Affinage

USP21

Ubiquitin carboxyl-terminal hydrolase 21 · UniProt Q9UK80

Length
565 aa
Mass
62.7 kDa
Annotated
2026-06-11
68 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP21 is a cysteine deubiquitinase that hydrolyzes polyubiquitin chains—predominantly K48- and K63-linked—and acts more weakly on ISG15 but not NEDD8, with a USP-domain architecture that presents a second ubiquitin/ISG15-binding surface explaining its polyUb processivity and cross-reactivity (PMID:21399617). Catalysis depends on the active-site cysteine C221, and structural work on the catalytic domain bound to an H2AK119ub nucleosome together with the finding that its N-terminal intrinsically disordered region autoinhibits enzymatic activity establishes a self-regulated enzyme whose activity is relieved by kinase-mediated phosphorylation of the IDR (PMID:41071870, PMID:23395819). A recurring theme across substrates is that USP21 stabilizes its targets by reversing K48-linked degradative ubiquitination: it sustains protein levels of transcription factors and signaling components including FOXP3 and GATA3 in Treg biology (PMID:27857073, PMID:23395819), Nanog and histone H2AK119 in stem-cell self-renewal (PMID:27886188), TCF7 and β-catenin in Wnt signaling (PMID:31488580, PMID:42091690), FOXM1 in cell-cycle progression (PMID:30865895), MEK2 in ERK signaling (PMID:29706623), and EGFR/Lyn in receptor signaling (PMID:40629473). In innate immunity USP21 functions as a negative regulator of type I interferon by deubiquitinating RIG-I (K63 chains) and STING (K27/K63 chains), the latter following p38-mediated phosphorylation of USP21 at Ser538 that recruits it to STING during viral infection—illustrating how post-translational modification of USP21 itself directs substrate engagement (PMID:24493797, PMID:28254948). The protein also localizes to centrosomes and microtubules through a discrete N-terminal motif (residues 59–75), where it controls microtubule regrowth, ciliogenesis, and Gli1/Hedgehog signaling output, and stabilizes the centrosomal substrate DPYSL2 to support cilium formation (PMID:22298430, PMID:27621083, PMID:40619097). Beyond canonical catalysis, USP21 can act as a deubiquitinase-independent scaffold, promoting the USP7–Mdm2 interaction to drive p53 degradation (PMID:42168156). Across many tissues these activities position USP21 as a frequently oncogenic and immunoregulatory enzyme, and a non-covalent inhibitor (BAY-805) provides chemical-genetic validation of its functions (PMID:36802665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2011 High

    Established USP21 as a polyubiquitin-cleaving cysteine DUB with defined linkage preferences and a structural basis for ubiquitin/ISG15 cross-reactivity, defining its core enzymatic identity.

    Evidence Crystal structure of USP21–linear diUb aldehyde complex plus in vitro cleavage assays against polyUb, ISG15, and NEDD8

    PMID:21399617

    Open questions at the time
    • Cellular substrate repertoire not addressed
    • No regulation of the enzyme defined at this stage
  2. 2012 High

    Localized USP21 to centrosomes and microtubules via a discrete N-terminal motif, linking the enzyme to cytoskeletal and ciliary functions distinct from its catalytic core.

    Evidence Subcellular localization survey, in vitro microtubule-binding with N-terminal deletions, siRNA knockdown with microtubule regrowth, ciliogenesis, and neurite outgrowth readouts

    PMID:22298430

    Open questions at the time
    • Centrosomal substrates not identified here
    • Whether catalytic activity is required for cytoskeletal effects unresolved
  3. 2013 Medium

    Connected USP21 catalysis (C221) to substrate stabilization in adaptive immunity and to histone H2A deubiquitination, broadening its role from in vitro chains to physiological substrates.

    Evidence Co-IP, in vivo ubiquitination assays, C221A catalytic mutant, FOXP3 promoter assays (GATA3); isoform identification and in vitro transcription with ubH2A readout

    PMID:23395819 PMID:24278184

    Open questions at the time
    • Ubiquitin linkage type on GATA3 not defined
    • Histone targeting specificity not structurally resolved at this stage
  4. 2014 High

    Defined USP21 as a negative regulator of innate antiviral signaling by removing K63-linked chains from RIG-I, establishing an in vivo immunoregulatory role.

    Evidence Co-IP, in vitro/in vivo DUB assays, USP21 KO MEFs/macrophages/BMDCs, chimeric mouse VSV infection model

    PMID:24493797

    Open questions at the time
    • Mechanism of USP21 recruitment to RIG-I not defined
    • Whether the same applies to other RLRs untested
  5. 2016 High

    Showed USP21 stabilizes the pluripotency factor Nanog (K48 chains) and is itself regulated by ERK phosphorylation, while also acting on promoter-bound H2AK119—coupling substrate selectivity to upstream signaling.

    Evidence Reciprocal Co-IP, in vitro DUB assays, USP21 KO mESC differentiation/reprogramming assays, domain mapping, ChIP for H2AK119ub

    PMID:27886188 PMID:29263902

    Open questions at the time
    • Mechanism by which ERK phosphorylation dissociates USP21 from Nanog not structurally defined
    • Generality of phospho-control across substrates unknown at this stage
  6. 2016 High

    Established USP21 control of immune-cell identity (FOXP3/Treg stability) and Hedgehog output (Gli1 at the centrosome), demonstrating spatially distinct regulatory roles.

    Evidence Treg-specific USP21 KO mice with in vivo FOXP3 ubiquitination assay and flow cytometry; Co-IP, Gli1 reporter, centrosomal IF, PKA phosphorylation assay

    PMID:27621083 PMID:27857073

    Open questions at the time
    • How centrosomal localization selects Gli1 vs other substrates unclear
    • Direct vs indirect effect on PKA phosphorylation of Gli1 not fully resolved
  7. 2017 High

    Defined the STING-directed antiviral mechanism and showed USP21 substrate recruitment is controlled by p38 phosphorylation at Ser538, formalizing PTM-driven substrate engagement.

    Evidence Co-IP, in vitro DUB assays (K27/K63), Ser538 phospho-site mapping, p38 inhibitor, USP21 KO cells, mouse HSV-1 infection model

    PMID:28254948

    Open questions at the time
    • Whether Ser538 phosphorylation affects catalysis or only localization not separated
    • Other kinases acting on USP21 not surveyed here
  8. 2017 Medium

    Extended USP21 to growth and proliferative signaling by stabilizing MEK2 (K48) and modulating Hippo via MARK kinases, linking the DUB to oncogenic pathways.

    Evidence Co-IP, K48-specific ubiquitination assay, xenograft (MEK2); Co-IP, ubiquitination, YAP/TAZ reporters in Drosophila and mammalian cells (Hippo)

    PMID:28969054 PMID:29706623

    Open questions at the time
    • Direct enzyme-substrate contacts not structurally mapped
    • Tissue specificity of Hippo regulation not defined
  9. 2019 High

    Identified FOXM1 and TCF7 as USP21 substrates driving cell-cycle progression and Wnt-dependent stemness, with in vivo tumor models linking the DUB to cancer phenotypes.

    Evidence RNAi screen, Co-IP, in vitro DUB assay, cell-cycle analysis, xenograft (FOXM1); Co-IP, ubiquitination, KrasG12D PDAC models, patient-derived lines (TCF7)

    PMID:30865895 PMID:31488580

    Open questions at the time
    • Ubiquitin chain linkage on FOXM1 not defined
    • How USP21 is targeted to these transcription factors mechanistically unclear
  10. 2021 Medium

    Broadened the substrate landscape to inflammasome assembly (AIM2), immune checkpoint (PD-L1), antiviral restriction of HIV-1 (Tat), and metabolic control in skeletal muscle (DNA-PKcs/ACLY), demonstrating pleiotropic deubiquitinase roles.

    Evidence Co-IP and ubiquitination assays with functional readouts (ASC speck/IL-1β; PD-L1 with C221A control; HIV-1 production with histone methylation assay; muscle-specific KO mice with omics and metabolic phenotyping)

    PMID:33827943 PMID:34470856 PMID:34523817 PMID:34956491

    Open questions at the time
    • For several substrates ubiquitin linkage type not defined
    • Single-lab Co-IP evidence for some interactions
  11. 2024 Medium

    Consolidated USP21 as a recurrently oncogenic K48-linkage DUB stabilizing diverse substrates (HSP90/ENO1, AhR, EGFR, p65, G3BP1, YBX1, FOXD1, TET2) across many cancers and tissues, with several upstream regulators (METTL3 m6A) and inhibitors (BAY-805, disulfiram) defined.

    Evidence Co-IP, K48-specific and site-specific ubiquitination assays, CRISPR KO, xenograft models, MS-based substrate ID, pharmacological inhibition

    PMID:35974001 PMID:38385089 PMID:38663220 PMID:38906857 PMID:38952265 PMID:39695128 PMID:39725149 PMID:41131631

    Open questions at the time
    • Most substrate interactions rest on single-lab Co-IP
    • Selectivity rules determining which substrates dominate in a given tissue unresolved
  12. 2025 High

    Resolved the structural basis of nucleosomal H2AK119ub recognition and established that the N-terminal IDR autoinhibits USP21 in a phosphorylation-reversible manner, unifying earlier observations of PTM-controlled activity.

    Evidence Cryo-EM of USP21–H2AK119ub nucleosome, AlphaFold-Multimer kinase screen, in vitro phosphorylation and DUB assays, AlphaFold3 autoinhibition modeling

    PMID:41071870

    Open questions at the time
    • Which physiological kinases relieve autoinhibition in vivo not confirmed
    • How autoinhibition intersects with substrate-specific recruitment unclear
  13. 2025 Medium

    Demonstrated deubiquitinase-independent scaffolding (USP7–Mdm2/p53 axis) and ciliary control via centrosomal DPYSL2 stabilization, refining USP21's catalytic and non-catalytic modes.

    Evidence Co-IP, catalytic-dead mutant analysis, CRC tumor models (scaffold); Usp21 KO mice multi-organ ciliary phenotyping, K48 ubiquitination assay, centrosomal IF (DPYSL2)

    PMID:40619097 PMID:42168156

    Open questions at the time
    • Structural basis of scaffolding not defined
    • Relative contribution of catalytic vs scaffold functions in vivo not quantified
  14. 2026 Medium

    Linked USP21-driven β-catenin stabilization to immune evasion through an ATF3–CCL4 axis controlling CD8+ T-cell trafficking, integrating its DUB activity with the tumor immune microenvironment.

    Evidence Syngeneic and humanized CRC models, CRISPR KO, BAY-805, K48 ubiquitination assay, ChIP (β-catenin on ATF3 promoter), anti-PD-1 combination

    PMID:42091690

    Open questions at the time
    • Direct β-catenin contact site not mapped
    • Generality across MSI/MSS subtypes only partly addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how USP21 achieves substrate selectivity among its very broad target set—how localization, IDR phosphorylation, and the second ubiquitin-binding surface are integrated to choose among the dozens of reported substrates in a given cell.
  • No unifying model of substrate discrimination
  • Few substrate interactions validated reciprocally beyond a single lab
  • In vivo hierarchy of substrates per tissue undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0098772 molecular function regulator activity 4 GO:0016787 hydrolase activity 3 GO:0008092 cytoskeletal protein binding 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005815 microtubule organizing center 3 GO:0005634 nucleus 2 GO:0005929 cilium 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 7 R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1640170 Cell Cycle 2
Partners
DDX58FOXM1FOXP3GATA3GLI1NANOGSTING1TCF7

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 USP21 cleaves polyubiquitin chains and with reduced activity targets ISG15, but is inactive against NEDD8. A crystal structure of USP21 in complex with linear diubiquitin aldehyde revealed a previously unidentified second Ub- and ISG15-binding surface on the USP domain core, explaining polyUb binding and cross-reactivity. Crystal structure (USP21–diUb aldehyde complex), in vitro cleavage assays with polyUb, ISG15, and NEDD8 substrates EMBO reports High 21399617
2012 USP21 localizes to centrosomes and microtubules; microtubule binding is direct and mediated by a novel motif in amino acids 59–75 of the N-terminus. Depletion of USP21 impairs radial microtubule regrowth after cold-induced depolymerization, reduces primary cilium formation, and inhibits NGF-induced neurite outgrowth. GFP-tagging and systematic subcellular localization survey; in vitro microtubule-binding assay with N-terminal deletion constructs; siRNA knockdown with functional readouts (microtubule regrowth, ciliogenesis, neurite outgrowth) Molecular biology of the cell High 22298430
2013 USP21 interacts with and deubiquitinates GATA3, stabilizing it at the post-translational level. The catalytic mutant C221A reduces this stabilization. FOXP3 transcriptionally activates USP21 upon TCR stimulation, creating a FOXP3–USP21–GATA3 regulatory loop in Treg cells. Co-immunoprecipitation, ubiquitination assay, catalytic mutant (C221A), siRNA knockdown, FOXP3 chromatin binding/promoter activation assay The Journal of biological chemistry Medium 23395819
2013 A short variant of USP21 (USP21SV) lacking a nuclear export signal localizes predominantly in the nucleus. Both USP21SV and the long variant (USP21LV) deubiquitylate histone H2A (ubH2A) and activate transcription in vitro. Identification of USP21SV isoform; differential localization by fluorescence microscopy; in vitro transcription assay with recombinant USP21 variants; ubH2A levels assessed by western blot PloS one Medium 24278184
2014 USP21 acts as a deubiquitinase for RIG-I, removing Lys63-linked polyubiquitin chains and thereby inhibiting RIG-I-mediated IFN signaling. USP21-deficient MEFs showed elevated RIG-I polyubiquitination, IRF3 phosphorylation, and IFN-α/β production. USP21 KO mice were more resistant to VSV infection with elevated IFN production. Co-immunoprecipitation; in vivo and in vitro deubiquitination assays; USP21 KO MEFs, peritoneal macrophages, BMDCs; chimeric bone marrow transplant mouse model; comparison with A20 and CYLD The Journal of experimental medicine High 24493797
2014 USP21 interacts with IL-33, deubiquitinates it to maintain its protein stability, and thereby sustains IL-33-mediated NF-κB p65 promoter activity. Depletion of USP21 reduces IL-33 protein levels and NF-κB p65 transcriptional activity. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, luciferase reporter assay International journal of clinical and experimental pathology Low 25197364
2015 SUMOylated BEND3 stabilizes the NoRC component TTF-1-interacting protein 5 (TIP5) via association with USP21 deubiquitinase, linking USP21 to rDNA silencing. Co-immunoprecipitation, ChIP, functional rDNA transcription assays in mammalian cells Proceedings of the National Academy of Sciences of the United States of America Medium 26100909
2016 USP21 interacts with, deubiquitinates, and stabilizes Nanog in mouse ESCs, preventing its proteasomal degradation. Loss of USP21 causes Nanog degradation, mESC differentiation, and reduced reprogramming efficiency. ERK-mediated phosphorylation of USP21 upon differentiation signals dissociates it from Nanog. USP21 is also recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119, facilitating Nanog-mediated gene expression. Co-immunoprecipitation, in vitro deubiquitination assay, USP21 KO mESCs, differentiation assays, reprogramming assay, ChIP for H2AK119ub Nature communications High 27886188
2016 USP21 deubiquitinates Nanog (K48-linked ubiquitin chain) and stabilizes it in mouse ESCs, but does not deubiquitinate Oct4 or Sox2. The C-terminal USP domain of USP21 and the C-domain of Nanog mediate this interaction. Co-immunoprecipitation in vivo and in vitro, domain mapping, in vitro deubiquitination assay, USP21 depletion/differentiation assay Signal transduction and targeted therapy Medium 29263902
2016 USP21 deubiquitinates FOXP3, maintaining its protein level in Treg cells and preventing generation of Th1-like Treg cells. Treg-specific USP21 KO mice display spontaneous T-cell activation and excessive Th1 skewing. Treg-specific USP21 KO mice (Usp21fl/fl × Foxp3-Cre), in vivo ubiquitination assay of FOXP3, flow cytometry analysis of Treg stability Nature communications High 27857073
2016 USP21 (centrosome-associated) interacts with KCTD6 and Gli1. Both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. USP21 recruits and stabilizes Gli1 at the centrosome, promoting PKA-mediated phosphorylation of Gli1, thereby suppressing Hedgehog signaling output. Co-immunoprecipitation, reporter assay for Gli1-dependent transcription, USP21 siRNA depletion and overexpression, immunofluorescence localization, PKA phosphorylation assay Journal of cell science Medium 27621083
2017 USP21 is a deubiquitinating enzyme for STING that removes K27/K63-linked polyubiquitin chains, negatively regulating DNA virus-induced type I IFN production. HSV-1 infection recruits USP21 to STING at late stage via p38-mediated phosphorylation of USP21 at Ser538. p38 inhibition enhances IFN production and protects mice from lethal HSV-1 infection. Co-immunoprecipitation, in vitro deubiquitination assay, phosphorylation site mapping (Ser538), p38 inhibitor treatment, USP21 KO cells, mouse HSV-1 infection model The Journal of experimental medicine High 28254948
2017 USP21 regulates Hippo pathway activity by controlling the stability of MARK kinases (which promote Hippo signaling), thereby modulating YAP/TAZ transcriptional co-activator activity. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, reporter assays for YAP/TAZ activity in Drosophila and mammalian systems Oncotarget Medium 28969054
2017 USP21 deubiquitinates EZH2 and stabilizes it in bladder carcinoma, promoting cell proliferation and metastasis. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown/overexpression, proliferation and invasion assays OncoTargets and therapy Low 28223825
2018 USP21 stabilizes MEK2 by decreasing its K48-linked polyubiquitination, thereby activating the ERK signaling pathway and promoting hepatocellular carcinoma growth. Co-immunoprecipitation, in vivo ubiquitination assay (K48 linkage), siRNA knockdown, ectopic overexpression, in vivo xenograft model Cell death & disease Medium 29706623
2019 USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, increasing its stability and upregulating the FOXM1 transcriptional network. USP21 depletion delays cell cycle progression and sensitizes basal-like breast cancer cells and xenograft tumors to paclitaxel. RNAi screen, Co-immunoprecipitation, in vitro deubiquitination assay, siRNA depletion, cell cycle analysis, xenograft mouse model Cell reports High 30865895
2019 USP21 deubiquitinates and stabilizes TCF7 (TCF/LEF transcription factor), promoting Wnt pathway activation and cancer cell stemness in pancreatic ductal adenocarcinoma. Co-immunoprecipitation, in vivo ubiquitination assay, USP21 KD/OE, PDAC mouse models (KrasG12D-driven), patient-derived cell lines Genes & development High 31488580
2019 USP21 interacts with and deubiquitinates Goosecoid (GSC), negatively regulating GSC-dependent Sox6 reporter transcription without affecting GSC protein stability. Co-immunoprecipitation, Sox6 reporter assay, ubiquitination assay, ATDC5 cell functional assays Bioscience reports Low 31253698
2020 USP21 deubiquitinates and stabilizes YY1, promoting NSCLC cell proliferation, migration, and invasion. YY1 transcriptionally activates SNHG16, and SNHG16 in turn increases USP21 via miR-4500 sponging, forming a regulatory axis. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA/shRNA knockdown, in vitro and in vivo tumor assays, luciferase reporter Experimental & molecular medicine Medium 31956270
2021 USP21 deubiquitinates and stabilizes FOXM1 in cervical cancer; FOXM1 activates the Hippo-YAP1 pathway (promoting nuclear YAP1 translocation), conferring radioresistance. USP21 knockdown enhances radiosensitivity in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, colony survival assay, apoptosis assay, xenograft model Human cell Medium 34825342
2021 USP21 binds to AIM2 upon DNA stimulation, deubiquitinates it to increase its protein stability, and is required for AIM2 inflammasome assembly (AIM2-ASC complex formation). Depletion of USP21 does not affect AIM2 DNA-binding ability but inhibits inflammasome complex formation. Co-immunoprecipitation, in vivo ubiquitination assay, USP21 siRNA knockdown, inflammasome assembly assay (ASC speck formation), IL-1β secretion assay Journal of immunology Medium 34470856
2021 USP21 deubiquitinates and stabilizes PD-L1. In vitro deubiquitination assay showed USP21-WT but not catalytic mutant C221A reduces polyubiquitin chains on PD-L1. Co-immunoprecipitation, in vitro deubiquitination assay, catalytic mutant C221A, siRNA knockdown, overexpression American journal of translational research Medium 34956491
2021 USP21 inhibits HIV-1 production by deubiquitinating the HIV-1 transactivator Tat (destabilizing it) and by reducing cyclin T1 mRNA levels through increased H3K9 methylation at the cyclin T1 promoter, thereby limiting Tat-dependent transcriptional elongation. Co-immunoprecipitation, in vivo ubiquitination assay, dominant-negative ubiquitin mutant, chromatin methylation assay (H3K9me), HIV-1 production assay Journal of virology Medium 33827943
2021 USP21 in skeletal muscle deubiquitinates DNA-PKcs and ACLY, leading to AMPK inhibition. Loss of USP21 promotes oxidative fibre type switching, increases muscle mass, enhances mitochondrial biogenesis, fatty acid oxidation, and thermogenesis, and protects against diet-induced obesity and insulin resistance. Whole-body and skeletal muscle-specific KO mice, transcriptomics, proteomics, lipidomics, in vivo metabolic phenotyping, Co-IP to identify substrates DNA-PKcs and ACLY, high-fat diet model Journal of cachexia, sarcopenia and muscle Medium 34523817
2022 USP21 directly interacts with FOXD1, reverting its proteolytic ubiquitination and stabilizing FOXD1 protein. Silencing USP21 enhances FOXD1 polyubiquitination, promotes proteasomal degradation, and attenuates mesenchymal identity in glioblastoma stem cells. Co-immunoprecipitation, in vitro/in vivo ubiquitination assay, USP21 siRNA knockdown, FOXD1 rescue, GBM xenograft model Cell death & disease Medium 35974001
2023 USP21 interacts with and deubiquitinates AURKA, preventing its degradation and promoting laryngeal cancer cell proliferation, migration, and invasion. Interaction confirmed by Co-IP and GST pull-down. Co-immunoprecipitation, GST pull-down, ubiquitination assay, siRNA knockdown, rescue by AURKA overexpression The Kaohsiung journal of medical sciences Low 36919585
2023 YOD1 interacts with USP21 and deubiquitinates MARK kinases. YOD1 and USP21 mutually deubiquitinate each other; YOD1 regulates USP21 protein stability, but USP21 does not stabilize YOD1. Both cooperate to promote cell proliferation via Hippo pathway modulation. Co-immunoprecipitation, GST pull-down, western blot ubiquitination assay, cell proliferation assays, YAP/p-YAP western blot Cancer cell international Low 37743467
2023 BAY-805 is a potent non-covalent USP21 inhibitor identified via HTS and structure-based optimization. It engages USP21 with high affinity (SPR, CETSA) and activates NF-κB in a cell-based reporter assay, validating USP21's role in NF-κB regulation. High-throughput screening, structure-based optimization, surface plasmon resonance (SPR), CETSA, NF-κB reporter assay Journal of medicinal chemistry Medium 36802665
2024 USP21 deubiquitinates and stabilizes HSP90 via K48-linked deubiquitination in cholangiocarcinoma, which increases HIF1A expression, upregulating glycolytic enzyme genes (ENO2, ENO3, ALDOC, ACSS2). USP21 also directly stabilizes ENO1 to promote aerobic glycolysis. Co-immunoprecipitation, in vitro/in vivo K48-linked deubiquitination assay, siRNA knockdown, glycolysis assays, xenograft model International journal of biological sciences Medium 38385089
2024 USP21 deubiquitinates AhR at K432, removing K48-linked polyubiquitin chains and stabilizing AhR protein. Paradoxically, USP21-mediated deubiquitination of AhR at K432 inhibits AhR transcriptional activity in a deubiquitinating-dependent manner, thereby suppressing Th17 cell differentiation. Co-immunoprecipitation, K48-linked ubiquitination assay, site-directed mutagenesis (K432), siRNA KD, Th17 differentiation assay in vitro and in vivo (Rag1-/- adoptive transfer colitis model) Journal of leukocyte biology Medium 38952265
2024 USP21 binds to and deubiquitinates EGFR, reducing EGFR degradation and enhancing EGFR stability. USP21-KO colon cancer cells show reduced EGF-driven proliferation, migration, colony formation, and tumor spheroid formation. CRISPR/Cas9 USP21-KO, Co-immunoprecipitation, ubiquitination assay, in vitro cancer progression assays, NSG xenograft model, BAY-805 inhibitor treatment Cell death discovery Medium 39695128
2024 USP21 deubiquitinates and stabilizes TET2 in airway epithelial cells, inhibiting cigarette smoke extract-induced TET2 degradation and thereby attenuating apoptosis. Co-immunoprecipitation, ubiquitination assay, USP21 knockdown, TET2 overexpression, apoptosis assay in vitro and in vivo COPD model iScience Low 38439981
2024 USP21 deubiquitinates and stabilizes p65 (NF-κB) via K48-linked deubiquitination in bladder cancer cells, promoting cancer progression. USP21 directly interacts with p65 as confirmed by mechanistic studies. Co-immunoprecipitation, K48-linked ubiquitination assay, USP21 siRNA knockdown/overexpression, xenograft model, pharmacological inhibition (20-HE) Translational oncology Medium 38663220
2024 USP21 deubiquitinates and stabilizes G3BP1, which activates Wnt/β-Catenin signaling to promote esophageal squamous cell carcinoma proliferation and metastasis. Disulfiram abolishes USP21-mediated G3BP1 stability. Co-immunoprecipitation, in vivo ubiquitination assay, rescue assay, in vitro and in vivo ESCC tumor models, disulfiram inhibitor treatment Oncogenesis Medium 38906857
2024 USP21 deubiquitinates and stabilizes YBX1; YBX1 in turn enhances transcription of HIF1A, promoting prostate cancer malignancy via the HIF1 signaling pathway. YBX1 was identified as the primary substrate by Co-IP coupled with mass spectrometry. Co-IP/mass spectrometry substrate identification, Co-immunoprecipitation, ubiquitination assay, dual-luciferase reporter assay, ChIP, siRNA knockdown, Bay-805 inhibitor, patient-derived organoids Journal of translational medicine Medium 41131631
2024 USP21 stabilizes H2BFS (histone H2B family member S) through deubiquitination in hepatocellular carcinoma. METTL3-mediated m6A methylation of USP21 mRNA regulates USP21 expression, linking epitranscriptomic regulation to USP21-mediated substrate stabilization. MeRIP assay (m6A), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression, xenograft model Biochemical genetics Low 39680331
2024 Disulfiram impairs USP21-mediated deubiquitination of MOF at lysine K257, leading to increased MOF ubiquitination and degradation, thereby suppressing Wnt/β-Catenin signaling and ESCC progression. Co-immunoprecipitation, site-specific ubiquitination assay (K257), disulfiram treatment, in vitro and in vivo ESCC models Cancer letters Medium 39725149
2025 Cryo-EM structure of USP21 catalytic domain bound to an H2AK119ub nucleosome revealed a recognition mode distinct from other H2AK119-specific DUBs. The N-terminal intrinsically disordered region (IDR) of USP21 autoinhibits its enzymatic activity. Kinases identified by AlphaFold-Multimer virtual screen phosphorylate the IDR, relieving autoinhibition and activating USP21. Cryo-EM structure determination of USP21–H2AK119ub nucleosome complex; AlphaFold-Multimer virtual screen; in vitro phosphorylation and DUB activity assays; AlphaFold3 structural modeling of autoinhibition Science advances High 41071870
2025 USP21 deubiquitinates DPYSL2 (removing K48-linked ubiquitin), increasing DPYSL2 centrosomal abundance. Loss of USP21 leads to proteasomal degradation of DPYSL2 at centrosomes and causes ciliary defects in kidney, liver, and trachea of Usp21 KO mice. Usp21 KO mice (multi-organ phenotyping), Co-immunoprecipitation, K48-linked ubiquitination assay, immunofluorescence localization at centrosome/basal body, proteasome inhibitor rescue Journal of genetics and genomics Medium 40619097
2025 USP21 acts as a scaffold (in a deubiquitinase activity-independent manner) to facilitate USP7-Mdm2 interaction, enhancing Mdm2 stability and consequently promoting p53 ubiquitination and degradation, thereby suppressing p53 tumor suppressor activity in colorectal cancer. Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis (activity-independent scaffolding), siRNA knockdown, CRC cell lines, in vivo tumor models Cell death discovery Medium 42168156
2025 USP21 deubiquitinates and stabilizes EGFR and Lyn in NSCLC cells, preventing their ubiquitination and degradation and sustaining oncogenic signaling. USP21-KO suppresses tumor growth in xenograft models. USP21-KO lung cancer cell lines (CRISPR), Co-immunoprecipitation, ubiquitination assay, in vivo xenograft, BAY-805 inhibitor treatment Biomarker research Medium 40629473
2025 USP21 deubiquitinates and stabilizes ALDH2 in vascular smooth muscle cells, promoting VSMC dedifferentiation and phenotypic changes that exacerbate abdominal aortic aneurysm. Pharmacological inhibition of USP21 with disulfiram reduces AAA progression. USP21 global KO and VSMC-specific KO mice (angiotensin II and PPE models), Co-immunoprecipitation/mass spectrometry substrate identification, proteomic analysis, disulfiram treatment, ALDH2E506K mutant mice Cell reports. Medicine Medium 40925375
2026 USP21 stabilizes β-catenin by removing K48-linked ubiquitin chains, enabling its nuclear translocation. Nuclear β-catenin binds the ATF3 promoter to upregulate ATF3, which transcriptionally represses CCL4, limiting CD8+ T-cell trafficking via CCL4-CCR5 axis and promoting immune evasion in colorectal cancer. Syngeneic mouse CRC models (MSI-H and MSS), CRISPR Usp21 KO, BAY-805 treatment, Co-immunoprecipitation, K48-linkage ubiquitination assay, ChIP (β-catenin on ATF3 promoter), huCD34+ humanized mice with anti-PD-1 Cellular & molecular immunology Medium 42091690
2026 USP21 interacts with SMARCB1 via Co-immunoprecipitation and prevents its ubiquitin-mediated proteasomal degradation under hypoxia in hepatocellular carcinoma cells, stabilizing SMARCB1 to sustain its oncogenic and immunosuppressive activities. Cycloheximide chase assay, Co-immunoprecipitation, loss/gain-of-function experiments, transcriptomic analysis Biochemical and biophysical research communications Low 41637985

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. The Journal of experimental medicine 159 24493797
2011 Polyubiquitin binding and cross-reactivity in the USP domain deubiquitinase USP21. EMBO reports 155 21399617
2012 Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosome- and microtubule-associated functions. Molecular biology of the cell 106 22298430
2017 p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation. The Journal of experimental medicine 94 28254948
2019 FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer. Cell reports 84 30865895
2019 USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. Genes & development 84 31488580
2016 USP21 prevents the generation of T-helper-1-like Treg cells. Nature communications 81 27857073
2013 Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3. The Journal of biological chemistry 79 23395819
2016 The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog. Nature communications 77 27886188
2020 The USP21/YY1/SNHG16 axis contributes to tumor proliferation, migration, and invasion of non-small-cell lung cancer. Experimental & molecular medicine 75 31956270
2018 The deubiquitinase USP21 stabilizes MEK2 to promote tumor growth. Cell death & disease 66 29706623
2017 USP21 promotes cell proliferation and metastasis through suppressing EZH2 ubiquitination in bladder carcinoma. OncoTargets and therapy 56 28223825
2016 USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency. Signal transduction and targeted therapy 43 29263902
2016 The centrosomal deubiquitylase USP21 regulates Gli1 transcriptional activity and stability. Journal of cell science 37 27621083
2015 BEND3 represses rDNA transcription by stabilizing a NoRC component via USP21 deubiquitinase. Proceedings of the National Academy of Sciences of the United States of America 37 26100909
2021 Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes. Journal of cachexia, sarcopenia and muscle 32 34523817
2022 USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1. Cell death & disease 29 35974001
2021 De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer. Frontiers in cell and developmental biology 28 33791299
2017 Erratum: USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency. Signal transduction and targeted therapy 28 29266131
2024 USP21 deubiquitinates and stabilizes HSP90 and ENO1 to promote aerobic glycolysis and proliferation in cholangiocarcinoma. International journal of biological sciences 26 38385089
2021 USP21 regulates Hippo signaling to promote radioresistance by deubiquitinating FOXM1 in cervical cancer. Human cell 26 34825342
2014 Deubiquitination and stabilization of IL-33 by USP21. International journal of clinical and experimental pathology 25 25197364
2021 USP21 Deubiquitinase Regulates AIM2 Inflammasome Activation. Journal of immunology (Baltimore, Md. : 1950) 23 34470856
2023 Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21. Journal of medicinal chemistry 22 36802665
2017 USP21 regulates Hippo pathway activity by mediating MARK protein turnover. Oncotarget 21 28969054
2021 Deubiquitination and Stabilization of PD-L1 by USP21. American journal of translational research 19 34956491
2020 Identification of hsa_circ_0039053 as an up-regulated and oncogenic circRNA in hepatocellular carcinoma via the miR-637-mediated USP21 activation. Journal of Cancer 19 33123285
2021 USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B-cell lymphoma. Journal of clinical laboratory analysis 16 33389794
2020 USP21 upregulation in cholangiocarcinoma promotes cell proliferation and migration in a deubiquitinase-dependent manner. Asia-Pacific journal of clinical oncology 16 33052017
2013 The USP21 short variant (USP21SV) lacking NES, located mostly in the nucleus in vivo, activates transcription by deubiquitylating ubH2A in vitro. PloS one 16 24278184
2021 Deubiquitinating Enzyme USP21 Inhibits HIV-1 Replication by Downregulating Tat Expression. Journal of virology 15 33827943
2024 USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer. Cell death discovery 14 39695128
2023 USP21 contributes to the aggressiveness of laryngeal cancer cells by deubiquitinating and stabilizing AURKA. The Kaohsiung journal of medical sciences 14 36919585
2024 USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling. Oncogenesis 12 38906857
2023 c-JUN-induced upregulation of LINC00174 contributes to colorectal cancer proliferation and invasion through accelerating USP21 expression. Cell biology international 12 37434557
2017 Deubiquitylating Nanog: novel role of USP21 in embryonic stem cell maintenance. Signal transduction and targeted therapy 10 29263917
2024 The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer. Bioorganic chemistry 9 38688196
2023 Synergistic effect of YOD1 and USP21 on the Hippo signaling pathway. Cancer cell international 9 37743467
2022 USP21 accelerates the proliferation and glycolysis of esophageal cancer cells by regulating the STAT3/FOXO1 pathway. Tissue & cell 9 36095935
2000 Sequencing, tissue distribution and chromosomal assignment of a novel ubiquitin-specific protease USP23. Biochimica et biophysica acta 9 10786635
2023 USP21 Promotes the Progression of Nasopharyngeal Carcinoma by Regulating FOXM1. Stem cells international 8 36820242
2023 Design and development of novel potential inhibitors of the human USP21 enzyme using a pharmacophore-based virtual screening technique. Journal of molecular recognition : JMR 8 37096811
2024 Discovery of novel small molecules targeting the USP21/JAK2/STAT3 axis for the treatment of triple-negative breast cancer. European journal of medicinal chemistry 7 38776807
2024 TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells. iScience 6 38439981
2024 Disulfiram impairs USP21-mediated MOF-K257 deubiquitination to inhibit esophageal squamous cell carcinoma progression. Cancer letters 6 39725149
2021 Schistosoma japonicum Infection in Treg-Specific USP21 Knockout Mice. Journal of immunology research 6 33628844
2024 KLF15 suppresses stemness of pancreatic cancer by decreasing USP21-mediated Nanog stability. Cellular and molecular life sciences : CMLS 5 39367978
2019 USP21 modulates Goosecoid function through deubiquitination. Bioscience reports 5 31253698
2025 USP21-EGFR-Lyn axis drives NSCLC progression and therapeutic potential of USP21 inhibition. Biomarker research 4 40629473
2025 USP21/YBX1/HIF1-α promotes the progression of prostate cancer. Journal of translational medicine 4 41131631
2024 20-hydroxyecdysone suppresses bladder cancer progression via inhibiting USP21: A mechanism associated with deubiquitination and degradation of p65. Translational oncology 4 38663220
2024 Deubiquitination of aryl hydrocarbon receptor by USP21 negatively regulates T helper 17 cell differentiation. Journal of leukocyte biology 4 38952265
2023 circCD2AP promotes epithelial mesenchymal transition and stemness in bladder cancer by regulating FOXQ1/USP21 axis. iScience 4 38292422
2021 Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation. Genes & development 4 34599002
2025 Targeting USP21 to inhibit abdominal aortic aneurysm progression by suppressing the phenotypic transition of vascular smooth muscle cells. Cell reports. Medicine 2 40925375
2025 Exploring bioactive phytoconstituents as USP21 inhibitors for therapeutic development against cancer. Scientific reports 1 40320442
2025 GTF3C2 Promotes the Proliferation of Hepatocellular Carcinoma Cells through the USP21/MEK2/ERK1/2 Pathway. Journal of clinical and translational hepatology 1 40385937
2025 USP21 deubiquitinates DPYSL2 and enhances its centrosomal abundance to promote cilium formation. Journal of genetics and genomics = Yi chuan xue bao 1 40619097
2025 Mechanism of USP21 autoinhibition and histone H2AK119 deubiquitination. Science advances 1 41071870
2025 Inhibition of the U12-type splicing factor ZCRB1 mediates retention of the USP21 minor intron to suppress malignant progression in hepatocellular carcinoma. Hepatology international 1 41258964
2024 Molecular hybridization assisted multi-technique approach for designing USP21 inhibitors to halt catalytic triad-mediated nucleophilic attack and suppress pancreatic ductal adenocarcinoma progression: A molecular dynamics study. Computers in biology and medicine 1 39270458
2024 METTL3-Mediated m6A Methylation of USP21 Contributes to Hepatocellular Carcinoma Progression by Stabilizing H2BFS Through Deubiquitination. Biochemical genetics 1 39680331
2023 Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling. Biotechnology and applied biochemistry 1 37964466
2026 USP21-mediated SMARCB1 stabilization under hypoxia may influence tumor progression and immune response in HCC. Biochemical and biophysical research communications 0 41637985
2026 USP21 drives immune evasion in colorectal cancer via deubiquitination and stabilization of β-catenin. Cellular & molecular immunology 0 42091690
2026 USP21 functions as an oncogenic regulator of the Mdm2-p53 axis in colorectal cancer. Cell death discovery 0 42168156
2025 USP21 is involved in the development of chronic hepatitis B by modulating the immune microenvironment. European journal of medical research 0 40205504
2025 Usp21 Knockout Causes Abnormal Lipid Metabolism in Mouse and Its Polymorphism Correlates with Hypercholesterolemia in Outpatients. International journal of molecular sciences 0 41096992

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