Affinage

USP4

Ubiquitin carboxyl-terminal hydrolase 4 · UniProt Q13107

Length
963 aa
Mass
108.6 kDa
Annotated
2026-06-11
91 papers in source corpus 57 papers cited in narrative 56 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP4 is a nucleocytoplasmic-shuttling ubiquitin-specific protease (cysteine deubiquitylase) that controls the stability and activity of a broad set of signaling proteins by cleaving K48- and K63-linked polyubiquitin and monoubiquitin from its substrates (PMID:9464533, PMID:11018721, PMID:20141612). Catalysis depends on the active-site cysteine (C311), and its full turnover is governed allosterically by the N-terminal DUSP-Ubl domain, which promotes ubiquitin product discharge through a conformational change near the active site (PMID:21331078, PMID:25404403). USP4 moves between nucleus and cytoplasm via a defined nuclear export signal and an importin-recognized nuclear import signal (PMID:15494318), with nuclear entry and spliceosomal substrate access supplied by binding to the SART3 HAT-repeat scaffold; AKT-mediated phosphorylation drives nuclear-to-cytoplasmic/membrane relocalization and stabilizes the enzyme (PMID:22706160, PMID:27060135, PMID:42091674). Through these activities USP4 acts as a hinge across multiple pathways: it stabilizes the TGF-β type I receptor and deubiquitylates SMAD4 to potentiate TGF-β/activin/BMP signaling (PMID:22706160, PMID:28468752); it deubiquitylates TAK1, TRAF2/TRAF6, and IRF3 to tune NF-κB and interferon responses (PMID:21331078, PMID:22029577, PMID:38556105); it stabilizes RIG-I and MAVS to promote antiviral innate immunity (PMID:23388719, PMID:39589880); and it promotes DNA-end resection and homologous recombination through CtIP/MRN and BRCA1, requiring auto-deubiquitylation for these interactions (PMID:26455393, PMID:26387952, PMID:38734703). USP4 also engages the p53 axis by stabilizing the E3 ligase ARF-BP1 to lower p53, a role corroborated by Usp4-knockout mice showing elevated p53-dependent phenotypes (PMID:21522127). In cancer contexts USP4 stabilizes pro-tumorigenic substrates including Twist1, β-catenin, PKM2, and PES1 to drive stemness, metabolism, and proliferation (PMID:32549341, PMID:39266638, PMID:39856683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Establishing that USP4 is a bona fide enzyme answered whether the gene encodes catalytic activity rather than merely a sequence motif, defining it as a cysteine-dependent deubiquitylase.

    Evidence in vitro deubiquitination assay with catalytic-cysteine-to-alanine mutagenesis and cellular fractionation

    PMID:11018721 PMID:9464533

    Open questions at the time
    • No physiological substrate identified at this stage
    • Chain-linkage preference not yet defined
  2. 2001 High

    Identifying pRb and pocket-protein binding addressed how the originally oncogenic USP4 might connect to growth control, linking it physically to the Rb tumor-suppressor pathway.

    Evidence reciprocal Co-IP, in vitro binding, and motif mutagenesis

    PMID:11571651 PMID:11571652

    Open questions at the time
    • Whether USP4 deubiquitylates pRb was not shown
    • Functional consequence of the interaction for Rb activity unresolved
  3. 2004 High

    Mapping functional export and import signals answered how USP4 localization is determined, establishing it as an actively shuttling enzyme with cell-type-dependent distribution.

    Evidence live-cell imaging, leptomycin B export inhibition, Rev-GFP export assay, importin binding, USP4-specific antibodies

    PMID:15494318

    Open questions at the time
    • Signals controlling the shuttling equilibrium not identified here
    • Functional importance of nuclear versus cytoplasmic pools undefined
  4. 2009 Medium

    Demonstrating dual K48/K63 chain hydrolysis and Wnt suppression via NLK/TCF4 defined USP4's biochemical breadth and its first signaling pathway role.

    Evidence RNAi screen, luciferase reporter, Co-IP, ubiquitin chain hydrolysis assay

    PMID:20141612

    Open questions at the time
    • Direct TCF4 deubiquitylation in vitro not fully resolved
    • Mechanism of NLK-driven nuclear accumulation unclear
  5. 2011 High

    Linking USP4 to TAK1 and to ARF-BP1/p53 answered how it represses NF-κB and modulates apoptosis/senescence, providing the first in vivo genetic evidence of its role.

    Evidence in vitro deubiquitination with C311A mutant, Co-IP, NF-κB reporter, Usp4 knockout mouse and MEF assays

    PMID:21331078 PMID:21522127

    Open questions at the time
    • Context-dependent positive versus negative NF-κB regulation not reconciled
    • Whether p53 and NF-κB effects share a common pathway unresolved
  6. 2012 High

    Identifying TβRI stabilization and AKT-mediated regulation answered how USP4 promotes TGF-β-driven EMT and how upstream kinase signaling controls USP4 localization and stability.

    Evidence genome-wide gain-of-function screen, in vitro DUB assay, AKT kinase assay, fractionation, metastasis assays

    PMID:22706160

    Open questions at the time
    • Phosphosites on USP4 not exhaustively mapped here
    • How phosphorylation alters catalytic activity vs trafficking not separated
  7. 2014 High

    Defining the DUSP-Ubl domain's allosteric role answered the long-standing question of why full-length USP4 turns over substrate efficiently, revealing product-discharge acceleration as the mechanism.

    Evidence pre-steady-state kinetics, structural analysis, domain deletion/mutation

    PMID:25404403

    Open questions at the time
    • Whether substrate-specific partners modulate this allostery in cells untested
    • Structure of full-length enzyme with substrate not solved
  8. 2016 High

    Solving the SART3-DUSP/UBL structure answered how USP4 is delivered to the nucleus and to spliceosomal substrates, coupling scaffold binding to localization and activity.

    Evidence X-ray crystallography, affinity measurement, NLS-mutant localization and activity assays

    PMID:27060135

    Open questions at the time
    • Spliceosomal substrate identity not defined in this study
    • Whether AKT phosphorylation competes with SART3 binding unknown
  9. 2017 High

    Showing SMAD4 deubiquitylation and CtIP/MRN-dependent HR established two mechanistically distinct roles—developmental TGF-β signaling and DNA-end resection—and revealed auto-deubiquitylation as a prerequisite for HR engagement.

    Evidence in vitro DUB assays, zebrafish/mESC functional rescue, MS mapping of USP4 ubiquitylation sites, HR reporter

    PMID:26387952 PMID:26455393 PMID:28468752

    Open questions at the time
    • How USP4 is recruited to DNA damage sites mechanistically undefined
    • Relationship between SMAD4 monoubiquitin removal and receptor-level TGF-β regulation not integrated
  10. 2017 High

    Identifying RIG-I substrate stabilization positioned USP4 as a positive regulator of antiviral interferon signaling, distinct from its NF-κB-suppressing roles.

    Evidence Co-IP, K48-linkage-specific DUB assay, IFN-β reporter, viral replication assay

    PMID:23388719

    Open questions at the time
    • Why USP4 expression falls after RIG-I activation mechanistically unclear
    • Linkage-specificity determinants at substrate level undefined
  11. 2024 High

    Mapping site-specific MAVS (K461) and IRF3 regulation refined how USP4 sets the threshold of innate immune signaling, including a p53-PBLD-USP4-MAVS axis and an interferon-suppressive role in cancer.

    Evidence site-specific ubiquitination mapping, K48/K63-specific DUB assays, PBLD knockout mouse, IRF3 nuclear localization, syngeneic model

    PMID:38556105 PMID:39589880

    Open questions at the time
    • How USP4 selects opposing pro- versus anti-interferon outcomes across tissues unresolved
    • Coordination with the RIG-I/TRAF6 arms not unified
  12. 2024 Medium

    Expanding the substrate set to BRCA1, PES1, RAB7A and others demonstrated USP4's reach into HR repair, ribosome biogenesis, and autophagic trafficking, broadening its cellular footprint.

    Evidence Co-IP, chain-specific ubiquitination assays, HR/ribosome/autophagy functional readouts, conditional knockout mice

    PMID:38734703 PMID:39266638 PMID:39663592

    Open questions at the time
    • Most substrate relationships rest on single-lab studies without reciprocal cross-validation
    • Whether localization gating determines which substrates are engaged not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP4 selects among its many substrates and reconciles opposing roles (tumor suppressor via p53/Rb versus oncogenic stabilizer of Twist1/β-catenin/PKM2) in a context-dependent manner remains unresolved.
  • No unifying model linking localization, phosphorylation state, and substrate choice
  • Substrate-specificity determinants of K48 vs K63 vs monoubiquitin cleavage undefined
  • In vivo substrate hierarchy across tissues not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2
Partners
ARF-BP1CTIPMAVSRIG-ISART3SMAD4TAK1TRAF6
Complex memberships
MRE11-RAD50-NBS1 (MRN) complex

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The mouse Unp (USP4 ortholog) protein contains a putative nuclear localization signal and consensus sequences for binding to the retinoblastoma gene product (pRb), and its overexpression causes tumorigenic transformation of NIH3T3 cells. cDNA cloning, sequence analysis, NIH3T3 transformation assay Oncogene Medium 8336951
1994 The Unp (USP4) protein is localized in the nucleus, as demonstrated by expression of the protein product and subcellular localization analysis. Subcellular localization/immunofluorescence of expressed protein Oncogene Medium 8183569
1998 Human UNP/USP4 encodes two cytoplasmic isoforms with deubiquitinating activity; mutation of the conserved catalytic cysteine to alanine abolishes deubiquitination activity. Endogenous protein localizes primarily to the cytoplasm. Deubiquitination assay, site-directed mutagenesis, cellular fractionation, immunocytochemistry Oncogene High 9464533
2000 Mouse Unp and human Unph (USP4) are active deubiquitinating enzymes that cleave ubiquitin from natural and engineered linear ubiquitin-protein fusions including polyubiquitin precursors; mutation of conserved Cys and His residues abolishes activity; USP4 does not generally disrupt ubiquitin-dependent proteolysis of N-end rule or non-N-end rule substrates in yeast. In vitro deubiquitination assay, site-directed mutagenesis, yeast degradation assay Biochimica et biophysica acta High 11018721
2001 USP4 (Unp) specifically interacts with the retinoblastoma protein (pRb) in cells; this interaction is sensitive to site-directed mutations analogous to those in viral oncoproteins that disrupt Rb binding. Co-immunoprecipitation, in vitro binding, site-directed mutagenesis Oncogene High 11571651 11571652
2001 USP4 (Unp) also associates with the pocket proteins p107 and p130 in addition to pRb; these associations are detectable in vitro and in cells. Co-immunoprecipitation, in vitro binding assay Oncogene Medium 11571651
2004 USP4 undergoes nucleocytoplasmic shuttling: it contains a functional nuclear export signal (133VEVYLLELKL142) and a nuclear import signal (766QPQKKKK772) recognized by importin α/β. Inhibition of nuclear export with leptomycin B causes nuclear accumulation of both exogenous and endogenous USP4. The equilibrium of USP4 localization varies between cell types. Live-cell fluorescence imaging (RFP-USP4), leptomycin B treatment, Rev-GFP export assay, importin binding assay, highly specific antibodies distinguishing USP4 from USP15 The Journal of biological chemistry High 15494318
2005 USP4 binds to the C-terminus of the A2A adenosine receptor (A2AR), deubiquitinates it, and thereby enhances its cell surface expression by relaxing ER quality control. This effect is specific to the A2AR C-terminus and is not seen with USP14 or the metabotropic glutamate receptor-5. Co-immunoprecipitation, cell surface expression assay, ubiquitination assay, C-terminal truncation mutants Molecular pharmacology Medium 16339847
2006 USP4 (UnpEL) functions as a deubiquitinating enzyme in human cells and specifically deconjugates ubiquitin from the interacting protein Ro52 via its isopeptidase activity. USP4 co-localizes with Ro52 in cytoplasmic rod-like structures when Ro52 is overexpressed. Co-immunoprecipitation, deubiquitination assay in HEK293T cells, immunofluorescence co-localization Biochemical and biophysical research communications Medium 16316627
2009 USP4 suppresses canonical Wnt signaling; its knockdown activates β-catenin-dependent transcription. USP4 has dual hydrolysing activity for K48- and K63-conjugated polyubiquitin chains, interacts with Nemo-like kinase (NLK) and TCF4, and deubiquitinates TCF4. Overexpression of catalytically active NLK promotes nuclear accumulation of USP4. RNAi screen, luciferase reporter assay, co-immunoprecipitation, ubiquitin chain hydrolysis assay Journal of cellular and molecular medicine Medium 20141612
2011 USP4 deubiquitinates TAK1 by removing K63-linked polyubiquitin chains both in vitro and in vivo; TNFα induces USP4-TAK1 association; overexpression of catalytically active USP4 but not the C311A catalytic mutant inhibits TAK1 polyubiquitination and NF-κB activation; knockdown of USP4 enhances TAK1 polyubiquitination and downstream NF-κB signaling. USP4 also negatively regulates IL-1β-, LPS-, and TGFβ-induced NF-κB activation. In vitro deubiquitination assay, co-immunoprecipitation, NF-κB reporter assay, siRNA knockdown, catalytic mutant (C311A) Cell death and differentiation High 21331078
2011 USP4 directly interacts with and deubiquitinates ARF-BP1, leading to ARF-BP1 stabilization and subsequent reduction of p53 levels. Usp4 knockout mice show enhanced apoptosis in thymus and spleen after ionizing radiation, and Usp4−/− MEFs exhibit retarded growth, premature senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints consistent with elevated p53. Co-immunoprecipitation, in vitro deubiquitination, Usp4 knockout mouse analysis, MEF functional assays The EMBO journal High 21522127
2012 USP4 directly interacts with TGF-β type I receptor (TβRI) and acts as a deubiquitylating enzyme to stabilize TβRI at the plasma membrane, counteracting SMAD7-SMURF2-mediated ubiquitylation and degradation. AKT directly associates with and phosphorylates USP4, relocating nuclear USP4 to the cytoplasm and membrane and maintaining its protein stability. USP4 depletion mitigates TGF-β-induced EMT and metastasis. AKT-induced breast cancer cell migration is inhibited by USP4 depletion. Genome-wide gain-of-function screen, co-immunoprecipitation, in vitro deubiquitylation assay, AKT kinase assay, subcellular fractionation, siRNA knockdown, metastasis assays Nature cell biology High 22706160
2012 USP4 specifically interacts with TRAF2 and TRAF6 (but not TRAF3) and deubiquitinates both in vitro and in vivo in a deubiquitinase activity-dependent manner. The USP domain of USP4 mediates interaction with TRAF6 independently of deubiquitinase activity. USP4 negatively regulates TNFα- and IL-1β-induced NF-κB activation and cancer cell migration. Co-immunoprecipitation, in vitro deubiquitination assay, NF-κB reporter, domain mapping, cell migration assay The Biochemical journal High 22029577
2012 USP4 interacts with the S9/Rpn6 subunit of the 26S proteasome via an internal ubiquitin-like (UBL) domain. Co-immunoprecipitation, domain mapping Biochemical and biophysical research communications Medium 23022198
2013 USP4 interacts with RIG-I and removes K48-linked polyubiquitination chains from RIG-I, thereby stabilizing RIG-I protein and positively regulating RIG-I-mediated IFN-β signaling and antiviral response. USP4 expression is attenuated after virus-induced RIG-I activation. Co-immunoprecipitation, ubiquitin chain-linkage-specific deubiquitination assay, siRNA knockdown, IFN-β reporter assay, viral replication assay Journal of virology High 23388719
2014 USP4 has its catalytic triad in a productive conformation but requires its N-terminal DUSP-Ubl domain for full catalytic turnover. The DUSP-Ubl domain enhances ubiquitin dissociation after substrate hydrolysis ('product discharge'), and binding of the DUSP-Ubl domain promotes a conformational change in a switching loop near the active site. Pre-steady-state kinetics, structural analysis, domain deletion/mutation experiments Nature communications High 25404403
2015 USP4 promotes DNA-end resection and homologous recombination (HR) by interacting with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites. USP4 itself is ubiquitylated on multiple sites including cysteine residues, and auto-deubiquitylation of these sites is required for USP4 to interact with CtIP/MRN and to promote HR. Co-immunoprecipitation, HR reporter assay, DNA damage sensitivity assay, mass spectrometry identification of ubiquitylation sites, catalytic mutant analysis Molecular cell High 26387952 26455393
2015 USP4 interacts directly with and deubiquitinates HDAC2, stabilizing HDAC2 and leading to compromised p53 acetylation, impaired p53 transcriptional activation, and downregulation of TNFα-induced NF-κB activation. Co-immunoprecipitation, in vitro deubiquitination assay, p53 acetylation assay, NF-κB reporter assay Oncogene Medium 26411366
2016 The crystal structure of the SART3 HAT repeat domain in complex with the DUSP-UBL domains of USP4 was determined. USP4 binds SART3 at the β-structured linker between DUSP and UBL domains (Kd ~0.9 μM). SART3 recruits USP4 to the nucleus via its NLS; removal of SART3 NLS prevents nuclear entry of USP4 and abrogates its deubiquitinase activity toward spliceosomal substrates. X-ray crystallography, binding affinity measurement, nuclear localization assay, deubiquitinase activity assay with SART3 NLS mutants Nucleic acids research High 27060135
2017 USP4 deubiquitinates SMAD4 by removing inhibitory monoubiquitination, thereby strongly inducing activin/BMP signaling. SMURF2 is recruited to SMAD4 upon ligand stimulation and triggers SMAD4 monoubiquitination. Depletion of USP4 in mouse embryonic stem cells increases monoubiquitinated SMAD4 and decreases BMP- and activin-induced cell fate changes. USP4 depletion in zebrafish causes defective cell migration and epiboly, both rescued by SMAD4. Co-immunoprecipitation, in vitro deubiquitination, mESC differentiation assay, zebrafish morpholino knockdown with rescue The EMBO journal High 28468752
2017 USP4 preferentially removes monoubiquitination from HAS2 (hyaluronan synthase 2), interacts with HAS2 in membrane preparations, and suppression of USP4 increases hyaluronan synthesis. DUB screen, co-immunoprecipitation from membrane fractions, ubiquitination assay, siRNA knockdown with hyaluronan production measurement Oncogenesis Medium 28604766
2017 USP4 physically interacts with IRF8 and stabilizes it via K48-linked deubiquitination in regulatory T cells, thereby promoting the suppressive function of Treg cells. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), USP4 inhibitor treatment, Treg functional suppression assay FEBS letters Medium 28477415
2017 USP4 suppresses myoblast differentiation by downregulating MyoD activity in a catalytic-independent manner. USP4 knockdown enhances myogenesis and reduces HDAC1 and HDAC4 activity/protein levels. The effect on myogenesis involves AKT and p38 MAPK signaling pathways. siRNA knockdown, overexpression with catalytic mutant, C2C12 differentiation assay, immunoblot for myogenic markers Cellular signalling Medium 28336234
2018 USP4 interacts with TRAF6 and positively regulates RLR-induced NF-κB signaling by removing K48-linked ubiquitin chains from TRAF6, preventing TRAF6 degradation. Overexpression of USP4 suppresses EV71 replication. Co-immunoprecipitation, K48-linkage-specific deubiquitination assay, NF-κB reporter, viral replication assay Scientific reports Medium 30194441
2019 USP4 co-immunoprecipitates with AQP2 from mpkCCD14 cells and mouse kidney; USP4 can deubiquitylate AQP2 in vitro; shRNA knockdown of USP4 decreases AQP2 protein abundance and reduces VP-induced AQP2 membrane accumulation, associated with higher levels of ubiquitylated AQP2, without affecting AQP2 mRNA levels. AQP2 protein half-life is reduced in USP4 knockdown cells. Co-immunoprecipitation, in vitro deubiquitylation assay, shRNA knockdown, VP-stimulation membrane accumulation assay, protein half-life assay Cells High 30901874
2019 USP4 deficiency exacerbates hepatic ischaemia/reperfusion injury by inducing activation of TAK1/JNK signaling pathways; TAK1 inhibition abolishes USP4 protective function in vitro, placing USP4 upstream of TAK1 in this context. USP4 knockout mouse model, TAK1 pharmacological inhibition, hepatic I/R model, pathway analysis Clinical science Medium 30622220
2019 USP4 was identified as a downstream target of PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation and PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway, thereby indirectly stabilizing USP4. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, in vivo xenograft International journal of cancer Medium 31219614
2019 Phosphorylation status of USP4 (analogous to USP15 Thr149/Thr219) regulates its nuclear-cytoplasmic distribution and deubiquitinase activity. Treatment with cyclin-dependent kinase inhibitor purvalanol A causes changes in USP4 localization and activity, dependent on phosphorylation. Nuclear-cytoplasmic fractionation, mass spectrometry, CDK inhibitor treatment, activity assay Journal of molecular biology Medium 31330151
2020 USP4 binds to, deubiquitinates, and stabilizes Twist1 protein. Silencing USP4 reduces Oct4, Sox2, and CD133+ cell population and inhibits tumorsphere formation in lung cancer cells. USP4-promoted stemness is effectively rescued by simultaneous silencing of Twist1. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, tumorsphere formation, rescue experiment Cancers Medium 32549341
2022 USP4 deubiquitinates PDGFRβ (removing both K63 and K48-linked chains), does not affect receptor stability but alters the speed of PDGFRβ trafficking toward early endosomes, and leads to prolonged/shifted STAT3 activation in response to PDGF-BB. Deletion of USP4 leads to decreased proliferative response to PDGF-BB stimulation. DUB overexpression screen, co-immunoprecipitation, receptor trafficking assay, STAT3 activation assay, USP4 knockout Cellular and molecular life sciences Medium 35064336
2022 USP4 and its paralog USP15 regulate alternative splicing of SRSF1; depletion of USP4 impairs SRSF1 splicing, promoting an alternative isoform (SRSF1-3) subject to nonsense-mediated mRNA decay, and thereby impairs lung cancer cell proliferation. siRNA knockdown, RT-PCR for alternative splicing, rescue with SRSF1 overexpression, proliferation assay Cell death discovery Medium 35027535
2023 USP4 interacts with cortactin (CTTN) via proximal labeling in HCT116 cells, and this interaction promotes cell migration independently of USP4 deubiquitinase activity on cortactin; USP4 overexpression increases cortactin phosphorylation by regulating Src/FAK binding to cortactin. Proximity labeling (BioID), co-immunoprecipitation, cortactin phosphorylation assay, migration assay, CTTN knockdown rescue FASEB journal Medium 37039823
2023 USP4 stabilizes TAK1 protein via deubiquitination in esophageal squamous cell carcinoma cells, and promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway. Co-immunoprecipitation, deubiquitination assay, MEK/ERK pathway inhibition (U0126), loss/gain-of-function, in vivo xenograft Cell death & disease Medium 37949874
2023 USP4 interacts with and deubiquitinates PKM2, stabilizing it and promoting cell proliferation and glycolysis (glucose uptake and lactate production) in gastric cancer cells. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, metabolic assays (glucose uptake, lactate production), MTT proliferation assay PloS one Medium 37624791
2023 Vialinin A inhibits USP4 deubiquitinating enzyme activity, leading to enhanced K48-ubiquitination and proteasomal degradation of Keap1, thereby activating Nrf2-dependent antioxidant response; overexpression of USP4 reverses these neuroprotective effects. USP4 enzymatic inhibition assay, co-immunoprecipitation, ubiquitination assay, luciferase reporter, USP4 overexpression rescue in vivo (MCAO model) Phytomedicine Medium 38176274
2024 USP4 interacts with SART3 and deubiquitinates TUT1 (terminal uridylyl transferase 1), a key U4/U6 spliceosome regulator; SART3 enhances USP4 deubiquitinating activity toward TUT1; USP4 orchestrates subnuclear relocalization of TUT1 from the nucleolus to the nucleoplasm and facilitates stability of U6 snRNA. Co-immunoprecipitation, ubiquitination assay, immunofluorescence for TUT1 localization, U6 snRNA stability assay Biochemical and biophysical research communications Medium 38310689
2024 USP4 interacts with, deubiquitinates and stabilizes BRCA1, maintaining its protein level. USP4 knockdown decreases BRCA1, impairs homologous recombination-mediated DSB repair, increases genome instability, and confers resistance to DNA damage agents and PARP inhibitors. Co-immunoprecipitation, ubiquitination assay, HR reporter assay, DNA damage sensitivity assay, genome instability assay NPJ breast cancer Medium 38734703
2024 USP4 deubiquitinates RAB7A; reduced USP4 levels in periodontitis lead to RAB7A ubiquitination, impairing autophagosome-lysosome fusion and lysosomal trafficking. Upregulation of USP4 attenuates periodontitis in vivo. Proteomics analysis, co-immunoprecipitation, ubiquitination assay, autophagy flux assay, in vivo periodontitis model Autophagy Medium 39663592
2024 USP4 deubiquitinates and stabilizes PES1, facilitating ribosome biogenesis and protein synthesis in proliferating hematopoietic stem cells and leukemic cells; Usp4 deletion decreases protein synthesis and HSC reconstitution capacity. Co-immunoprecipitation, ubiquitination assay, ribosome biogenesis assay, protein synthesis measurement, Usp4 conditional knockout mouse Leukemia Medium 39266638
2024 USP4 impedes the nuclear localization of IRF3 by deubiquitinating the K63-polyubiquitin chain of both TRAF6 and IRF3, thereby suppressing the tumor-intrinsic interferon response and antitumor immunity in colorectal cancer. Co-immunoprecipitation, K63-specific deubiquitination assay, IRF3 nuclear localization assay, siRNA knockdown, syngeneic mouse model Cancer letters Medium 38556105
2024 USP4 deubiquitinates MAVS by removing K48-linked ubiquitin chains at Lys461, stabilizing MAVS and promoting antiviral innate immunity. This activity is activated through the p53-USP4-MAVS signaling axis downstream of PBLD. Co-immunoprecipitation, site-specific ubiquitination assay (K48 chains, Lys461 of MAVS), PBLD knockout mouse, IFN-I response assay Proceedings of the National Academy of Sciences High 39589880
2024 USP4 interacts with, deubiquitinates and stabilizes CARM1, promoting its activity; CARM1 stabilization by USP4 upregulates SLC7A11 expression, contributing to breast cancer cell malignancy. Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, rescue experiment Clinical breast cancer Medium 39500657
2025 USP4 directly cleaves both Lys48- and Lys63-linked polyubiquitin chains of ANXA2, with the Lys63-linked chains at K28 mediating ANXA2 Y24 phosphorylation. K10 acetylation of ANXA2 enhances its interaction with USP4. USP4 stabilizes ANXA2 and promotes glioblastoma stem cell maintenance and radioresistance via BMX-mediated STAT3 activation. Co-immunoprecipitation, chain-specific ubiquitination assay, phosphorylation assay, acetylation assay, siRNA knockdown, tumorsphere assay, radioresistance assay Cell death and differentiation Medium 40185997
2025 FBXO3 binds to and stabilizes USP4 by disrupting the interaction between USP4 and DNPEP (which mediates USP4 degradation), thereby stabilizing Twist1 via USP4 deubiquitinase activity and promoting breast cancer metastasis. PI3K/p110αH1047R facilitates phosphorylation and stabilization of FBXO3 via ERK1. Co-immunoprecipitation, protein stability assay, ubiquitination assay, siRNA knockdown, in vivo breast cancer metastasis model PLoS biology Medium 38134227
2025 USP4 interacts with and stabilizes PGAM5 by removing K48-linked ubiquitin chains, thereby regulating mitochondrial dynamics and promoting mitophagy in esophageal squamous cell carcinoma. Co-immunoprecipitation, K48-specific ubiquitination assay, mitochondrial function assays (MMP, mtROS), in vivo tumor model Molecular carcinogenesis Medium 41176636
2025 USP4 interacts with, deubiquitinates, and stabilizes LDHA protein in papillary thyroid carcinoma cells, and promotes PTC proliferation by modulating MAPK and AKT signaling pathways. Co-immunoprecipitation, deubiquitination assay, MAPK/AKT pathway analysis, siRNA knockdown, proliferation assay Aging Medium 39393052
2025 USP4 modulates ZBP1 ubiquitination: USP4 interacts with, deubiquitinates, and stabilizes ZBP1 in microglia. AKT-mediated phosphorylation is required to maintain USP4 protein stability. Pharmacological inhibition of USP4 with Vialinin A leads to ZBP1 degradation and reduces microglial PANoptosis after traumatic brain injury. Co-immunoprecipitation, deubiquitination assay, AKT phosphorylation analysis, Vialinin A inhibitor treatment, TBI mouse model Cell death and differentiation Medium 42091674
2025 USP4 stabilizes β-catenin and Twist1 proteins in colorectal cancer cells by deubiquitinating them; a novel small molecule inhibitor U4-I05 binds the catalytic C311 site of USP4 and triggers proteasomal degradation of β-catenin and Twist1, inhibiting cancer stemness. Virtual screening, co-immunoprecipitation, ubiquitination assay, catalytic site binding assay, cancer stemness assay (organoids, xenograft), site-specific mutant (C311) Journal of translational medicine Medium 39856683
2025 USP4 deubiquitinates and stabilizes NR4A1, protecting it from ubiquitination-mediated degradation; MEF2A transcriptionally activates USP4 expression by binding its promoter; the MEF2A-USP4-NR4A1 axis suppresses ER stress and apoptosis in multiple myeloma cells. Co-immunoprecipitation, ubiquitination assay, ChIP assay, luciferase reporter, siRNA knockdown, xenograft model FASEB journal Medium 41186214
2025 USP4 deubiquitinates and stabilizes KLF2 protein; KLF2 transcriptionally regulates HMGA2; the USP4/KLF2/HMGA2 cascade regulates cell growth, apoptosis, and bortezomib sensitivity in drug-resistant multiple myeloma cells. Co-immunoprecipitation, protein stability assay, luciferase reporter, ChIP assay, functional growth and apoptosis assays Journal of orthopaedic surgery and research Medium 40022160
2025 USP4 deubiquitinates and stabilizes SRC-1, enhancing its protein stability; the USP4-SRC-1 axis inhibits M2 macrophage polarization via the NF-κB pathway and is validated in an OVA-induced asthma model in vivo. Co-immunoprecipitation, ubiquitination assay, flow cytometry for macrophage polarization, NF-κB pathway analysis, in vivo OVA model Experimental lung research Medium 40493388
2025 USP4 stabilizes PAF1 by directly binding and reducing its K48-linked polyubiquitination, counteracting CNOT4-mediated PAF1 degradation and promoting NSCLC cell proliferation in vitro and tumor growth in vivo. Co-immunoprecipitation, K48-ubiquitination assay, rescue assay, CCK-8 proliferation, xenograft model Respiratory research Medium 41857610
2025 USP4 removes Lys48-linked polyubiquitin chains from the A2A receptor (A2AR) via deubiquitination at the C311 site in gastric cancer cells, stabilizing A2AR, modulating autophagy, and inhibiting ferroptosis. Co-immunoprecipitation, K48-specific ubiquitination assay, catalytic mutant (C311), autophagy and ferroptosis assays Cellular and molecular life sciences Medium 41051500
2026 USP4 interacts with and stabilizes CENPF via deubiquitination in colorectal cancer; USP4 expression positively correlates with CENPF protein (but not mRNA) levels in clinical samples; USP4-mediated CENPF upregulation is a critical regulator of CRC metastasis. Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, in vivo metastasis model, clinical sample correlation Cell death & disease Medium 39922805
2026 USP4, enriched in melatonin-preconditioned exosomes, directly interacts with and deubiquitinates ARNTL (a core circadian regulator), stabilizing its protein levels and suppressing ferroptosis in skin flap cells. H3K18 lactylation upregulates USP4 mRNA, enhancing USP4 translation within exosomes. Co-immunoprecipitation, deubiquitination assay, m6A modification analysis, ferroptosis assay, in vivo flap model Clinical and translational medicine Medium 41482632

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nature cell biology 280 22706160
2011 USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation. Cell death and differentiation 141 21331078
2012 Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration. The Biochemical journal 137 22029577
2011 USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. The EMBO journal 135 21522127
2005 The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor. Molecular pharmacology 113 16339847
2013 USP4 positively regulates RIG-I-mediated antiviral response through deubiquitination and stabilization of RIG-I. Journal of virology 104 23388719
1995 Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung tumors. Oncogene 91 7784062
2018 H19/miR-148a/USP4 axis facilitates liver fibrosis by enhancing TGF-β signaling in both hepatic stellate cells and hepatocytes. Journal of cellular physiology 88 30362572
2014 The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange. Nature communications 80 25404403
2009 The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway. Journal of cellular and molecular medicine 76 20141612
2015 USP4 Auto-Deubiquitylation Promotes Homologous Recombination. Molecular cell 71 26455393
2019 Targeting the circBMPR2/miR-553/USP4 Axis as a Potent Therapeutic Approach for Breast Cancer. Molecular therapy. Nucleic acids 69 31302495
2015 USP4 inhibits p53 and NF-κB through deubiquitinating and stabilizing HDAC2. Oncogene 66 26411366
1994 The Unp proto-oncogene encodes a nuclear protein. Oncogene 66 8183569
1993 Unp, a mouse gene related to the tre oncogene. Oncogene 65 8336951
1999 Identification, functional characterization, and chromosomal localization of USP15, a novel human ubiquitin-specific protease related to the UNP oncoprotein, and a systematic nomenclature for human ubiquitin-specific proteases. Genomics 59 10444327
2015 Evolution of the highly networked deubiquitinating enzymes USP4, USP15, and USP11. BMC evolutionary biology 54 26503449
2015 The Deubiquitylating Enzyme USP4 Cooperates with CtIP in DNA Double-Strand Break End Resection. Cell reports 53 26387952
2017 USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling. The EMBO journal 49 28468752
1998 The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines. Oncogene 45 9464533
2021 Spotlight on USP4: Structure, Function, and Regulation. Frontiers in cell and developmental biology 43 33681193
2016 USP4 promotes invasion of breast cancer cells via Relaxin/TGF-β1/Smad2/MMP-9 signal. European review for medical and pharmacological sciences 43 27049265
2020 The Deubiquitinase USP4 Stabilizes Twist1 Protein to Promote Lung Cancer Cell Stemness. Cancers 39 32549341
2004 Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme. The Journal of biological chemistry 38 15494318
2023 USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1. Cell death & disease 33 37949874
2023 Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing METTL3-mediated m6A methylation of THRAP3, RBM25, and USP4. Cell cycle (Georgetown, Tex.) 32 36762777
2018 Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma. Journal of cellular and molecular medicine 32 29542252
2017 Downregulation of USP4 Promotes Activation of Microglia and Subsequent Neuronal Inflammation in Rat Spinal Cord After Injury. Neurochemical research 31 28755289
2016 Structural basis for recruiting and shuttling of the spliceosomal deubiquitinase USP4 by SART3. Nucleic acids research 31 27060135
2022 MIR99AHG inhibits EMT in pulmonary fibrosis via the miR-136-5p/USP4/ACE2 axis. Journal of translational medicine 29 36138468
2019 A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis. International journal of cancer 28 31219614
2006 Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity. Biochemical and biophysical research communications 28 16316627
2017 The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function. Oncogenesis 27 28604766
2017 USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells. FEBS letters 26 28477415
2001 The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein. Oncogene 26 11571652
2018 USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication. Scientific reports 24 30194441
2001 Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130. Oncogene 24 11571651
2019 Phosphorylation of USP15 and USP4 Regulates Localization and Spliceosomal Deubiquitination. Journal of molecular biology 23 31330151
2023 FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis. PLoS biology 22 38134227
2020 The Effects of the Transforming Growth Factor-β1 (TGF-β1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures. Medical science monitor : international medical journal of experimental and clinical research 22 32308208
2015 AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4. BMC cell biology 22 25885904
2022 USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1. Cell death discovery 21 35027535
2022 LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition. Environmental toxicology 21 35841383
2000 Characterization of the ubiquitin-specific protease activity of the mouse/human Unp/Unph oncoprotein. Biochimica et biophysica acta 21 11018721
2025 Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells. Cell death and differentiation 19 40185997
2023 Vialinin A alleviates oxidative stress and neuronal injuries after ischaemic stroke by accelerating Keap1 degradation through inhibiting USP4-mediated deubiquitination. Phytomedicine : international journal of phytotherapy and phytopharmacology 19 38176274
2018 USP4 expression independently predicts favorable survival in lung adenocarcinoma. IUBMB life 18 29667299
2019 USP4 deficiency exacerbates hepatic ischaemia/reperfusion injury via TAK1 signalling. Clinical science (London, England : 1979) 17 30622220
2017 MiR-148a suppresses invasion and induces apoptosis of breast cancer cells by regulating USP4 and BIM expression. International journal of clinical and experimental pathology 17 31966687
2024 Deubiquitinase USP4 suppresses antitumor immunity by inhibiting IRF3 activation and tumor cell-intrinsic interferon response in colorectal cancer. Cancer letters 15 38556105
2024 USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis. Autophagy 15 39663592
2019 The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance. Cells 15 30901874
2022 The Deubiquitinating Enzyme USP4 Functions as an Oncoprotein in Gastric Cancer and Mediates NF-κB Signaling by Regulating PRL-3 Expression. Frontiers in bioscience (Landmark edition) 14 36336860
2023 USP4 promotes the proliferation and glucose metabolism of gastric cancer cells by upregulating PKM2. PloS one 13 37624791
2022 Transcriptome Analysis and Single-Cell Sequencing Analysis Constructed the Ubiquitination-Related Signature in Glioma and Identified USP4 as a Novel Biomarker. Frontiers in immunology 13 35774799
2020 SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis. Molecular therapy. Nucleic acids 13 33376627
2019 Inhibition of USP4 attenuates pathological scarring by downregulation of the TGF‑β/Smad signaling pathway. Molecular medicine reports 13 31173246
2024 PBLD enhances antiviral innate immunity by promoting the p53-USP4-MAVS signaling axis. Proceedings of the National Academy of Sciences of the United States of America 12 39589880
2023 Selenium Ameliorated Oxidized Fish Oil-Induced Lipotoxicity via the Inhibition of Mitochondrial Oxidative Stress, Remodeling of Usp4-Mediated Deubiquitination, and Stabilization of Pparα. Antioxidants & redox signaling 12 37265154
2020 Interpreting In Vitro Release Performance from Long-Acting Parenteral Nanosuspensions Using USP-4 Dissolution and Spectroscopic Techniques. Molecular pharmaceutics 12 32267708
2017 Ubiquitin-specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic-independent manner. Cellular signalling 12 28336234
2023 Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 37039823
2022 Deubiquitinating enzymes USP4 and USP17 finetune the trafficking of PDGFRβ and affect PDGF-BB-induced STAT3 signalling. Cellular and molecular life sciences : CMLS 10 35064336
2025 A novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation. Journal of translational medicine 9 39856683
2023 Curcumin inhibits the development of colorectal cancer via regulating the USP4/LAMP3 pathway. Naunyn-Schmiedeberg's archives of pharmacology 9 37728623
2021 USP4 is pathogenic in allergic airway inflammation by inhibiting regulatory T cell response. Life sciences 9 34144056
2012 The ubiquitin specific protease-4 (USP4) interacts with the S9/Rpn6 subunit of the proteasome. Biochemical and biophysical research communications 9 23022198
1998 Genomic structure of Unp, a murine gene encoding a ubiquitin-specific protease. Biochimica et biophysica acta 9 9602026
2024 USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression. Leukemia 6 39266638
2024 USP4/CARM1 Axis Promotes the Malignant Transformation of Breast Cancer Cells by Upregulating SLC7A11 Expression. Clinical breast cancer 6 39500657
2022 Rainbow trout USP4 downregulates LPS-induced inflammation by removing the K63-linked ubiquitin chain on TAK1. Fish & shellfish immunology 6 36372204
2025 USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer. Cell death & disease 5 39922805
2025 USP4 promotes proliferation and metastasis in human lung adenocarcinoma. Scientific reports 3 40169699
2024 The deubiquitinating enzyme USP4 regulates BRCA1 stability and function. NPJ breast cancer 3 38734703
2023 High USP4 mRNA is associated with an HPV-positive status in head and neck squamous cell carcinoma patients. Journal of cancer research and clinical oncology 3 37308746
2026 Melatonin-engineered MSCs-exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival. Clinical and translational medicine 2 41482632
2025 A novel mechanism in regulating drug sensitivity, growth, and apoptosis of bortezomib-resistant multiple myeloma cells: the USP4/KLF2/HMGA2 cascade. Journal of orthopaedic surgery and research 2 40022160
2025 USP4-Deubiquitinated PGAM5 Regulates Mitochondrial Dynamics in the Progression of Esophageal Squamous Cell Carcinoma. Molecular carcinogenesis 1 41176636
2024 USP4 regulates TUT1 ubiquitination status in concert with SART3. Biochemical and biophysical research communications 1 38310689
2024 The Deubiquitinating Enzyme USP4 Promotes Trophoblast Dysfunction by Stabilizing RYBP. Cell biochemistry and biophysics 1 39405024
2026 lncRNA AL445238.2‑USP4 axis regulates cell survival and stemness in colon cancer. International journal of oncology 0 41789601
2026 USP4 promotes non-small cell lung cancer tumorigenesis by antagonizing CNOT4-mediated degradation of PAF1. Respiratory research 0 41857610
2026 TRIM21 promotes colorectal cancer malignancy by coupling USP4/TGF-β signaling to ferroptosis-related homeostasis. Cytotechnology 0 41868708
2026 Targeting USP4 to inhibit TGF-β signaling: the antifibrotic potential of isovitexin in renal interstitial fibrosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41999707
2026 USP4 modulates ZBP1 ubiquitination to regulate microglial PANoptosis and functional outcomes following traumatic brain injury. Cell death and differentiation 0 42091674
2025 USP4-mediated deubiquitination of SRC-1 regulates macrophage polarization and asthma inflammation. Experimental lung research 0 40493388
2025 ATF2-mediated Transcriptional Activation of USP4 Stabilizes KMT2A Protein and Promotes Trophoblast Dysfunction. Reproductive sciences (Thousand Oaks, Calif.) 0 40804593
2025 USP4-Mediated deubiquitination of A2AR suppresses autophagy-dependent ferroptosis in gastric cancer. Cellular and molecular life sciences : CMLS 0 41051500
2025 USP4, Transcriptionally Activated by MEF2A, Protects Multiple Myeloma Cells From Endoplasmic Reticulum Stress-Mediated Apoptosis via Repressing NR4A1 Ubiquitination. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41186214
2024 USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway. Aging 0 39393052
2019 Retracted Article: Elevation of USP4 antagonizes oxygen glucose deprivation/reoxygenation-evoked microglia activation and neuroinflammation-mediated neurotoxicity via the TRAF6-NF-κB signaling. RSC advances 0 35530618

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