Affinage

USP20

Ubiquitin carboxyl-terminal hydrolase 20 · UniProt Q9Y2K6

Length
914 aa
Mass
102.0 kDa
Annotated
2026-04-28
43 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP20 is a deubiquitinating enzyme that removes K48- and K63-linked polyubiquitin chains from a broad repertoire of substrates, thereby governing cholesterol biosynthesis, innate immune signaling, autophagy, DNA damage checkpoint activation, receptor trafficking, and cardiac homeostasis. Its catalytic activity and substrate access are dynamically regulated by phosphorylation: mTORC1 phosphorylates S132/S134 to recruit USP20 to HMGCR for cholesterol pathway control (PMID:33177714); ATR phosphorylation stabilizes USP20 by disrupting the HERC2 E3 ligase interaction, enabling Claspin stabilization and Chk1 checkpoint signaling (PMID:25355518, PMID:25326330); PKA phosphorylation at S333 inactivates USP20 and dissociates it from the β2-adrenergic receptor, redirecting the receptor to lysosomal degradation (PMID:25666616); and IRAK1 phosphorylation at S334 reduces USP20 association with TRAF6, augmenting NF-κB signaling (PMID:37311534). USP20 is recruited to the ER membrane through VAP interaction despite lacking a transmembrane domain, where it deubiquitinates tail-anchored proteins after TRC40-mediated insertion and stabilizes the reticulophagy receptor RETREG1 to promote ER-phagy (PMID:33792613, PMID:38705724). In the heart, USP20 protects against pathological remodeling by stabilizing MYH7, deubiquitinating STAT3 K63-linked chains to suppress hypertrophic transcription, removing K63-linked ubiquitin from NLRP3 to block inflammasome activation, and stabilizing HuR to maintain GPX4 expression and prevent ferroptosis (PMID:39365672, PMID:40192103, PMID:41042219, PMID:41921794).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2009 High

    The first physiological substrate of USP20 was identified when it was shown to constitutively bind and deubiquitinate the β2-adrenergic receptor, establishing USP20 as a regulator of GPCR recycling versus lysosomal degradation.

    Evidence Co-IP, receptor trafficking assays, and knockdown in HEK293 cells

    PMID:19424180

    Open questions at the time
    • Phospho-regulation of USP20-β2AR interaction not yet defined
    • Whether USP20 acts on other GPCRs unknown
    • Chain-type specificity on β2AR not determined
  2. 2014 High

    Two independent studies converged to show that USP20 protein levels are themselves controlled by HERC2-mediated ubiquitination and that ATR-dependent phosphorylation under replication stress stabilizes USP20, which then deubiquitinates Claspin to activate the ATR-Chk1 checkpoint—revealing that USP20 is a signal-regulated DUB whose own stability is dynamically tuned.

    Evidence DUB screens, Co-IP, in vitro kinase assay, phospho-mutants, checkpoint activation assays, xenograft models

    PMID:25326330 PMID:25355518

    Open questions at the time
    • Specific ATR phosphorylation site on USP20 disrupting HERC2 not mapped to residue level
    • Whether HERC2-USP20 regulation extends beyond replication stress unclear
  3. 2015 High

    PKA phosphorylation of USP20-S333 was identified as a mechanism that inactivates USP20 catalytic activity upon β2AR agonist stimulation, directly linking cAMP signaling to DUB regulation and explaining how agonist-triggered receptor sorting toward autophagosomal/lysosomal degradation is achieved.

    Evidence Site-specific phosphorylation mapping, PKA activity assays, phospho-mutant constructs, LC3-II colocalization in trafficking assays

    PMID:25666616

    Open questions at the time
    • Whether S333 phosphorylation affects USP20 activity toward substrates other than β2AR not tested
    • Phosphatase responsible for USP20-S333 dephosphorylation not identified
  4. 2016 High

    USP20 was placed in the innate immune signaling pathway when USP18 was shown to recruit USP20 to STING for K48-linked deubiquitination, stabilizing STING and activating type I IFN responses—demonstrating that USP20 substrate access can be controlled by adapter proteins.

    Evidence Co-IP, in vitro deubiquitination, Usp18−/− MEF reconstitution, in vivo HSV-1 infection

    PMID:27801882

    Open questions at the time
    • Whether USP20 acts on STING independently of USP18 in all cell types unknown
    • Ubiquitin sites on STING targeted by USP20 not mapped
  5. 2017 High

    An unbiased DUB screen identified ERK3 as a USP20 substrate, extending USP20's functional reach to actin cytoskeleton remodeling and cell migration via an atypical MAPK pathway.

    Evidence Loss-of-function DUB screen, in vitro deubiquitination, actin organization and migration assays

    PMID:28167606

    Open questions at the time
    • Whether USP20 regulation of ERK3 is phosphorylation-dependent not tested
    • Structural basis of USP20-ERK3 interaction unknown
  6. 2018 High

    Multiple substrates were identified in rapid succession—β-catenin (Wnt signaling), ULK1 (autophagy initiation), and RIPK1 (TNF/NF-κB signaling)—establishing USP20 as a pleiotropic DUB acting across diverse signaling pathways.

    Evidence Co-IP, ubiquitination assays, LC3 puncta formation, NF-κB assays, in vitro deubiquitination of RIPK1 with purified enzyme, transgenic mouse atherosclerosis model

    PMID:29487085 PMID:29867130 PMID:30354204

    Open questions at the time
    • How USP20 discriminates among its many substrates in a given cellular context remains unclear
    • Whether ULK1 and β-catenin regulation by USP20 are interconnected not addressed
  7. 2019 High

    Usp20-knockout mice confirmed the physiological requirement for USP20 in STING-dependent antiviral defense, with genetic complementation showing STING is the critical downstream effector.

    Evidence Usp20−/− mice, HSV-1 lethal infection model, STING complementation in KO cells

    PMID:30814308

    Open questions at the time
    • Whether USP20 regulates other innate sensors beyond STING not explored in this model
    • Cell-type-specific contributions (myeloid vs. epithelial) not dissected
  8. 2020 High

    The mTORC1-USP20-HMGCR axis was discovered, revealing that feeding-state metabolic signals control cholesterol biosynthesis by phosphorylating USP20 at S132/S134 to recruit it to the HMGCR complex—the first demonstration that nutrient-sensing kinases directly regulate a DUB for metabolic substrate stabilization.

    Evidence Liver-specific Usp20 KO mice, S132A/S134A knock-in mice, phosphorylation mapping, HMGCR(K248R) rescue

    PMID:33177714

    Open questions at the time
    • Whether other mTORC1 substrates cooperate with USP20 phosphorylation not tested
    • Tissue-specific differences in this axis beyond liver not explored
  9. 2020 High

    Unbiased dual DUB library screens identified USP20 as the principal stabilizer of SNAI2/SLUG, linking USP20 to epithelial-mesenchymal transition and breast cancer metastasis.

    Evidence 65-gene cDNA and 98-gene siRNA DUB library screens, in vivo metastasis model

    PMID:32943575

    Open questions at the time
    • Phospho-regulatory input controlling USP20-SNAI2 interaction not identified
    • Whether USP20 targets SNAI2 in non-cancer contexts unknown
  10. 2021 High

    USP20 (with USP33) was identified as an ER-resident deubiquitinase for tail-anchored membrane proteins, revealing a quality-control checkpoint that removes ubiquitin after TRC40-mediated ER insertion rather than triggering degradation.

    Evidence Biochemical fractionation, ER insertion assays, knockdown, TRC40 interaction studies

    PMID:33792613

    Open questions at the time
    • Full spectrum of TA-protein substrates not defined
    • Whether USP20 vs. USP33 have non-overlapping TA substrates unclear
  11. 2023 High

    IRAK1-mediated phosphorylation of USP20-S334 was shown to diminish TRAF6 deubiquitination and amplify NF-κB activation during IL-1β signaling, with CRISPR knock-in mice demonstrating in vivo relevance for neointimal hyperplasia—adding a fourth kinase input to USP20 regulation.

    Evidence In vitro kinase assay with purified IRAK1, CRISPR/Cas9 S334A knock-in mice, neointimal hyperplasia model

    PMID:37311534

    Open questions at the time
    • Whether IRAK1-USP20 axis operates in immune cells beyond SMCs not tested
    • How S334 phosphorylation structurally alters TRAF6 binding not resolved
  12. 2024 High

    USP20 was shown to be recruited to the ER via VAP interaction, where it stabilizes the reticulophagy receptor RETREG1/FAM134B by removing K48/K63 chains, positioning USP20 as a spatial regulator of selective ER-phagy at defined ER subdomains.

    Evidence DUB screen, in vitro deubiquitination, super-resolution SIM imaging, reticulophagy flux measurement

    PMID:38705724

    Open questions at the time
    • Whether USP20-VAP interaction is regulated by phosphorylation unknown
    • Whether other reticulophagy receptors are USP20 substrates not tested
  13. 2024 Medium

    The HERC2-USP20-ULK1 axis was validated in patient-derived fibroblasts from HERC2-deficient individuals, showing that p38 kinase disrupts the HERC2-USP20 interaction to increase USP20 levels and autophagy—connecting USP20 regulation to a neurodevelopmental disorder.

    Evidence Patient-derived fibroblasts, Co-IP, p38 activation assays, lysosomal inhibitor experiments

    PMID:38570483

    Open questions at the time
    • Direct link between elevated USP20/autophagy and neurological phenotype not established
    • p38 phosphorylation site on USP20 or HERC2 not mapped
  14. 2025 High

    Active-site-resolved substrate mapping revealed that USP20 deubiquitinates STAT3 at K177 (K63-linked) via H645 to suppress hypertrophic gene transcription, and NLRP3 at K243 (K63-linked) via C154 to block inflammasome assembly—demonstrating site- and chain-specific mechanisms in cardiac protection.

    Evidence Active-site mutagenesis (H645, C154), ubiquitination site mapping, cardiomyocyte-specific KO mice, CLP sepsis model, NLRP3 KO epistasis

    PMID:40192103 PMID:41042219

    Open questions at the time
    • Whether H645 and C154 represent two independent catalytic residues or context-dependent usage is not clarified
    • Structural basis for K63 vs. K48 chain-type selectivity on different substrates unresolved
  15. 2026 High

    USP20 was linked to ferroptosis resistance through two independent mechanisms: direct stabilization of GPX4 via K48-chain removal in cancer, and stabilization of HuR (at K154) which post-transcriptionally maintains GPX4 mRNA in cardiomyocytes—with genetic epistasis using HuR-CKO mice confirming pathway dependence.

    Evidence Co-IP with LC-MS/MS, site-specific ubiquitination mapping, cardiomyocyte-specific and HuR-CKO mice, in vivo tumor models

    PMID:41844497 PMID:41921794

    Open questions at the time
    • Whether GPX4 is a direct deubiquitination substrate in cardiomyocytes (vs. indirect via HuR) not reconciled between the two studies
    • Upstream signals regulating USP20's ferroptosis-protective function not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP20 achieves substrate selectivity among its >15 identified substrates in different cellular contexts, and the structural basis for its chain-type discrimination, remain major unresolved questions.
  • No full-length crystal or cryo-EM structure of USP20
  • No systematic substrate prioritization mechanism defined
  • Functional redundancy with USP33 not genetically dissected in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 19 GO:0016787 hydrolase activity 10
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 18 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 2 R-HSA-1430728 Metabolism 1
Partners
ADRB2CLASPINHERC2HMGCRSTINGULK1USP18VAPA

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 mTORC1 phosphorylates USP20 at S132 and S134 in the feeding/post-prandial state (triggered by insulin and glucose), which recruits USP20 to the HMGCR complex where it removes ubiquitin from HMGCR and stabilizes it, preventing its proteasomal degradation and promoting cholesterol biosynthesis. Liver-specific Usp20 deletion and USP20(S132A/S134A) knock-in mice abolish feeding-induced HMGCR stabilization. In vivo knock-in/knockout mouse models, co-immunoprecipitation, phosphorylation mapping, pharmacological inhibition, rescue with constitutively stable HMGCR(K248R) Nature High 33177714
2009 USP20 (and USP33) constitutively bind the β2 adrenergic receptor (β2AR) and deubiquitinate it, inhibiting lysosomal trafficking and promoting receptor recycling from late-endosomal compartments and resensitization at the cell surface. After agonist stimulation, USP20/33 dissociate from β2AR, allowing ubiquitination; upon prolonged stimulation, they reassociate to drive deubiquitination and recycling. Co-immunoprecipitation, receptor trafficking assays, deubiquitinase activity assays, overexpression and knockdown experiments The EMBO journal High 19424180
2016 USP18 recruits USP20 to STING (MITA), and USP20 catalytically removes K48-linked ubiquitin chains from STING, stabilizing it and promoting IRF3/NF-κB activation and type I IFN induction after DNA virus infection. USP18 facilitates USP20-mediated deubiquitination of STING independently of USP18's own enzymatic activity. Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, Usp18-/- MEF reconstitution, in vivo HSV-1 infection model Cell research High 27801882
2018 USP20 deubiquitinates β-catenin to control its stability, thereby regulating canonical Wnt/β-catenin signaling and promoting cancer cell proliferation, invasion, and migration. USP20 knockdown increases β-catenin polyubiquitination and enhances its turnover. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, cell proliferation/invasion assays Cell death and differentiation Medium 29867130
2020 USP20 deubiquitinates and stabilizes the transcription factor SNAI2/SLUG, promoting breast cancer metastasis. Identified via comprehensive gain- and loss-of-function DUB screens (65-gene cDNA library and 98-gene siRNA library). DUB cDNA library screen, siRNA library screen, ubiquitination assay, migration/invasion assays, in vivo metastasis model Genes & development High 32943575
2014 ATR phosphorylates USP20 in response to replication stress, causing dissociation of the E3 ligase HERC2 from USP20 (which normally promotes USP20 degradation) and stabilizing USP20. Stabilized USP20 then deubiquitinates and stabilizes Claspin, enhancing ATR-Chk1 checkpoint signaling. DUB screen, co-immunoprecipitation, ubiquitination assay, phosphorylation mapping, siRNA knockdown, checkpoint activation assays Nucleic acids research High 25326330 25355518
2014 HERC2 acts as an E3 ubiquitin ligase that ubiquitinates USP20 under unperturbed conditions, promoting its proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 disrupts HERC2 binding, stabilizing USP20. USP20 in turn deubiquitinates K48-linked polyubiquitinated Claspin, stabilizing Claspin and promoting CHK1 phosphorylation. Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay, xenograft tumor model, chromosome instability assay Nucleic acids research High 25326330
2015 Upon β2AR activation, the cAMP-dependent protein kinase A isoform PKAα rapidly phosphorylates USP20 on serine 333 (human), causing a characteristic SDS-PAGE mobility shift, blocking its deubiquitinase activity, promoting its dissociation from the activated β2AR complex, and facilitating trafficking of ubiquitinated β2AR to autophagosomes for lysosomal degradation. Dephosphorylation of USP20-S333 has reciprocal effects, restoring deubiquitinase activity and promoting plasma membrane recycling. Site-specific phosphorylation mapping, PKA activity assay, β2AR trafficking assays with autophagosome/LC3-II colocalization, dominant-negative/phospho-mutant constructs The Journal of biological chemistry High 25666616
2018 USP20 acts as a positive regulator of autophagy initiation by binding to and stabilizing ULK1 (removing ubiquitin moiety and preventing lysosomal degradation) at basal state. USP20 depletion by RNAi inhibits LC3 puncta formation. At later stages of autophagy, USP20 dissociates from ULK1, resulting in enhanced ULK1 degradation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, LC3 puncta formation assay, autophagy flux analysis EMBO reports High 29487085
2018 USP20 associates with components of the TNFR1 signaling pathway, including RIPK1. TNF induces greater RIPK1 ubiquitination in SMCs expressing dominant-negative USP20. Purified USP20 deubiquitinates RIPK1 in vitro, attenuating TNF-induced NFκB activation and reducing atherosclerosis in vivo. Co-immunoprecipitation, in vitro deubiquitination assay with purified USP20, transgenic/dominant-negative mouse models, NFκB activation assay, en face atherosclerosis quantification Arteriosclerosis, thrombosis, and vascular biology High 30354204
2019 USP20 interacts with STING (MITA) and removes K48-linked ubiquitin chains from STING after HSV-1 infection, stabilizing STING and promoting IRF3 and IκBα phosphorylation and type I IFN induction. Usp20-/- mice show increased susceptibility to lethal HSV-1 infection; STING complement into Usp20-/- cells fully restores antiviral signaling. Co-immunoprecipitation, in vitro deubiquitination assay, Usp20-/- mouse model, HSV-1 infection assay, IRF3/IκBα phosphorylation analysis, genetic complementation Journal of immunology High 30814308
2017 USP20 interacts with ERK3 (an atypical MAPK) and deubiquitinates it both in vitro and in intact cells, stabilizing ERK3 protein. USP20 regulates actin cytoskeleton organization and cell migration in an ERK3-dependent manner. Identified by unbiased loss-of-function DUB screen. DUB loss-of-function screen, co-immunoprecipitation, in vitro deubiquitination assay, overexpression/depletion, actin organization and cell migration assays Molecular and cellular biology High 28167606
2020 USP20 deubiquitinates K48-linked polyubiquitin chains from p62/sequestosome-1, stabilizing p62 and thereby promoting formation of the atypical PKCζ-RIPK1-p62 complex required for TNFα-mediated NFκB activation and cell survival. USP20 depletion disrupts this complex and increases apoptosis. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NFκB activation assay, apoptosis assay International journal of molecular sciences Medium 32354117
2021 USP20 (and USP33) are ER-associated deubiquitinases that remove ubiquitin chains from tail-anchored (TA) membrane proteins after their insertion into the ER. TA proteins are ubiquitinated by cytosolic protein quality control machinery immediately upon synthesis, but are not degraded; instead they are handed to the TRC40 targeting factor and delivered to the ER, where USP20/33 deubiquitinate them. Biochemical fractionation, ubiquitination assay, knockdown, ER insertion assay, TRC40 interaction studies The Journal of cell biology High 33792613
2023 IRAK1 phosphorylates USP20 on Ser334 (mouse)/Ser333 (human) in response to IL-1β stimulation in vascular smooth muscle cells, which diminishes USP20's association with TRAF6 and thereby augments K63-linked polyubiquitination of TRAF6 and downstream NFκB activation, SMC inflammation, and neointimal hyperplasia. USP20-S334A knock-in mice (CRISPR/Cas9-generated) develop ~50% less neointimal hyperplasia. In vitro phosphorylation with purified IRAK1, CRISPR/Cas9 knock-in mice, siRNA silencing, Co-IP, ubiquitination assay, active-site ubiquitin probe, neointimal hyperplasia model The Journal of biological chemistry High 37311534
2024 USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B by cleaving both K48- and K63-linked ubiquitin chains. USP20 is recruited to the ER through interaction with VAPs (VAMP-associated proteins) despite lacking a transmembrane domain. At specific ER subdomains enriched with RETREG1, USP20 and VAPs facilitate recruitment of early autophagy proteins including WIPI2, promoting reticulophagy under starvation conditions. DUB screen, co-immunoprecipitation, in vitro deubiquitination assay, super-resolution structured illumination microscopy, knockdown/KO assays, reticulophagy flux measurement Autophagy High 38705724
2024 USP20 deubiquitinates MYH7 (myosin heavy chain 7) and prevents its K48-linked polyubiquitination-mediated degradation in the heart during pressure overload. USP20-KO mice develop maladaptive eccentric cardiac hypertrophy with increased MYH7 degradation, cardiomyocyte apoptosis, and mortality after transverse aortic constriction. USP20 knockout mouse model, transverse aortic constriction, quantitative mass spectrometry, ubiquitination assay, echocardiography, histology American journal of physiology. Heart and circulatory physiology Medium 39365672
2025 USP20 deubiquitinates STAT3 by removing K63-linked ubiquitin chains specifically at K177 via its H645 active site (catalytic residue), reducing STAT3 phosphorylation and nuclear translocation, thereby inhibiting STAT3 transcriptional activity at the CARM1 promoter and leading to upregulated CARM1 expression that mitigates cardiac hypertrophy. Co-IP with LC-MS/MS substrate identification, CUT&Tag sequencing, active-site mutagenesis (H645), ubiquitination site mapping (K177), siRNA/overexpression in cardiomyocytes, STAT3 inhibitor (Stattic) rescue Advanced science High 40192103
2025 USP20 deubiquitinates NLRP3 by removing K63-linked ubiquitin chains at K243 via its active site C154, which disrupts NLRP3's interaction with ASC and suppresses NLRP3 inflammasome activation and subsequent pyroptosis in cardiomyocytes during sepsis. Co-IP with LC-MS/MS, active-site mutagenesis (C154), ubiquitination site mapping (K243), cardiomyocyte-specific USP20 CKO mice, NLRP3 KO mice, AAV9 overexpression, LPS/CLP sepsis model Clinical and translational medicine High 41042219
2024 USP20 interacts with HIF1α (hypoxia-inducible factor 1α) and stabilizes it by deubiquitination in T-ALL cells, co-localizing with HIF1A to jointly modulate target gene expression. USP20 is regulated by super-enhancers in T-ALL. Mass spectrometry, RNA-seq, co-immunoprecipitation, CUT&Tag sequencing, shRNA knockdown, in vivo tumor model, USP20 inhibitor (GSK2643943A) Acta pharmaceutica Sinica. B Medium 41049757
2025 USP20 deubiquitinates and stabilizes PINK1 by hydrolyzing K48-linked polyubiquitin chains, promoting mitophagy under mitochondrial depolarization (CCCP treatment). CCCP treatment accelerates USP20's deubiquitinating activity toward PINK1, facilitating degradation of impaired mitochondria and enhancing mitochondrial quality control. Co-immunoprecipitation, ubiquitination assay, in vitro deubiquitination assay, mitophagy assay (CCCP treatment), knockdown/overexpression bioRxivpreprint Medium bio_10.1101_2025.03.30.646148
2024 HERC2 deficiency leads to increased USP20 protein levels, which correlates with enhanced ULK1 stability and upregulated autophagy (elevated LC3-II). p38 kinase activation disrupts the HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels, establishing the HERC2-USP20-ULK1 axis as an autophagy regulatory pathway relevant to a neurodevelopmental disorder. Co-immunoprecipitation, immunoblotting in patient-derived fibroblasts, lysosomal inhibitor experiments, p38 activation assays Cell death discovery Medium 38570483
2021 USP20 directly interacts with PTEN and its overexpression preserves PTEN levels during ischemic/OGD-reperfusion conditions in neurons and microglia. Suppression of PTEN abolished USP20-mediated protection against neuroinflammation and neuron death. Co-immunoprecipitation, overexpression in MCAO mouse model and OGD/R cell model, PTEN inhibitor rescue experiment, immunofluorescence International immunopharmacology Low 34953448
2022 USP20 deubiquitinates MCL1 to regulate its stability; USP20 knockdown increases MCL1 polyubiquitination and turnover, sensitizing esophageal cancer cells to chemotherapy. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell viability assay Biochemical and biophysical research communications Low 35063767
2022 USP20 interacts with and deubiquitinates SOX4, regulating its stability and promoting colorectal cancer EMT and metastasis. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Transwell migration/invasion assay Pathology, research and practice Low 35405623
2025 The zf-UBP and DUSP2 auxiliary domains of USP20 are short linear motif (SLiM)-binding domains with similar binding profiles to those of USP33, explaining functional redundancy between USP20 and USP33 for substrate targeting. Proteomic-peptide phage display, peptide arrays, affinity measurements (systematic biochemical characterization of 29 USP auxiliary domains) bioRxivpreprint Medium bio_10.1101_2025.09.22.676098
2026 USP20 directly binds STING (in cardiomyocytes in the context of diabetic cardiomyopathy) and promotes STING degradation through the autophagy pathway by deubiquitinating p62 via its active site C154, thereby reducing STING-mediated inflammatory signaling and cardiac remodeling. LC-MS/MS with Co-IP, cardiomyocyte-specific KO mice, active-site mutant (C154), db/db and HFD/STZ diabetic mouse models FASEB journal Medium 41637663
2026 USP20 removes K48-linked polyubiquitination from GPX4, preventing its proteasomal degradation and maintaining cellular antioxidant capacity, enabling ferroptosis evasion and TKI resistance in renal cell carcinoma and lung cancer. Co-immunoprecipitation, ubiquitination assay, genetic ablation, pharmacological inhibition, in vivo tumor model Redox biology Medium 41844497
2026 USP20 deubiquitinates HuR at lysine 154 by specifically cleaving K48-linked polyubiquitin chains via its ubiquitin-specific protease domain, preventing HuR proteasomal degradation. Stabilized HuR binds GPX4 mRNA to suppress its degradation, thereby mitigating ferroptosis and doxorubicin-induced cardiomyopathy. Co-IP with LC-MS/MS, site-specific ubiquitination mapping (K154), cardiomyocyte-specific KO mice, HuR-CKO mice (epistasis), AAV9 overexpression, scRNA-seq International journal of biological macromolecules High 41921794
2026 USP20 negatively regulates RAB8A activity by selectively removing K48-linked polyubiquitin chains from its inactive form, thereby restricting RAB8A-dependent GLUT1 vesicular trafficking to the cell surface and reducing glucose uptake in pancreatic cancer cells. Co-immunoprecipitation, ubiquitination assay, GLUT1 trafficking assay, in vitro and in vivo functional assays, KPC mouse-derived primary PDAC cells Cancer letters Medium 41651399
2017 NMR characterization of the ZnF-UBP domain of USP20 revealed a global fold of three α-helices and four β-strands. This domain potentially helps USP20 recruit its ubiquitin substrates. NMR spectroscopy (1H, 13C, 15N backbone and side-chain resonance assignments) Biomolecular NMR assignments Medium 28091961
2025 Foxp1 transcription factor directly regulates USP20 expression in cardiomyocytes; USP20 in turn prevents HIF1α degradation (deubiquitination-mediated stabilization), thereby regulating metabolic transition from fatty acid oxidation to glycolysis via Hand1 to control cardiomyocyte proliferation and heart regeneration. Cardiomyocyte-specific loss/gain-of-function, single-cell transcriptome analysis, AAV9 in vivo experiments, chromatin analysis Advanced science Low 39899693

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. Nature 209 33177714
2009 The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization. The EMBO journal 151 19424180
2016 USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA. Cell research 140 27801882
2018 USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization. Cell death and differentiation 86 29867130
2020 Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2. Genes & development 77 32943575
2014 HERC2-USP20 axis regulates DNA damage checkpoint through Claspin. Nucleic acids research 65 25355518
2014 HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability. Nucleic acids research 54 25326330
2023 LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1-TINCR-USP20-PD-L1 axis. Cell death & disease 52 36725842
2018 The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation. EMBO reports 48 29487085
2018 USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 39 30354204
2015 Phosphorylation of the deubiquitinase USP20 by protein kinase A regulates post-endocytic trafficking of β2 adrenergic receptors to autophagosomes during physiological stress. The Journal of biological chemistry 38 25666616
2017 Deubiquitinating enzyme USP20 is a positive regulator of Claspin and suppresses the malignant characteristics of gastric cancer cells. International journal of oncology 32 28350092
2024 USP20 deubiquitinates and stabilizes the reticulophagy receptor RETREG1/FAM134B to drive reticulophagy. Autophagy 29 38705724
2019 USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA. Journal of immunology (Baltimore, Md. : 1950) 29 30814308
2020 The Deubiquitinating Enzyme USP20 Regulates the TNFα-Induced NF-κB Signaling Pathway through Stabilization of p62. International journal of molecular sciences 25 32354117
2017 Deubiquitinating Enzyme USP20 Regulates Extracellular Signal-Regulated Kinase 3 Stability and Biological Activity. Molecular and cellular biology 23 28167606
2021 USP20 mitigates ischemic stroke in mice by suppressing neuroinflammation and neuron death via regulating PTEN signal. International immunopharmacology 18 34953448
2021 Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins. The Journal of cell biology 14 33792613
2022 USP20 regulates the stability of EMT transcription factor SOX4 and influences colorectal cancer metastasis. Pathology, research and practice 13 35405623
2023 Phosphorylation of USP20 on Ser334 by IRAK1 promotes IL-1β-evoked signaling in vascular smooth muscle cells and vascular inflammation. The Journal of biological chemistry 12 37311534
2021 USP18 and USP20 restrict oHSV-1 replication in resistant human oral squamous carcinoma cell line SCC9 and affect the viability of SCC9 cells. Molecular therapy oncolytics 11 34901390
2022 The deubiquitinating enzyme USP20 regulates the stability of the MCL1 protein. Biochemical and biophysical research communications 9 35063767
2025 Cardiomyocyte Foxp1-Specific Deletion Promotes Post-injury Heart Regeneration via Targeting Usp20-HIF1ɑ-Hand1 Signaling Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 8 39899693
2017 1H, 13C and 15N backbone and side-chain resonance assignments of the ZnF-UBP domain of USP20/VDU2. Biomolecular NMR assignments 7 28091961
2025 USP20 as a super-enhancer-regulated gene drives T-ALL progression via HIF1A deubiquitination. Acta pharmaceutica Sinica. B 4 41049757
2024 A novel PDIA3/FTO/USP20 positive feedback regulatory loop induces osteogenic differentiation of preosteoblast in osteoporosis. Cell biology international 4 38321831
2024 USP20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality. American journal of physiology. Heart and circulatory physiology 4 39365672
2024 Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder. Cell death discovery 3 38570483
2024 USP20 mediates malignant phenotypic changes in bladder cancer through direct interactions with YAP1. Neoplasia (New York, N.Y.) 3 39674114
2025 Cardiomyocyte-Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40192103
2022 Sleeve gastrectomy improves lipid dysmetabolism by downregulating the USP20-HSPA2 axis in diet-induced obese mice. Frontiers in endocrinology 2 36636478
2026 Cardiomyocyte-Derived USP20 Attenuates Diabetic Cardiomyopathy by Facilitating the Degradation of STING and Mitigating STING-Mediated Inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 41637663
2025 UCMSCs-derived exosomal SLIT2 alleviates ischemic stroke through the β-catenin/TCF4/USP20 signaling pathway. The International journal of neuroscience 1 40272090
2025 USP20 competitively binds to STUB1 to enhance CTSL expression and promote epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Clinical and translational medicine 1 41261048
2024 [Expression and clinical significance of USP20 in oral squamous cell carcinoma]. Shanghai kou qiang yi xue = Shanghai journal of stomatology 1 39719836
2021 Expression, purification and characterization of the second DUSP domain of deubiquitinase USP20/VDU2. Protein expression and purification 1 33529762
2026 USP20-Driven Cholesterol Metabolism Links Inflammatory Signaling to Malignancy and Stromal Coevolution in Pancreatic Cancer. Cancer research 0 41196022
2026 USP20-RAB8A signaling axis restricts pancreatic cancer progression by disrupting GLUT1 vesicular trafficking and inhibiting glucose uptake. Cancer letters 0 41651399
2026 USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination. International journal of biological sciences 0 41800264
2026 USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers. Redox biology 0 41844497
2026 Targeting ULK1 and USP20 to modulate autophagy and chemosensitivity in cancer cell lines. Biomedical reports 0 41859356
2026 Ubiquitin-specific protease 20(USP20) mitigates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing HuR. International journal of biological macromolecules 0 41921794
2025 Cardiomyocyte USP20 alleviates septic cardiomyopathy by deubiquitinating and inhibiting NLRP3 activity. Clinical and translational medicine 0 41042219