecules Medium 39988167
2024 Gracilioether A (marine polyketide) binds USP5 as identified by DARTS and t-LiP-MS; SPR confirms direct interaction; molecular docking identifies binding regions on the USP5 protein. DARTS (Drug Affinity Responsive Target Stability), t-LiP-MS (targeted-Limited Proteolysis-Mass Spectrometry), SPR, in silico molecular docking Marine drugs Medium 38248666
2025 USP5 interacts with YTHDF1 and removes K11-linked polyubiquitination to stabilize it. mTORC1 activation by insulin phosphorylates USP5 and promotes its dimerization, enhancing YTHDF1 protection. CUL7-FBXW8 E3 ligase counteracts USP5 by promoting YTHDF1 degradation. USP5/YTHDF1 deficiency increases PD-L1 expression and suppresses immune gene expression, facilitating immune evasion. Co-IP, K11-linkage-specific ubiquitination assay, mTORC1 inhibitor experiments, dimerization assay, CUL7-FBXW8 KO, PD-L1 and immune gene expression analysis, anti-PD-L1 combination tumor model Nature communications High 39900921
2025 A de novo heterozygous missense mutation R24W in USP5 causes pain insensitivity in a pediatric patient; CRISPR knock-in mice with R24W show resistance to acute and chronic pain. Mutant USP5-R24W exhibits dramatically reduced enzymatic activity but stronger interactions with Cav3.2, acting as a dominant-negative regulator of Cav3.2 upregulation during inflammation. Human genetics (de novo mutation), CRISPR knock-in mice, behavioral pain assays (acute, CFA, neuropathic), Cav3.2 and USP5 protein level measurement, enzymatic activity assay for R24W mutant, Co-IP for Cav3.2 binding The Journal of experimental medicine High 40377597
2025 USP5 knockout in cardiomyocytes causes accumulation of polyubiquitin chains and protein aggregates, increased UPS activity, increased autophagic flux, cardiac remodeling, and dilated cardiomyopathy; USP5 interacts with the proteasomal subunit PSMD14. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Cardiomyocyte-specific Usp5 KO mouse, Co-IP with PSMD14, ubiquitin chain analysis, proteasome activity assay, autophagic flux assay, cardiac function measurements, hUSP5 overexpression in disease models Science advances High 39841822
2025 USP5 deubiquitylates FcεRIγ (the γ-subunit of the high-affinity IgE receptor), reversing its K48-linked polyubiquitylation and stabilizing it; USP5 knockdown increases Cbl-b E3 ligase binding to FcεRIγ, enhancing its ubiquitylation and degradation, reducing IgE-mediated mast cell activation and allergic inflammation in mice. Co-IP, K48-specific ubiquitylation assay, USP5 knockdown in mast cells/HEK293T, Cbl-b interaction assay, β-hexosaminidase/histamine release assay, in vivo mouse allergy model, WP1130 inhibitor Science signaling High 40729432
2025 FASN-mediated palmitoylation of USP5 promotes USP5–GPX4 interaction; USP5 stabilizes GPX4 by binding and deubiquitinating it. FASN knockdown reduces USP5 palmitoylation, decreasing GPX4 stability and promoting ferroptosis in breast cancer cells. Co-IP/mass spectrometry, Co-IP confirmation of USP5–GPX4 interaction, palmitoylation assay, ubiquitination assay for GPX4, FASN/USP5 knockdown, ferroptosis markers (Fe2+, ROS, MDA), tumor xenograft Journal of experimental & clinical cancer research Medium 41088402
2025 MSK1 phosphorylates Snail and promotes deubiquitination rather than inhibiting ubiquitination; USP5 is identified as the deubiquitinase that binds MSK1-phosphorylated Snail to increase its stability, thereby promoting EMT and CRC metastasis. Co-IP, ubiquitination assay, kinase assay for MSK1-Snail phosphorylation, USP5 identification as DUB for phospho-Snail, cell migration/invasion assays, in vivo metastasis model Experimental & molecular medicine Medium 40164688
2025 USP5 interacts with RIPK1 via Co-IP and deubiquitinates it to promote its stabilization; USP5 deficiency reduces RIPK1 kinase activity–mediated pyroptosis (GSDMD cleavage) in cardiac endothelial cells during myocardial ischemia/reperfusion injury. Co-IP, immunoprecipitation, Western blot for RIPK1/GSDMD, USP5 deficiency mouse model, RIPK1flox/flox Cdh5-Cre model, confocal co-localization, siUSP5 in CMECs Cell communication and signaling Medium 39350285
2025 USP5 deubiquitinates NFATC1 to prevent its degradation in coronary artery endothelial cells; NFATC1 interacts with TLR4 to activate NF-κB signaling. USP5 deletion mitigates KD serum-induced inflammation and injury by reducing NFATC1 stability and TLR4-mediated NF-κB activation. Co-IP for USP5–NFATC1 and NFATC1–TLR4, Western blot, ubiquitination assay, shRNA knockdown, NF-κB pathway readout (p-P65, p-IκBα), ELISA for cytokines, flow cytometry for apoptosis Inflammation Medium 40053057
2025 ApoEVs from MSCs are enriched in highly acetylated USP5; these vesicles promote nuclear translocation of USP5 in nucleus pulposus cells, where USP5 prevents ubiquitin-mediated degradation of E2F1 by deubiquitinating it, reducing DNA damage and apoptosis. In degenerated discs, USP5 is abnormally retained in the cytoplasm, causing aberrant E2F1 degradation. Proteomics of ApoEVs, subcellular fractionation (nuclear vs cytoplasmic USP5 localization), Co-IP, ubiquitination assay for E2F1, live imaging/immunofluorescence, transplantation model Journal of extracellular vesicles Medium 40831373
2025 USP5 is identified as a deubiquitinase for the AML1-ETO (AE) fusion oncoprotein; USP5 knockdown decreases AML cell growth and induces differentiation in t(8;21) AML. A selective USP5 inhibitor (WCY-8-67) targeting the UBA2 domain induces USP5 protein aggregation/precipitation and effectively inhibits AML cell growth in PDX models. High-throughput screening, genetic KD, UBA2 domain-targeted inhibitor characterization, protein aggregation assay, in vivo AML xenograft and PDX models Science translational medicine Medium 40991730
2025 Tipe1 recruits USP5 to inhibit K48-linked ubiquitination degradation of Gαs in pancreatic β-cells, stabilizing Gαs and maintaining cAMP signaling for insulin secretion and β-cell proliferation; β-cell-specific Tipe1 knockout mice show aggravated diabetic phenotypes. Co-IP (Tipe1–USP5–Gαs complex), K48-specific ubiquitination assay for Gαs, β-cell-specific Tipe1 KO (Ins2-Tipe1BKO) mouse, insulin secretion and β-cell mass assays, cAMP/Gαs agonist rescue Advanced science Medium 38417114
2025 USP5 directly interacts with PFKP (phosphofructokinase platelet isoform) via Co-IP confirmed by mass spectrometry; USP5 deubiquitinates PFKP to stabilize it, activating aerobic glycolysis and promoting triple-negative breast cancer progression. Co-IP/mass spectrometry, Co-IP confirmation, ubiquitination assay for PFKP, in vitro binding assay, glycolysis assay (glucose uptake, lactate), shRNA knockdown, xenograft Breast cancer research Medium 38217030

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity. Neuron 214 25189210
2020 Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation. Molecular cell 177 33217317
2008 Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. The Journal of biological chemistry 170 19098288
2023 METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Cancer communications (London, England) 145 36602428
2019 USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma. Theranostics 117 30809294
2021 USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3. Autophagy 113 34486483
2019 Structure and function of USP5: Insight into physiological and pathophysiological roles. Pharmacological research 83 31756387
2023 ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy. Nature communications 76 37208329
2011 PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Molecular carcinogenesis 76 21976412
2017 Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis. Cell death & disease 75 28933784
2021 USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1. Cell death & disease 66 34741014
2018 Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. Journal of cell science 64 29567855
2017 USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein. Biochemical and biophysical research communications 64 28807830
2014 Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway. Oncotarget 60 24980819
2021 Deubiquitinase USP5 promotes non-small cell lung cancer cell proliferation by stabilizing cyclin D1. Translational lung cancer research 54 34858787
2012 Two ZnF-UBP domains in isopeptidase T (USP5). Biochemistry 53 22283393
2022 USP5-Beclin 1 axis overrides p53-dependent senescence and drives Kras-induced tumorigenicity. Nature communications 52 36528652
2017 Identification of interleukin-1 beta as a key mediator in the upregulation of Cav3.2-USP5 interactions in the pain pathway. Molecular pain 44 28741432
2018 Overexpression of USP5 contributes to tumorigenesis in non-small cell lung cancer via the stabilization of β-catenin protein. American journal of cancer research 43 30555744
2016 A cell-permeant peptide corresponding to the cUBP domain of USP5 reverses inflammatory and neuropathic pain. Molecular pain 42 27130589
2022 USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α. Journal of cellular physiology 40 35102545
2016 TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity. Cell reports 40 27974205
2019 Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis. Acta pharmacologica Sinica 38 31197245
2020 USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt/β-Catenin Pathway. Frontiers in pharmacology 37 32477134
2008 Determination of aflatoxin B(1) levels in deep-red ground pepper (isot) using immunoaffinity column combined with ELISA. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 33 18276054
2017 Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma. Oncotarget 32 28881591
2017 The deubiquitinating enzyme USP5 promotes pancreatic cancer via modulating cell cycle regulators. Oncotarget 30 29029505
2019 Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5-WT1-E-cadherin signalling pathway in pancreatic ductal adenocarcinoma. Journal of cellular and molecular medicine 29 31845546
2020 Cav3.2 overexpression in L4 dorsal root ganglion neurons after L5 spinal nerve cutting involves Egr-1, USP5 and HMGB1 in rats: An emerging signaling pathway for neuropathic pain. European journal of pharmacology 28 32971090
2021 Macrophage-derived extracellular vesicles regulates USP5-mediated HDAC2/NRF2 axis to ameliorate inflammatory pain. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 34423867
2021 USP5 Sustains the Proliferation of Glioblastoma Through Stabilization of CyclinD1. Frontiers in pharmacology 27 34483932
2024 PFKP deubiquitination and stabilization by USP5 activate aerobic glycolysis to promote triple-negative breast cancer progression. Breast cancer research : BCR 25 38217030
2019 SUMOylation regulates USP5-Cav3.2 calcium channel interactions. Molecular brain 25 31455361
2023 USP5: Comprehensive insights into structure, function, biological and disease-related implications, and emerging therapeutic opportunities. Molecular and cellular probes 24 38049041
2022 SIX5-activated LINC01468 promotes lung adenocarcinoma progression by recruiting SERBP1 to regulate SERPINE1 mRNA stability and recruiting USP5 to facilitate PAI1 protein deubiquitylation. Cell death & disease 23 35387981
2020 Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Mediators of inflammation 23 32214906
1998 The genomic organization of Isopeptidase T-3 (ISOT-3), a new member of the ubiquitin specific protease family (UBP). Gene 22 9841226
2022 A Synthetically Accessible Small-Molecule Inhibitor of USP5-Cav3.2 Calcium Channel Interactions with Analgesic Properties. ACS chemical neuroscience 21 35113527
2023 A pan-cancer analysis of the role of USP5 in human cancers. Scientific reports 20 37268697
2014 The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development. Biochemical and biophysical research communications 20 25152394
2017 USP5/Leon deubiquitinase confines postsynaptic growth by maintaining ubiquitin homeostasis through Ubiquilin. eLife 19 28489002
2024 USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 38973363
2021 Structure-Activity Relationship of USP5 Inhibitors. Journal of medicinal chemistry 18 34648286
2018 Disrupting USP5/Cav3.2 interactions protects female mice from mechanical hypersensitivity during peripheral inflammation. Molecular brain 18 30340616
2016 Smurf1 represses TNF-α production through ubiquitination and destabilization of USP5. Biochemical and biophysical research communications 17 27133717
2014 Drosophila USP5 controls the activation of apoptosis and the Jun N-terminal kinase pathway during eye development. PloS one 17 24643212
2019 miR-125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5. Journal of cellular biochemistry 16 31452281
2017 The deubiquitinating enzyme Usp5 regulates Notch and RTK signaling during Drosophila eye development. FEBS letters 16 28140449
2023 Icariside II, a Prenyl-Flavonol, Alleviates Inflammatory and Neuropathic Pain by Inhibiting T-Type Calcium Channels and USP5-Cav3.2 Interactions. ACS chemical neuroscience 15 37116219
2021 USP5 Promotes Uterine Corpus Endometrial Carcinoma Cell Growth and Migration via mTOR/4EBP1 Activation. Cancer management and research 15 34012297
2023 The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy. Cell death & disease 14 37607937
2023 DEPDC1B-mediated USP5 deubiquitination of β-catenin promotes breast cancer metastasis by activating the wnt/β-catenin pathway. American journal of physiology. Cell physiology 14 37642235
2024 Chemoproteomics Reveals USP5 (Ubiquitin Carboxyl-Terminal Hydrolase 5) as Promising Target of the Marine Polyketide Gracilioether A. Marine drugs 13 38248666
2023 USP5 knockdown alleviates lung cancer progression via activating PARP1-mediated mTOR signaling pathway. Biology direct 13 37060095
2023 USP5 promotes lipopolysaccharide-induced apoptosis and inflammatory response by stabilizing the TXNIP protein. Hepatology communications 13 37534934
2016 USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila. The Journal of biological chemistry 13 26917723
2025 USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation. Nature communications 12 39900921
2024 BRD7 enhances the radiosensitivity of nasopharyngeal carcinoma cells by negatively regulating USP5/METTL3 axis-mediated homologous recombination repair. International journal of biological sciences 12 39664566
2020 Zebrafish ubiquitin-specific peptidase 5 (USP5) activates interferon resistance to the virus by increase the expression of RIG-I. Gene 12 32407768
2019 Tumor necrosis factor related apoptosis inducing ligand (TRAIL) regulates deubiquitinase USP5 in tumor cells. Oncotarget 12 31645897
2015 Ion mobility-mass spectrometry reveals conformational flexibility in the deubiquitinating enzyme USP5. Proteomics 12 25641936
2024 USP5 facilitates bladder cancer progression by stabilizing the c-Jun protein. Cancer cell international 11 38229092
2024 E2F1-regulated USP5 contributes to the tumorigenic capacity of glioma stem cells through the maintenance of OCT4 stability. Cancer letters 11 38643837
2020 Corrigendum: USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt/β-Catenin Pathway. Frontiers in pharmacology 10 32670065
2019 Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain. Journal of medicinal chemistry 10 31663737
2025 The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes. Science advances 8 39841822
2025 USP5-Rich Apoptotic Extracellular Vesicles Regulate Nucleus Pulposus Cells Apoptosis and DNA Damage Repair by Preventing E2F1 Proteasomal Degradation. Journal of extracellular vesicles 8 40831373
2024 The deubiquitinase USP5 promotes cholangiocarcinoma progression by stabilizing YBX1. Life sciences 8 38692507
2025 MSK1 promotes colorectal cancer metastasis by increasing Snail protein stability through USP5-mediated Snail deubiquitination. Experimental & molecular medicine 7 40164688
2025 Sodium butyrate increases USP5-mediated ubiquitination degradation of GPX4 and enhances anti-cancer efficacy of anti-PD-1 antibody. Biochemical pharmacology 7 40216263
2025 USP5-Mediated PD-L1 deubiquitination regulates immunotherapy efficacy in melanoma. Journal of translational medicine 7 40640907
2025 FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination. Journal of experimental & clinical cancer research : CR 7 41088402
2024 Structure-based virtual screening of novel USP5 inhibitors targeting the zinc finger ubiquitin-binding domain. Computers in biology and medicine 7 38603896
2024 USP5 promotes tumor progression by stabilizing SLUG in bladder cancer. Oncology letters 7 39397799
2024 Beta-Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gαs/cAMP Signaling via USP5. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 38417114
2024 USP5 promotes tumorigenesis by activating Hedgehog/Gli1 signaling pathway in osteosarcoma. American journal of cancer research 6 38590401
2024 Unraveling the Immune Regulatory Functions of USP5: Implications for Disease Therapy. Biomolecules 6 38927085
2024 Deubiquitinase USP5 regulates RIPK1 driven pyroptosis in response to myocardial ischemic reperfusion injury. Cell communication and signaling : CCS 6 39350285
2022 Usp5, Usp34, and Otu1 deubiquitylases mediate DNA repair in Drosophila melanogaster. Scientific reports 6 35393473
2025 USP5 motivates immunosuppressive microenvironment in multiple myeloma by activating STAT2-PFKFB4-mediated glycolysis. Cancer immunology, immunotherapy : CII 5 40274624
2025 A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain. The Journal of experimental medicine 5 40377597
2024 USP5 facilitates diabetic retinopathy development by stabilizing ROBO4 via deubiquitination. Cellular signalling 5 38735506
2025 USP5 Binds and Stabilizes EphA2 to Increase Nasopharyngeal Carcinoma Radioresistance. International journal of biological sciences 4 39897046
2025 USP5 deubiquitinates and stabilizes IMPDH2, to promote hepatocellular carcinoma progression. Oncogene 4 40164869
2024 USP5 negatively regulates the activation of NLRP3 inflammasomes and participates in the pathological and physiological processes of Sjogren's syndrome. International immunopharmacology 4 38772301
2024 The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1. The Journal of biological chemistry 4 39032648
2024 USP5-dependent HDAC1 promotes cisplatin resistance and the malignant progression of non-small cell lung cancer by regulating RILP acetylation levels. Thoracic cancer 4 39582290
2014 A ubiquitin shuttle DC-UbP/UBTD2 reconciles protein ubiquitination and deubiquitination via linking UbE1 and USP5 enzymes. PloS one 4 25207809
2025 PDK1-mediated phosphorylation of USP5 modulates NF-κB signalling to enhance osteosarcoma growth. International journal of biological macromolecules 3 39988167
2025 USP5 Suppresses Ferroptosis in Bladder Cancer Through Stabilization of GPX4. Current issues in molecular biology 3 40136465
2025 CYP1B1 promotes angiogenesis and sunitinib resistance in clear cell renal cell carcinoma via USP5-mediated HIF2α deubiquitination. Neoplasia (New York, N.Y.) 3 40435846
2025 Inhibition of USP5 Attenuates Atherosclerosis by Suppressing PDCD4-Mediated Endothelial Dysfunction: Evidence from In Vitro HUVEC and In Vivo Models. Cardiovascular toxicology 3 40569501
2025 USP5 regulates ferroptosis in colorectal cancer by targeting the YBX3/SLC7A11 axis through lysosomal degradation. Cell death & disease 3 41213937
2022 USP5 enhances SGTA mediated protein quality control. PloS one 3 35895711
2025 Endogenous peptide CBDP1 inhibits clear cell renal cell carcinoma progression by targeting USP5/YTHDF2/TRPM5 axis. Journal of translational medicine 2 39863860
2025 USP5 Deletion Inhibits KD Serum Induced-Human Coronary Artery Endothelial Cell Dysfunction by Regulating the NFATC1/TLR4-Mediated NF-κB Signaling Pathway in Kawasaki Disease. Inflammation 2 40053057
2025 USP5 inhibition via bone marrow-targeted engineered exosomes for myeloproliferative neoplasms therapy. Journal of nanobiotechnology 2 40646529
2025 USP5 deubiquitylates and stabilizes FcεRIγ to enhance IgE-induced mast cell activation and allergic inflammation. Science signaling 2 40729432
2025 METTL1-driven epitranscriptomic enhancement of TXNDC12 boosts c-Myc stability through USP5 in HNSCC. Experimental & molecular medicine 2 40750708
2025 USP5 inhibition enables potential therapy for t(8;21) AML through ubiquitin-mediated AML1-ETO degradation in patient-derived xenografts. Science translational medicine 2 40991730

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