Affinage

USP4

Ubiquitin carboxyl-terminal hydrolase 4 · UniProt Q13107

Length
963 aa
Mass
108.6 kDa
Annotated
2026-04-28
90 papers in source corpus 40 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP4 is a cysteine-class deubiquitylase that cleaves both K48- and K63-linked polyubiquitin chains from a remarkably broad substrate repertoire, thereby controlling protein stability, receptor trafficking, signal transduction, DNA repair, and RNA metabolism. Its N-terminal DUSP-UBL domain allosterically accelerates ubiquitin product release to enhance catalytic turnover, and its subcellular distribution is dynamically regulated by AKT-mediated phosphorylation (promoting cytoplasmic/membrane localization), CDK-dependent phosphorylation, intrinsic NES/NLS sequences, and SART3-dependent nuclear import (PMID:25404403, PMID:22706160, PMID:15494318, PMID:27060135, PMID:31330151). In the cytoplasm, USP4 deubiquitylates TGF-β type I receptor, TAK1, TRAF2/6, RIG-I, MAVS, PDGFRβ, and other targets to modulate TGF-β, NF-κB, and innate antiviral signaling, while in the nucleus it promotes homologous recombination by auto-deubiquitylation-dependent recruitment of CtIP to the MRN complex and stabilizes BRCA1 and spliceosomal factors such as PRP31 and TUT1 (PMID:22706160, PMID:21331078, PMID:23388719, PMID:39589880, PMID:26455393, PMID:38734703, PMID:38310689). USP4 also stabilizes ARF-BP1 to attenuate p53 levels, deubiquitylates PES1 to support ribosome biogenesis in hematopoietic stem cells, and removes monoubiquitin from SMAD4 to sustain activin/BMP signaling during embryonic development (PMID:21522127, PMID:39266638, PMID:28468752).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Establishing that USP4 is an active deubiquitylase answered whether the UNP oncogene product possesses intrinsic catalytic activity: both major human isoforms cleave ubiquitin fusions in a conserved-cysteine-dependent manner, and endogenous protein localizes mainly to the cytoplasm.

    Evidence In vitro deubiquitylation assay with active-site Cys→Ala mutagenesis, immunocytochemistry and fractionation in human cells

    PMID:11018721 PMID:9464533

    Open questions at the time
    • No physiological substrate identified
    • Chain-type specificity not yet determined
    • Regulation of catalytic activity unknown
  2. 2004 High

    Identification of a functional NES and NLS within USP4 resolved how the enzyme partitions between nucleus and cytoplasm, establishing it as a nucleocytoplasmic-shuttling DUB whose localization equilibrium varies by cell type.

    Evidence Leptomycin B treatment, Rev-GFP export assay, specific antibodies and live imaging in multiple cell lines

    PMID:15494318

    Open questions at the time
    • Signals regulating the balance were unknown
    • No upstream kinase controlling shuttling had been identified
  3. 2005 High

    Demonstration that USP4 deubiquitylates the A2A adenosine receptor to promote its ER-to-surface trafficking provided the first evidence that USP4 regulates receptor abundance at the plasma membrane by relaxing ER quality control.

    Evidence Co-IP, cell-surface expression assay with C-terminal truncation controls

    PMID:16339847

    Open questions at the time
    • Ubiquitin chain type on receptor not specified
    • Generality to other GPCRs untested
  4. 2011 High

    Showing that USP4 removes K63-linked ubiquitin from TAK1 and deubiquitylates ARF-BP1 to stabilize it and suppress p53 placed USP4 as a negative regulator of both NF-κB and p53 pathways, with Usp4-knockout MEFs displaying elevated p53, premature senescence, and resistance to transformation.

    Evidence Co-IP, in vitro DUB assay, catalytic-dead C311A mutant, NF-κB reporter, Usp4-KO MEFs with p53 activity readouts

    PMID:21331078 PMID:21522127

    Open questions at the time
    • Whether TAK1 and ARF-BP1 regulation are coordinated in the same cell context was unclear
    • In vivo tumor phenotype of Usp4-null mice not characterized
  5. 2012 High

    Discovery that AKT phosphorylates USP4 to relocalize it to the cytoplasm/membrane where it deubiquitylates TβRI—counteracting SMAD7-SMURF2-mediated degradation—connected growth-factor signaling to TGF-β pathway potentiation and identified a mechanistic basis for USP4-driven EMT and metastasis.

    Evidence Genome-wide gain-of-function screen, Co-IP, in vitro DUB assay, phosphorylation assay, subcellular fractionation, siRNA with migration/metastasis readout

    PMID:22706160

    Open questions at the time
    • Identity of AKT phosphosite(s) on USP4 not fully resolved
    • In vivo metastasis model limited to xenograft
  6. 2012 High

    Identification of TRAF2 and TRAF6 as additional USP4 substrates, combined with the earlier TAK1 finding, established USP4 as a multi-node suppressor of NF-κB signaling acting on both receptor-proximal adaptors and kinases.

    Evidence Co-IP, in vitro DUB assay, NF-κB reporter, specificity controls (no TRAF3 interaction)

    PMID:22029577

    Open questions at the time
    • Whether USP4 acts on these substrates sequentially or in distinct complexes was unknown
  7. 2013 High

    Finding that USP4 removes K48-linked ubiquitin from RIG-I to stabilize it and promote IFN-β production revealed a pro-antiviral role, contrasting with its anti-inflammatory NF-κB suppression—demonstrating substrate-specific, chain-type-specific functional outcomes.

    Evidence Co-IP, in vitro DUB assay, siRNA KD, overexpression with viral replication readout

    PMID:23388719

    Open questions at the time
    • Whether USP4 acts on RIG-I before or after its signaling activation was unresolved
    • Relationship to MAVS regulation not yet explored
  8. 2014 High

    Kinetic dissection of USP4's DUSP-UBL domain showed it allosterically accelerates ubiquitin product discharge rather than enhancing substrate binding or catalysis per se, providing the first quantitative enzymatic mechanism for a multi-domain DUB.

    Evidence Pre-steady-state kinetics, systematic domain deletions, switching-loop characterization

    PMID:25404403

    Open questions at the time
    • No full-length crystal structure
    • How this allosteric mechanism is modulated by phosphorylation or SART3 binding remained open
  9. 2015 High

    Demonstrating that USP4 auto-deubiquitylation on cysteine residues is required for CtIP binding and recruitment to DSBs, promoting HR-mediated repair, established a non-canonical catalytic-activity-dependent but non-substrate-directed role in the DNA damage response.

    Evidence HR repair assays, live-cell damage-site recruitment, auto-DUB assay, confirmed independently in two journals

    PMID:26387952 PMID:26455393

    Open questions at the time
    • Which cysteine residues are auto-deubiquitylated was not mapped
    • Relationship to BRCA1 stabilization was not yet known
  10. 2016 High

    Crystal structure of the SART3 HAT domain bound to USP4's DUSP-UBL domains revealed the molecular basis of SART3-driven nuclear import and showed that this import is essential for USP4's spliceosomal deubiquitylase function.

    Evidence X-ray crystallography, binding affinity measurements, fractionation, DUB activity toward spliceosomal substrates

    PMID:27060135

    Open questions at the time
    • Full repertoire of nuclear USP4 spliceosomal substrates unknown
    • Whether DUSP-UBL allosteric mechanism is altered by SART3 binding was untested
  11. 2017 High

    Discovery that USP4 removes SMURF2-mediated monoubiquitination from SMAD4 to sustain activin/BMP signaling—validated by zebrafish epiboly defects rescued by SMAD4—extended USP4's TGF-β superfamily role beyond receptor-level regulation to intracellular signal transducers.

    Evidence In vitro DUB assay, USP4-depleted mouse ESCs and zebrafish morphants, SMAD4 epistasis rescue

    PMID:28468752

    Open questions at the time
    • Whether USP4 acts on SMAD4 in the nucleus or cytoplasm was not fully resolved
  12. 2019 Medium

    CDK-mediated phosphorylation was shown to regulate USP4–SART3 interaction and nuclear localization, adding a second kinase-dependent regulatory input (alongside AKT) that controls subcellular partitioning and substrate access.

    Evidence Mass spectrometric phosphosite identification, CDK inhibitor treatment, fractionation, DUB activity toward PRP31

    PMID:31330151

    Open questions at the time
    • Specific CDK family member responsible not identified
    • Interplay between AKT and CDK phosphorylation unclear
  13. 2024 Medium

    Identification of MAVS K461 as a USP4 deubiquitylation site, BRCA1 stabilization by USP4 affecting PARP-inhibitor sensitivity, PES1 deubiquitylation supporting ribosome biogenesis in HSCs, and RAB7A deubiquitylation promoting autophagosome–lysosome fusion collectively demonstrated that USP4 operates across diverse cellular processes including innate immunity, DNA repair, translation, and membrane trafficking.

    Evidence Co-IP and ubiquitination assays with site-specific mutations, conditional Usp4 KO mice, functional HR/PARP-inhibitor/ribosome-biogenesis/autophagy-flux assays

    PMID:38734703 PMID:39266638 PMID:39589880 PMID:39663592

    Open questions at the time
    • Most 2024 substrates validated by single labs
    • No integrated model of how USP4 prioritizes among >20 known substrates
    • Structural basis of substrate selectivity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive structural model of full-length USP4, the rules governing substrate selectivity among its numerous targets, and the physiological integration of AKT/CDK phosphorylation with SART3 binding to direct substrate engagement in specific cellular contexts remain unresolved.
  • No full-length USP4 structure
  • Substrate triage mechanism unknown
  • In vivo phenotyping of tissue-specific Usp4 knockouts incomplete
  • Therapeutic targeting strategy undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 11 GO:0140096 catalytic activity, acting on a protein 10
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2
Partners
MAP3K7RBBP5RBBP6SART3SMAD4TGFBR1TRAF2TRAF6

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 USP4 directly interacts with and deubiquitylates TGF-β type I receptor (TβRI), preventing its SMAD7-SMURF2-mediated ubiquitination and degradation, thereby controlling TβRI levels at the plasma membrane and potentiating TGF-β signaling. Genome-wide gain-of-function screen, Co-IP, in vitro deubiquitylation assay, siRNA knockdown with EMT/metastasis readout Nature cell biology High 22706160
2012 AKT directly phosphorylates USP4, relocating it from the nucleus to the cytoplasm/membrane and maintaining its protein stability; AKT-induced breast cancer cell migration requires USP4 and TβRI kinase activity. Co-IP, phosphorylation assay, subcellular fractionation, siRNA knockdown with migration assay Nature cell biology High 22706160
2011 USP4 deubiquitinates TAK1 (removing K63-linked polyubiquitin chains) in vitro and in vivo; TNFα induces USP4–TAK1 association, and USP4 catalytic mutant C311A fails to suppress TAK1 polyubiquitination or NF-κB activation. Co-IP, in vitro deubiquitylation assay, catalytic-dead mutant (C311A), siRNA knockdown with NF-κB reporter Cell death and differentiation High 21331078
2012 USP4 specifically interacts with TRAF2 and TRAF6 (but not TRAF3) and deubiquitinates them in vitro and in vivo in a catalytic-activity-dependent manner, suppressing TNFα- and IL-1β-induced NF-κB activation and cancer cell migration. Co-IP, in vitro deubiquitylation assay, NF-κB reporter, siRNA knockdown The Biochemical journal High 22029577
2011 USP4 interacts with and deubiquitinates ARF-BP1, stabilizing it and thereby reducing p53 levels; USP4 knockout MEFs show elevated p53, premature senescence, and resistance to oncogenic transformation. Co-IP, in vitro deubiquitylation assay, Usp4 knockout mouse (MEFs), p53 activity assays The EMBO journal High 21522127
2005 USP4 (Usp4) binds to the C-terminus of the A2A adenosine receptor and deubiquitinates it, relaxing ER quality control and enhancing cell-surface expression of functionally active receptor. Co-IP, cell-surface expression assay, C-terminally truncated receptor controls, comparison with Usp14 Molecular pharmacology High 16339847
2013 USP4 interacts with RIG-I and removes K48-linked polyubiquitin chains from RIG-I, preventing its degradation and stabilizing it to promote RIG-I-triggered IFN-β signaling and antiviral response. Co-IP, in vitro deubiquitylation assay, siRNA knockdown, overexpression with viral replication readout Journal of virology High 23388719
2014 The N-terminal DUSP-Ubl domain of USP4 enhances catalytic turnover by promoting dissociation of ubiquitin product after substrate hydrolysis (allosteric regulation of product discharge), a mechanism requiring all USP4 domains including a switching loop near the active site. Pre-steady-state kinetics, domain deletion analysis, structural/biochemical characterization Nature communications High 25404403
2009 USP4 has dual hydrolysing activity for K48- and K63-conjugated polyubiquitin chains; it interacts with Nemo-like kinase (NLK) and TCF4, and NLK overexpression promotes nuclear accumulation of USP4; TCF4 is a substrate of USP4-dependent deubiquitination, placing USP4 as a regulator of canonical Wnt signaling. RNAi DUB library screen, Co-IP, ubiquitin chain specificity assay, β-catenin/TCF reporter Journal of cellular and molecular medicine Medium 20141612
2015 USP4 promotes DNA double-strand break end resection and homologous recombination by interacting with CtIP and the MRE11-RAD50-NBS1 complex; USP4 auto-deubiquitylation on cysteine residues is required for CtIP binding, CtIP recruitment to damage sites, and HR repair. Co-IP, HR repair assays, siRNA knockdown, auto-deubiquitylation assay, damage-site recruitment by live imaging/foci Molecular cell High 26387952 26455393
2017 USP4 removes inhibitory monoubiquitination from SMAD4 (added by SMURF2 upon R-SMAD-SMAD4 complex formation), thereby sustaining SMAD4 activity and promoting activin/BMP signaling; zebrafish depleted of USP4 show defective epiboly rescued by SMAD4. Co-IP, in vitro deubiquitylation assay, USP4-depleted mouse ESCs and zebrafish morphants, epistasis with SMAD4 The EMBO journal High 28468752
2004 USP4 (Usp4) shuttles between nucleus and cytoplasm via a nuclear export signal (133VEVYLLELKL142) and a nuclear import signal (766QPQKKKK772) recognized by importin α/β; equilibrium of localization varies by cell type. Leptomycin B treatment, Rev-GFP export assay, specific antibodies distinguishing Usp4 from Usp15, live imaging The Journal of biological chemistry High 15494318
2016 Crystal structure of SART3 HAT repeat domain in complex with the DUSP-UBL domains of USP4 reveals that USP4 binds SART3 at the β-structured linker between DUSP and UBL domains; SART3 nuclear localization signal drives nuclear import of USP4, and removal of SART3 NLS prevents USP4 nuclear entry and abrogates its deubiquitinase activity toward spliceosomal substrates. X-ray crystallography, binding affinity measurements, nuclear-cytoplasmic fractionation, deubiquitylation assay Nucleic acids research High 27060135
2015 USP4 interacts with HDAC2 and deubiquitinates it, stabilizing HDAC2 protein; accumulated HDAC2 reduces p53 acetylation and transcriptional activation, and suppresses TNFα-induced NF-κB activation. Co-IP, in vitro deubiquitylation assay, overexpression/knockdown with p53 acetylation and NF-κB reporter readouts Oncogene Medium 26411366
2001 USP4 (UNP/Unp) physically associates with the retinoblastoma protein pRb and related pocket proteins p107 and p130; association is sensitive to site-directed mutations analogous to those in viral oncoproteins. Co-IP in cells, in vitro binding assay, site-directed mutagenesis Oncogene Medium 11571651 11571652
2000 Murine Unp (USP4 ortholog) and human Unph/USP4 are active deubiquitinating enzymes that cleave ubiquitin from natural and engineered linear ubiquitin-protein fusions, including polyubiquitin precursor; mutation of conserved Cys and His residues abolishes activity. In vitro deubiquitylation assay, site-directed mutagenesis of active-site Cys and His Biochimica et biophysica acta High 11018721
1998 Both major isoforms of human UNP/USP4 are functional deubiquitinating enzymes; mutation of a critical conserved cysteine to alanine abolishes activity; endogenous UNP protein localizes primarily to the cytoplasm. Deubiquitylation assay, active-site mutagenesis (Cys→Ala), cellular fractionation, immunocytochemistry Oncogene High 9464533
2006 USP4 (UnpEL) functions as a deubiquitinating enzyme in human cells, deconjugating ubiquitin specifically from its interacting partner Ro52 via isopeptidase activity; USP4 colocalizes with unubiquitinated Ro52 in cytoplasmic rod-like structures. Co-IP, in vitro deubiquitylation assay, immunofluorescence colocalization Biochemical and biophysical research communications Medium 16316627
2017 USP4 interacts with IRF8 and stabilizes it via K48-linked deubiquitination in regulatory T cells; USP4 depletion increases IRF8 polyubiquitination and impairs Treg suppressive function. Co-IP, ubiquitination assay, USP4 inhibitor treatment, functional Treg suppression assay FEBS letters Medium 28477415
2019 USP4 co-immunoprecipitates with and deubiquitylates AQP2 in vitro and in kidney cells; USP4 knockdown decreases AQP2 protein abundance and reduces vasopressin-induced AQP2 apical membrane accumulation by increasing AQP2 ubiquitylation. Co-IP from mouse kidney and mpkCCD14 cells, in vitro deubiquitylation assay, shRNA knockdown with membrane accumulation and protein half-life assays Cells Medium 30901874
2017 USP4 preferentially removes monoubiquitination from HAS2 and interacts with HAS2 in membrane preparations; USP4 suppression increases hyaluronan synthesis, opposite to the effect of USP17. DUB cDNA library screen, Co-IP from membrane fractions, siRNA knockdown with hyaluronan production assay Oncogenesis Medium 28604766
2012 USP4 interacts with the S9/Rpn6 subunit of the proteasome via its internal ubiquitin-like (UBL) domain. Co-IP, domain mapping Biochemical and biophysical research communications Low 23022198
2019 CDK-mediated phosphorylation of USP4 regulates its interaction with SART3 and consequent nuclear localization; purvalanol A (CDK inhibitor) causes nuclear translocation of USP4 and alters its deubiquitinase activity toward spliceosomal substrate PRP31. Nuclear-cytoplasmic fractionation, mass spectrometric phosphosite identification, CDK inhibitor treatment, activity assay Journal of molecular biology Medium 31330151
2017 USP4 suppresses MyoD-driven myoblast differentiation in a catalytic-activity-independent manner; USP4 knockdown enhances myogenesis and decreases HDAC1/HDAC4 activity; USP4 effect is correlated with AKT and p38 MAPK pathways. siRNA knockdown of USP4 in C2C12 cells, catalytic-dead mutant comparison, myogenesis marker assays Cellular signalling Medium 28336234
2020 USP4 binds to and deubiquitinates Twist1, stabilizing it and promoting lung cancer stemness; USP4 overexpression-induced stemness is rescued by Twist1 silencing. Co-IP, ubiquitination assay, siRNA rescue experiment, tumorsphere formation assay Cancers Medium 32549341
2024 USP4 interacts with and deubiquitinates BRCA1, stabilizing it; USP4 knockdown reduces BRCA1 protein levels, impairs homologous recombination, increases genome instability, and confers resistance to PARP inhibitors. Co-IP, ubiquitination assay, HR repair assay, USP4 knockdown with multiple functional readouts NPJ breast cancer Medium 38734703
2024 USP4 interacts with ANXA2, deubiquitinates Lys48- and Lys63-linked polyubiquitin chains on ANXA2 (with K63 at K28 mediating Y24 phosphorylation); K10 acetylation of ANXA2 enhances its interaction with USP4; USP4/ANXA2 promotes glioblastoma stem cell maintenance and radioresistance via BMX-mediated STAT3 activation. Co-IP, in vitro deubiquitylation assay, mutagenesis, ubiquitin chain type analysis, GSC functional assays Cell death and differentiation Medium 40185997
2024 USP4 deubiquitinates RAB7A; reduced USP4 in periodontitis leads to increased RAB7A ubiquitination, impairing lysosomal trafficking and autophagosome-lysosome fusion and aggravating periodontitis. Proteomics, Co-IP, ubiquitination assay, USP4 KD in macrophages with autophagy flux readout, 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-IP, ubiquitination assay, Usp4 conditional KO mouse, ribosome biogenesis assays Leukemia Medium 39266638
2023 USP4 interacts with and stabilizes PKM2 via deubiquitination; USP4 overexpression promotes glucose uptake and lactate production (Warburg effect) in gastric cancer cells, while USP4 knockdown reduces PKM2 and glycolysis. Co-IP, ubiquitination assay, immunofluorescence, glucose/lactate assays PloS one Medium 37624791
2024 USP4 deubiquitinates IRF3 K63-polyubiquitin chains and TRAF6, impeding IRF3 nuclear localization and suppressing the tumor-intrinsic interferon response in colorectal cancer; USP4 knockdown enhances T-cell infiltration and overcomes immune checkpoint blockade resistance. Co-IP, ubiquitination assay, IRF3 nuclear localization assay, syngeneic mouse tumor model Cancer letters Medium 38556105
2024 USP4 regulates TUT1 ubiquitination status in concert with SART3; USP4 expression reduces TUT1 ubiquitination, orchestrates subnuclear relocation of TUT1 from nucleolus to nucleoplasm, and stabilizes U6 snRNA. Co-IP, ubiquitination assay, subcellular localization imaging, U6 snRNA stability assay Biochemical and biophysical research communications Medium 38310689
2023 USP4 interacts with cortactin (CTTN) in HCT116 cells and promotes CTTN phosphorylation by regulating Src/FAK binding, enhancing cell migration independent of USP4 deubiquitylase activity on β-catenin. Proximity labeling (BioID), Co-IP, phosphorylation assay, migration assay with CTTN knockdown rescue FASEB journal Medium 37039823
2022 USP4 deubiquitinates PDGFRβ (removing both K48- and K63-linked chains), affecting the speed of receptor trafficking toward early endosomes and prolonging STAT3 activation in response to PDGF-BB; USP4 deletion reduces proliferative response to PDGF-BB. DUB overexpression screen, Co-IP, trafficking assay, STAT3 signaling assay, USP4 KO cells Cellular and molecular life sciences Medium 35064336
2023 USP4 interacts with and stabilizes TAK1 via deubiquitination in ESCC cells; USP4-promoted proliferation, migration, and invasion operate through the MEK/ERK signaling pathway. Co-IP, ubiquitination assay, siRNA/overexpression with MEK/ERK inhibitor epistasis, in vivo xenograft Cell death & disease Medium 37949874
2025 USP4 undergoes auto-deubiquitylation, which protects it from PROTAC-mediated targeted protein degradation; this distinguishes it from its paralog USP11, which is readily degradable. Chemical genetics PROTAC system, degradation assay, auto-deubiquitylation assay bioRxivpreprint Low bio_10.1101_2025.06.13.659525
2023 USP4 inhibits Keap1 deubiquitination; vialinin A (a USP4 inhibitor) promotes Keap1 ubiquitination and degradation, thereby activating the Nrf2-dependent antioxidant response and reducing neuronal apoptosis after ischemic stroke. Co-IP, USP4 activity assay with vialinin A, Keap1 ubiquitination assay, USP4 overexpression rescue, in vivo MCAO model Phytomedicine Medium 38176274
2024 USP4 stabilizes MAVS by deconjugating K48-linked ubiquitination at MAVS K461 during RNA virus infection, promoting antiviral IFN-I signaling; USP4 transcription is activated by the p53–PBLD axis. Co-IP, ubiquitination assay with site-specific mutation (K461), USP4 overexpression/KD, in vivo PBLD KO mouse model Proceedings of the National Academy of Sciences of the United States of America Medium 39589880
2025 USP4 deubiquitinates and stabilizes PGAM5 by removing K48-linked ubiquitin chains; USP4/PGAM5 axis promotes mitophagy and tumor growth in esophageal squamous cell carcinoma. Co-IP, ubiquitination assay, KD/OE with mitochondrial readouts, in vivo tumor model Molecular carcinogenesis Low 41176636

Source papers

Stage 0 corpus · 90 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 274 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 134 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 84 30362572
2014 The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange. Nature communications 79 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 69 26455393
2019 Targeting the circBMPR2/miR-553/USP4 Axis as a Potent Therapeutic Approach for Breast Cancer. Molecular therapy. Nucleic acids 68 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 48 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
2004 Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme. The Journal of biological chemistry 38 15494318
2020 The Deubiquitinase USP4 Stabilizes Twist1 Protein to Promote Lung Cancer Cell Stemness. Cancers 37 32549341
2018 Up-regulated deubiquitinase USP4 plays an oncogenic role in melanoma. Journal of cellular and molecular medicine 32 29542252
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.) 31 36762777
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
2023 USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1. Cell death & disease 30 37949874
2022 MIR99AHG inhibits EMT in pulmonary fibrosis via the miR-136-5p/USP4/ACE2 axis. Journal of translational medicine 29 36138468
2006 Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity. Biochemical and biophysical research communications 28 16316627
2019 A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis. International journal of cancer 27 31219614
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
2014 Function of wheat Ta-UnP gene in enhancing salt tolerance in transgenic Arabidopsis and rice. Biochemical and biophysical research communications 26 24953696
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
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 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
2022 USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1. Cell death discovery 20 35027535
2023 FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis. PLoS biology 19 38134227
2018 USP4 expression independently predicts favorable survival in lung adenocarcinoma. IUBMB life 18 29667299
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 17 38176274
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
2025 Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells. Cell death and differentiation 16 40185997
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
2019 The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance. Cells 14 30901874
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 USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis. Autophagy 12 39663592
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
2024 Deubiquitinase USP4 suppresses antitumor immunity by inhibiting IRF3 activation and tumor cell-intrinsic interferon response in colorectal cancer. Cancer letters 11 38556105
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
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 9 39589880
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
2025 A novel USP4 inhibitor that suppresses colorectal cancer stemness by promoting β-catenin and Twist1 degradation. Journal of translational medicine 7 39856683
2024 USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression. Leukemia 6 39266638
2022 Rainbow trout USP4 downregulates LPS-induced inflammation by removing the K63-linked ubiquitin chain on TAK1. Fish & shellfish immunology 6 36372204
2024 USP4/CARM1 Axis Promotes the Malignant Transformation of Breast Cancer Cells by Upregulating SLC7A11 Expression. Clinical breast cancer 5 39500657
2025 USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer. Cell death & disease 3 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 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
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