Affinage

USP22

Ubiquitin carboxyl-terminal hydrolase 22 · UniProt Q9UPT9

Length
525 aa
Mass
60.0 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP22 is a ubiquitin-specific protease that functions as the catalytic deubiquitylase subunit of the human SAGA transcriptional cofactor complex, where it removes monoubiquitin from histones H2A and H2B to regulate activator-driven transcription, chromatin state, RNA polymerase II elongation-coupled 3'-end processing, and DNA repair (PMID:18206973, PMID:18469533, PMID:22067483, PMID:29520062). Beyond histones, USP22 deubiquitylates and stabilizes a broad spectrum of non-histone substrates—including SIRT1, cyclin D1, HIF1α, KDM1A, RIPK3, KPNA2, PU.1, PPARγ, ATG5, BRCA2/PALB2, and STAT1—thereby controlling cell cycle progression, apoptosis, homologous recombination, necroptosis, autophagy, innate immune signaling, and lipid metabolism (PMID:22542455, PMID:30224477, PMID:31776228, PMID:27501329, PMID:33369872, PMID:32130408, PMID:29844011, PMID:35449157, PMID:35900990, PMID:31685642, PMID:33601053). Genetic deletion of Usp22 in mice causes embryonic lethality associated with SIRT1 destabilization and defective extra-embryonic vasculature, and conditional ablation reveals essential roles in B cell class switch recombination, iNKT cell development, intestinal lineage specification, and hematopoietic differentiation (PMID:22542455, PMID:30718289, PMID:29520062, PMID:32069354, PMID:26431380, PMID:29844011). USP22 catalytic activity, dependent on the conserved Cys185 active site, is stimulated by interaction with PALB2's WD40 domain, and its ZnF-UBP domain mediates both SIRT1 binding and acetylation-regulated association with the SAGA core complex (PMID:26143114, PMID:31685642, PMID:23382074).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 Medium

    Establishing that USP22 encodes a functional deubiquitinating enzyme provided the foundational enzymatic identity for the gene product.

    Evidence Gene cloning and biochemical deubiquitinase activity assay on recombinant human and mouse USP22

    PMID:16378762

    Open questions at the time
    • No physiological substrate identified
    • No cellular context established
    • Catalytic domain residues not yet mapped by mutagenesis
  2. 2008 High

    Identification of USP22 as the catalytic subunit of the human SAGA complex that deubiquitylates both H2B and H2A established its primary chromatin-level function and connected it to activator-driven transcription.

    Evidence Biochemical subunit identification, in vitro deubiquitylation of defined histone substrates, ChIP showing activator-dependent recruitment, loss-of-function transcriptional assays

    PMID:18206973 PMID:18469533

    Open questions at the time
    • Whether H2A and H2B deubiquitylation serve distinct transcriptional outcomes
    • No structural model of the DUB module on nucleosomes
  3. 2011 High

    Demonstrating that USP22 deubiquitylates the non-histone substrate FBP1 to regulate its chromatin occupancy rather than its stability, and that USP22 couples H2B deubiquitylation to RNA Pol II elongation and 3'-end processing, expanded USP22's mechanistic repertoire beyond simple histone deubiquitylation.

    Evidence RNAi knockdown with ChIP for FBP1 occupancy and H2Bub at the p21 locus; Pol II CTD Ser2P ChIP and polyadenylation cleavage assays with USP22 rescue

    PMID:21779003 PMID:22067483

    Open questions at the time
    • Whether FBP1 deubiquitylation occurs within or outside the SAGA complex context
    • Mechanism by which H2Bub loss promotes Ser2P and CPSF73 recruitment
  4. 2012 High

    Discovery that USP22 deubiquitylates and stabilizes SIRT1, modulating p53 acetylation and apoptosis, and that Usp22 knockout causes embryonic lethality, established USP22 as a critical non-histone deubiquitylase with essential developmental roles.

    Evidence Reciprocal Co-IP, in vivo ubiquitination assay, Usp22 knockout mouse with embryonic lethality, p53 acetylation readouts

    PMID:22542455

    Open questions at the time
    • Whether SIRT1 destabilization is the sole cause of lethality or whether histone-level effects contribute
    • Ubiquitin chain linkage on SIRT1 not defined
  5. 2013 High

    Mapping the USP22 ZnF-UBP domain as the SIRT1 interaction interface and showing that acetylation of K129 regulates DUB module association with SAGA revealed a post-translational feedback loop governing SAGA integrity.

    Evidence AP-MS interactome, domain mapping, K129 mutagenesis, in vitro deacetylation assay

    PMID:23382074

    Open questions at the time
    • Identity of the acetyltransferase that modifies K129
    • Whether K129 acetylation status changes in response to specific signaling
  6. 2013 High

    Showing that USP22 occupies the Sox2 promoter and deubiquitylates H2Bub to repress Sox2 transcription established USP22 as a gatekeeper of the self-renewal–differentiation switch in embryonic stem cells.

    Evidence USP22 knockout/knockdown in ESCs, ChIP at Sox2 locus, differentiation assays across three germ layers

    PMID:23760504

    Open questions at the time
    • How H2B deubiquitylation at Sox2 leads to repression rather than the expected activation
    • Whether USP22 acts via SAGA or independently at this locus
  7. 2015 Medium

    Active-site mutagenesis (C185S, Y513C) confirmed that USP22 catalytic activity is necessary for cell cycle regulation and for controlling levels of BMI-1, c-Myc, cyclin D2, and p53, and in vivo hypomorphic models showed roles in intestinal and neural lineage specification.

    Evidence Catalytic mutant expression in HeLa cells with cell cycle analysis; Usp22 lacZ knock-in hypomorphic mouse with histological lineage analysis

    PMID:26143114 PMID:26431380

    Open questions at the time
    • Whether BMI-1 and c-Myc are direct substrates or indirectly affected via histone deubiquitylation
    • Mechanism linking USP22 reduction to altered intestinal lineage frequencies independent of global H2Bub1
  8. 2016 High

    Discovery that phosphorylated KDM1A is recruited to USP22 for deubiquitylation-dependent stabilization, leading to H3K4 demethylation and cancer stem cell gene repression, revealed a phosphorylation-gated substrate recognition mechanism.

    Evidence Co-IP, phosphorylation-site mutagenesis, ChIP for KDM1A and H3K4me2, in vivo glioblastoma xenograft

    PMID:27501329

    Open questions at the time
    • Whether the GSK3β/CK1α phosphorylation switch operates in non-tumor contexts
    • No structural basis for phospho-dependent USP22–KDM1A recognition
  9. 2018 High

    Parallel studies established USP22's direct stabilization of cyclin D1 for G1 progression, its deubiquitylation of PU.1 to maintain myeloid differentiation, and its requirement for γH2AX formation and NHEJ during B cell class switch recombination, broadening USP22 from a transcription-focused enzyme to a regulator of cell cycle, hematopoiesis, and DNA repair.

    Evidence Cyclin D1: Co-IP, cycloheximide chase, cell cycle assays, xenograft; PU.1: conditional KO with Kras, bone marrow transplantation, PU.1 rescue; CSR: B cell-specific Usp22 KO, CSR/V(D)J assays, γH2AX and NHEJ reporters

    PMID:29520062 PMID:29844011 PMID:30224477

    Open questions at the time
    • Whether cyclin D1 deubiquitylation occurs via K48-linked chains specifically
    • How USP22-mediated H2B deubiquitylation mechanistically promotes γH2AX and c-NHEJ
  10. 2019 Medium

    Identification of PALB2 as both a direct substrate and an allosteric activator of USP22 catalytic activity, together with USP22's roles in stabilizing BRCA2 and recruiting Rad51 to DSBs, placed USP22 as a dedicated facilitator of homologous recombination repair; independently, HIF1α was shown as a USP22 substrate driving HCC stemness.

    Evidence HR: in vitro catalytic stimulation assay with PALB2 WD40, Co-IP, HR reporter; HIF1α: Co-IP, ubiquitination assay, ChIP, in vivo HCC model

    PMID:31685642 PMID:31776228

    Open questions at the time
    • No structural model for PALB2 WD40-mediated USP22 activation
    • Whether USP22–PALB2 interaction is regulated by DNA damage signaling
    • Single-lab status for both HR and HIF1α studies
  11. 2019 High

    Demonstrating that USP22 controls embryonic lethality through extra-embryonic vasculature defects involving TGFβ and RTK pathways clarified the developmental basis of the previously observed knockout lethality.

    Evidence Conditional Usp22 KO mice, endothelial/pericyte differentiation from ESCs, vessel formation assays, transcriptome analysis

    PMID:30718289

    Open questions at the time
    • Specific TGFβ/RTK pathway components that are direct USP22 substrates in placental development remain unidentified
  12. 2020 High

    A set of discoveries expanded USP22's role into innate immunity and cell death: USP22 stabilizes importin KPNA2 to enable IRF3 nuclear translocation and type I IFN production, deubiquitylates RIPK3 to restrain necroptosis, interacts with MED1 to deubiquitylate H2A for iNKT cell differentiation, and stabilizes STAT1 to promote IFNγ signaling and tumor immune sensitivity.

    Evidence KPNA2: KO cell lines and conditional KO mice, reconstitution, IRF3 imaging; RIPK3: ubiquitin remnant MS, site-directed mutagenesis, necroptosis assays; MED1/H2A: Co-IP, conditional iNKT KO, substrate-specific ChIP; STAT1: CRISPR screen, Co-IP, T cell killing assay

    PMID:32069354 PMID:32130408 PMID:33369872 PMID:33601053

    Open questions at the time
    • Which ubiquitin linkage on KPNA2 is removed by USP22
    • Whether RIPK3 deubiquitylation at K518 is K48- or K63-linked
    • Whether MED1-directed H2A deubiquitylation operates independently of SAGA
  13. 2022 High

    Further substrate and pathway diversification showed USP22 stabilizes PPARγ via K48-linked deubiquitylation to drive de novo lipogenesis, stabilizes ATG5 via K27/K48-linked deubiquitylation at K118 to promote autophagy and suppress NLRP3 inflammasome activation, and controls basal STING-dependent IFN-λ signaling in intestinal epithelial cells.

    Evidence PPARγ: Co-IP, K48-specific ubiquitination assay, in vivo HCC model; ATG5: K118 mutagenesis, linkage-specific assay, USP22 KO in vivo; STING: USP22 KO IEC lines, cGAMP stimulation, SARS-CoV-2 infection model

    PMID:35449157 PMID:35900990 PMID:35933402

    Open questions at the time
    • Whether USP22 directly deubiquitylates STING or acts indirectly
    • Whether the ATG5 K118 mechanism is conserved in non-immune cells
    • Structural basis for K48 vs K27 linkage selectivity on different substrates
  14. 2024 Medium

    Identification of demethylzeylasteral as a small molecule that directly binds USP22 (at Leu475/Arg419) and promotes its degradation, increasing PD-L1 ubiquitination, provided the first chemical tool for pharmacological USP22 targeting.

    Evidence Virtual screening, direct binding assay, ubiquitination and PD-L1 stability assays, syngeneic tumor model, molecular dynamics simulation

    PMID:39525573

    Open questions at the time
    • Binding affinity and selectivity over other USPs not rigorously established
    • Mechanism of USP22 degradation induction unclear
    • No co-crystal structure

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive substrate cataloging, a unifying model for how USP22 substrate selectivity is determined—whether through SAGA-dependent vs. SAGA-independent modes, phosphorylation-gated recognition, or adaptor-mediated recruitment—remains unresolved, and no high-resolution structure of human USP22 or its DUB module on a nucleosome has been reported.
  • No structure of human USP22 alone or in complex with nucleosome
  • Systematic analysis of SAGA-dependent vs. SAGA-independent substrates not performed
  • Relative contributions of histone vs. non-histone deubiquitylation to developmental and disease phenotypes not deconvolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0042393 histone binding 7 GO:0140110 transcription regulator activity 4 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 8 GO:0005694 chromosome 7 GO:0005829 cytosol 2 GO:0005768 endosome 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-4839726 Chromatin organization 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-73894 DNA Repair 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1430728 Metabolism 1 R-HSA-9612973 Autophagy 1
Partners
ATXN7L3BRCA2KDM1AKPNA2MED1PALB2RIPK3SIRT1
Complex memberships
SAGA DUB moduleSAGA complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 USP22 is a catalytic subunit of the human SAGA transcriptional cofactor complex, where it deubiquitylates histone H2B to enable activator-driven transcription, and is recruited to specific genes by activators such as Myc. Biochemical subunit identification, in vitro deubiquitylation assay, chromatin immunoprecipitation, loss-of-function with transcriptional readout Molecular cell High 18206973
2008 USP22, as part of the hSAGA complex, also deubiquitylates histone H2A in addition to H2B, opposing Polycomb-mediated H2A ubiquitylation. Biochemical substrate specificity assay with reconstituted histone substrates Cell cycle (Georgetown, Tex.) High 18469533
2012 USP22 interacts with and stabilizes SIRT1 by removing polyubiquitin chains from SIRT1, thereby reducing p53 acetylation and suppressing p53-dependent apoptosis; genetic deletion of Usp22 destabilizes SIRT1 and causes early embryonic lethality in mice. Co-immunoprecipitation, ubiquitination assay, RNAi knockdown, Usp22 knockout mouse model with apoptosis and p53 acetylation readouts Molecular cell High 22542455
2011 USP22 deubiquitinates the transcriptional regulator FBP1, and this deubiquitination does not alter FBP1 stability but instead promotes stable FBP1 occupancy at the p21 gene locus to regulate cell proliferation. RNAi knockdown, ubiquitination assay, chromatin immunoprecipitation, cell proliferation assays EMBO reports High 21779003
2016 Phosphorylation of KDM1A (LSD1) by GSK3β and CK1α induces its binding to USP22, which then deubiquitylates and stabilizes KDM1A, leading to H3K4 demethylation and repression of BMP2, CDKN1A, and GATA6 to promote cancer stem cell self-renewal and glioblastoma tumorigenesis. Co-immunoprecipitation, ubiquitination assay, mutagenesis of phosphorylation sites, ChIP, in vivo xenograft model Nature cell biology High 27501329
2018 USP22 directly deubiquitylates cyclin D1 (CCND1), protecting it from proteasomal degradation independently of the canonical phosphorylation/ubiquitylation pathway, thereby controlling G1 cell cycle progression. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, loss-of-function in cancer cell lines and xenograft models Proceedings of the National Academy of Sciences of the United States of America High 30224477
2017 USP22 promotes deubiquitination and stabilization of c-Myc in breast cancer cells, increasing c-Myc protein levels and tumorigenic activity. Co-immunoprecipitation, ubiquitination assay, USP22 knockdown/overexpression with c-Myc protein stability and colony formation readouts Journal of cellular physiology Medium 28160502
2013 USP22 is identified as a high-confidence interactor of SIRT1 via its ZnF-UBP domain; USP22 is acetylated on multiple lysines, and acetylation of K129 within the ZnF-UBP domain regulates interaction of the deubiquitinating module (DUBm) with the core SAGA complex; USP22-recruited SIRT1 promotes deacetylation of SAGA components. Comparative affinity purification-mass spectrometry, Co-IP, domain mapping, mutagenesis (H363Y SIRT1, K129 USP22), in vitro deacetylation assay Molecular and cellular biology High 23382074
2013 USP22 is required for embryonic stem cell differentiation; it occupies the Sox2 promoter and deubiquitylates H2Bub to repress Sox2 transcription, enabling the transition from self-renewal to lineage-specific differentiation. USP22 knockout/knockdown in ESCs, chromatin immunoprecipitation, differentiation assays across three germ layers The Journal of biological chemistry High 23760504
2018 Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, is required for proper DNA break repair during class switch recombination (CSR) and V(D)J recombination; Usp22 ablation in B cells impairs γH2AX formation and classical non-homologous end joining (c-NHEJ), with CSR to IgA being less reliant on Usp22/c-NHEJ than CSR to other isotypes. Conditional B cell-specific Usp22 knockout, CSR assays, γH2AX detection, NHEJ reporter assay, V(D)J recombination assay Nature communications High 29520062
2020 Cytoplasmic USP22 promotes nuclear translocation of IRF3 during viral infection by deubiquitinating and stabilizing the importin KPNA2; viral infection induces USP22-IRF3 association in a KPNA2-dependent manner, and USP22 or KPNA2 deficiency impairs IRF3 nuclear translocation and type I IFN production. Co-immunoprecipitation, ubiquitination assay, USP22/KPNA2 KO cell lines and conditional KO mice, reconstitution of KPNA2 in KO cells, IRF3 nuclear translocation imaging The Journal of experimental medicine High 32130408
2020 USP22 controls necroptotic cell death by deubiquitinating RIPK3 at lysines 42, 351, and 518; mutation of RIPK3 K518 reduces necroptosis-associated ubiquitination and amplifies necrosome formation and necroptotic cell death. Loss-of-function (USP22 KO), ubiquitin remnant profiling by mass spectrometry, RIPK3 site-directed mutagenesis, necroptosis assays in human tumor cell lines EMBO reports High 33369872
2020 USP22 directly interacts with and deubiquitinates PD-L1 to inhibit its proteasomal degradation; USP22 also stabilizes CSN5 through deubiquitination, and both USP22 and CSN5 facilitate each other's interaction with PD-L1, removing K6, K11, K27, K29, K33, and K63-linked ubiquitin chains. Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, protein half-life assay, flow cytometry, USP22 depletion in tumor cells Cell communication and signaling : CCS Medium 32665011
2019 USP22 deubiquitinates and stabilizes HIF1α, promoting hypoxia-induced hepatocellular carcinoma stemness and glycolysis; in TP53-mutant HCC, USP22 and HIF1α form a positive feedback loop. Immunoprecipitation, ubiquitination assay, ChIP assay, loss- and gain-of-function in HCC cells and in vivo mouse model Gut High 31776228
2022 USP22 directly interacts with, deubiquitinates (via K48-linked deubiquitination), and stabilizes PPARγ, which in turn increases ACC and ACLY expression to promote de novo fatty acid synthesis in hepatocellular carcinoma. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), loss-of-function, in vivo tumorigenesis experiments Nature communications High 35449157
2022 USP22 suppresses NLRP3 inflammasome activation by stabilizing ATG5 through decreasing K27- and K48-linked ubiquitination at ATG5 Lys118, thereby promoting ATG5-mediated autophagy and autophagic degradation of NLRP3. Co-immunoprecipitation, ubiquitination assay (site-specific mutagenesis of ATG5 K118), USP22 KO/knockdown in vivo and in vitro, autophagy/NLRP3 inflammasome readouts Autophagy High 35900990
2018 USP22 deficiency in hematopoietic cells expressing oncogenic Kras promotes AML transformation through impaired myeloid differentiation; USP22 functions as a PU.1 deubiquitylase that positively regulates PU.1 protein stability and PU.1 target gene expression, and PU.1 reconstitution rescues differentiation. Conditional USP22 KO mouse model with oncogenic Kras, bone marrow transplantation, ubiquitination assay, transcriptome profiling, PU.1 reconstitution rescue experiment Blood High 29844011
2019 USP22 loss in mice causes embryonic lethality due to defects in extra-embryonic placental vasculature; USP22 deletion disrupts TGFβ and receptor tyrosine kinase signaling pathways in endothelial cells and pericytes, impairing cell survival, differentiation, and vessel formation. Usp22 conditional knockout mice, endothelial/pericyte differentiation from ESCs, vessel formation assays, transcriptome analysis Development (Cambridge, England) High 30718289
2011 USP22 is required for efficient 3'-end cleavage/polyadenylation of JAK-STAT-inducible genes; USP22 knockdown increases H2Bub levels and reduces Ser2 phosphorylation of RNA Pol II CTD and CPSF73 recruitment, implicating H2B deubiquitination in coupling transcriptional elongation to 3'-end processing. RNAi knockdown, H2Bub ChIP, RNA Pol II CTD Ser2P ChIP, polyadenylation cleavage assay, USP22 overexpression rescue FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 22067483
2014 USP22 specifically interacts with and deubiquitinates NFATc2, stabilizing its protein levels via its deubiquitinase activity, which is required for IL-2 expression in T cells. Co-immunoprecipitation, ubiquitination assay, USP22 knockdown in T cells with IL-2 expression readout FEBS letters Medium 24561192
2019 USP22 interacts with and stabilizes BRCA2 and PALB2, is necessary for BRCA2, PALB2, and Rad51 recruitment to DNA double-strand breaks, and promotes homologous recombination; the interaction with PALB2's WD40 domain stimulates USP22 catalytic activity in vitro. Co-immunoprecipitation, in vitro catalytic activity assay, HR reporter assay, foci formation at DSBs, USP22 knockdown Molecular cancer research : MCR Medium 31685642
2019 USP22 functions as a XPC deubiquitylase; depletion of USP22 sensitizes prostate cancer cells to genotoxic insult, and XPC was identified as a critical mediator of USP22-mediated survival to DNA damage through ubiquitylome analysis. USP22 overexpression/depletion, ubiquitylome profiling, genotoxic sensitivity assays, mouse adult fibroblast model Cancer research Medium 31740444
2020 USP22 directly interacts with STAT1, deubiquitinates it, and improves its stability in melanoma cells; USP22 deficiency impairs IFNγ-JAK1-STAT1 signaling and reduces sensitivity to T cell-mediated killing. Co-immunoprecipitation, ubiquitination assay, USP22 KO in mouse and human melanoma cells, genome-wide CRISPR screen, T cell killing assay Molecular therapy : the journal of the American Society of Gene Therapy Medium 33601053
2020 USP22 interacts with Mediator subunit MED1 and deubiquitinates histone H2A (but not H2B) to enhance MED1-dependent transcription of IL-2Rβ and T-bet genes, controlling iNKT cell development and differentiation. Co-immunoprecipitation, USP22 conditional KO in iNKT cells, H2A/H2Bub ChIP, gene expression analysis The Journal of experimental medicine High 32069354
2022 USP22 controls basal STING activation and type III IFN (IFN-λ) signaling in intestinal epithelial cells; USP22-deficient cells show upregulated ISGs, increased IFN-λ secretion, and enhanced STAT1 signaling even without viral stimulation, and are protected from SARS-CoV-2 infection in a STING-dependent manner. USP22 KO intestinal epithelial cell lines, 2'3'-cGAMP stimulation assays, SARS-CoV-2 infection model, STING reconstitution/rescue experiments Cell death & disease Medium 35933402
2018 USP22 promotes epithelial-mesenchymal transition via the FAK signaling pathway in pancreatic cancer cells, inducing Ezrin redistribution and phosphorylation, cytoskeletal remodeling, and upregulation of Snail and ZEB1. USP22 overexpression/knockdown, FAK pathway inhibition, invasion/migration assays, EMT marker analysis Oncology reports Low 25070659
2014 USP22 interacts with MDMX and promotes its stabilization in NSCLC cells; USP22 silencing downregulates MDMX and activates the p53 pathway, and MDMX overexpression reverses USP22 silencing-induced growth arrest. Co-immunoprecipitation, USP22 shRNA knockdown, MDMX rescue experiment, p53 pathway analysis International journal of molecular sciences Medium 25547493
2015 USP22 directly interacts with and stabilizes COX-2 through deubiquitination; USP22 silencing reduces COX-2 protein half-life and inhibits lung carcinoma cell proliferation. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, USP22 knockdown Biochemical and biophysical research communications Medium 25817787
2018 USP22 deubiquitinates EGFR localized on late endosomes, preventing ubiquitination-mediated EGFR degradation and enhancing EGFR recycling after EGF stimulation, thereby sustaining activation of STAT3, AKT/mTOR, and MEK/ERK pathways. Co-immunoprecipitation, ubiquitination assay, EGFR recycling assay, endosomal localization studies, USP22 knockdown with pathway readouts Cancer letters Medium 29981430
2017 USP22 stabilizes BMI1 protein in gastric cancer cells through deubiquitination, promoting cancer stem cell self-renewal; TAT-BMI1 protein reconstitution rescues the stem cell properties lost upon USP22 knockdown. USP22 knockdown, BMI1 protein stability assay, TAT-BMI1 rescue experiment, sphere formation assay, xenograft model Oncotarget Medium 28415621
2021 USP22 deubiquitinates and stabilizes E2F6, leading to transcriptional repression of DUSP1 phosphatase, which in turn strengthens AKT activation in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assay, loss-of-function, transcriptional repression and AKT signaling readouts Cancer letters Medium 34339800
2021 USP22 deubiquitinates and stabilizes PTEN in pancreatic cancer, which then induces p21 (CDKN1A) expression by interacting with ANKHD1 and inhibiting ANKHD1 binding to the p21 promoter. Co-immunoprecipitation, ubiquitination assay, USP22 overexpression, ANKHD1 interaction assay, p21 promoter binding assay Molecular oncology Medium 34743406
2015 The catalytic deubiquitinase activity of USP22 (abolished by C185S mutation and reduced by Y513C mutation) is necessary for regulating HeLa cell cycle progression and controlling BMI-1, c-Myc, cyclin D2, and p53 levels. Active-site mutagenesis (C185S, Y513C), cell cycle analysis, western blot of downstream targets Gene Medium 26143114
2018 USP22 promotes homologous recombination repair by interacting with PALB2 (via its WD40 domain), which stimulates USP22 catalytic activity in vitro, and by stabilizing BRCA2 and PALB2 to enable Rad51 recruitment to DNA double-strand breaks. In vitro catalytic activity assay, Co-immunoprecipitation, HR reporter assay, foci formation assay, domain mapping Molecular cancer research : MCR Medium 31685642
2015 Reduction of Usp22 in mice impairs intestinal epithelial lineage specification and affects differentiated cell frequencies in the small intestine and brain, demonstrating a physiological role for USP22 in cell differentiation independent of global H2Bub1 changes. Usp22 hypomorphic mouse model (lacZ knock-in), histological analysis, cell lineage marker staining, H2Bub1 immunostaining Oncotarget Medium 26431380
2023 USP22 deubiquitinates and stabilizes Snail1 (an EMT transcription factor) in renal tubular epithelial cells under high-glucose conditions, promoting epithelial-to-mesenchymal transition and renal tubulointerstitial fibrosis in diabetic kidney disease. Co-immunoprecipitation, ubiquitination assay, USP22 overexpression/knockdown, deubiquitinase activity assay, in vivo db/db mouse model European journal of pharmacology Medium 37001578
2015 USP22 positively regulates RCAN1 protein stability by direct interaction and deubiquitination, opposing the actions of FBW7, NEDD4-2, and β-TrCP E3 ligases; interferon-α treatment dissociates RCAN1 from USP22, triggering RCAN1 ubiquitination and degradation. Co-immunoprecipitation, ubiquitination assay, E3 ligase competition assay, IFN-α treatment Journal of cellular physiology Medium 25546086
2022 PRDM1 enhances USP22 transcription, and USP22 then reduces SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription in hepatocellular carcinoma, leading to CD8+ T cell exhaustion. Immunoprecipitation, ubiquitination assay, transcriptional reporter assays, in vivo HCC mouse models, PD-1 mAb combination treatment Nature communications Medium 36509766
2005 Human USP22 and mouse Usp22 encode 525-amino acid proteins containing conserved Cys and His catalytic domains of the UBP deubiquitinase family, and biochemical assay confirmed they possess deubiquitinating enzyme activity. Gene cloning, sequence analysis, biochemical deubiquitinase activity assay Gene expression patterns : GEP Medium 16378762
2021 USP22 stabilizes the major ER chaperone HSPA5 in HER2+ breast cancer cells, actively suppressing the unfolded protein response (UPR); loss of USP22 destabilizes HSPA5, induces UPR, and sensitizes tumor cells to apoptosis and ER stress-targeting therapies. USP22 conditional KO in mouse HER2+-BC model, transcriptome analysis, HSPA5 protein stability assay, ER stress sensitivity assays Oncogene Medium 34007022
2023 USP22 deubiquitinates and stabilizes ZEB1, and is co-recruited with ZEB1 to the VEGFA promoter where it alters H2Bub1 levels to enhance ZEB1-mediated VEGFA transcription in hepatocellular carcinoma. Co-immunoprecipitation, ubiquitination assay, ChIP, USP22 knockdown with VEGFA and H2Bub1 readouts, in vivo xenograft model Cell death & disease Medium 36906615
2024 The small molecule demethylzeylasteral (Dem) binds to USP22 and promotes its degradation, resulting in increased ubiquitination and proteasomal degradation of PD-L1; molecular dynamics simulations identified Leu475 and Arg419 as key residues for USP22 inhibitor binding. Structure-based virtual screening, USP22 binding assay, ubiquitination assay, PD-L1 stability assay, in vivo syngeneic tumor model, molecular dynamics simulation Acta pharmaceutica Sinica. B Medium 39525573

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The putative cancer stem cell marker USP22 is a subunit of the human SAGA complex required for activated transcription and cell-cycle progression. Molecular cell 353 18206973
2012 USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. Molecular cell 262 22542455
2020 USP22 Protects Against Myocardial Ischemia-Reperfusion Injury via the SIRT1-p53/SLC7A11-Dependent Inhibition of Ferroptosis-Induced Cardiomyocyte Death. Frontiers in physiology 174 33192549
2019 USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut 165 31776228
2022 USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma. Nature communications 157 35449157
2016 Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nature cell biology 142 27501329
2008 USP22, an hSAGA subunit and potential cancer stem cell marker, reverses the polycomb-catalyzed ubiquitylation of histone H2A. Cell cycle (Georgetown, Tex.) 124 18469533
2017 Deubiquitinating enzyme USP22 positively regulates c-Myc stability and tumorigenic activity in mammalian and breast cancer cells. Journal of cellular physiology 123 28160502
2011 USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO reports 117 21779003
2020 The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells. Cell communication and signaling : CCS 103 32665011
2018 Control of CCND1 ubiquitylation by the catalytic SAGA subunit USP22 is essential for cell cycle progression through G1 in cancer cells. Proceedings of the National Academy of Sciences of the United States of America 103 30224477
2013 USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer research 101 24197134
2022 PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells. Nature communications 93 36509766
2017 USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway. Molecular oncology 91 28417539
2021 LncRNA KCNQ1OT1 Secreted by Tumor Cell-Derived Exosomes Mediates Immune Escape in Colorectal Cancer by Regulating PD-L1 Ubiquitination via MiR-30a-5p/USP22. Frontiers in cell and developmental biology 79 34350172
2005 The expression patterns of deubiquitinating enzymes, USP22 and Usp22. Gene expression patterns : GEP 79 16378762
2012 USP22 acts as an oncogene by the activation of BMI-1-mediated INK4a/ARF pathway and Akt pathway. Cell biochemistry and biophysics 71 21928107
2013 The epigenetic modifier ubiquitin-specific protease 22 (USP22) regulates embryonic stem cell differentiation via transcriptional repression of sex-determining region Y-box 2 (SOX2). The Journal of biological chemistry 70 23760504
2020 USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2. The Journal of experimental medicine 66 32130408
2018 MiR-30-5p suppresses cell chemoresistance and stemness in colorectal cancer through USP22/Wnt/β-catenin signaling axis. Journal of cellular and molecular medicine 66 30338942
2018 MicroRNA-29c Increases the Chemosensitivity of Pancreatic Cancer Cells by Inhibiting USP22 Mediated Autophagy. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 64 29807360
2017 MicroRNA-30e-5p suppresses non-small cell lung cancer tumorigenesis by regulating USP22-mediated Sirt1/JAK/STAT3 signaling. Experimental cell research 64 29174979
2012 Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non-small-cell lung cancer. Lung cancer (Amsterdam, Netherlands) 64 22717106
2020 USP22 controls necroptosis by regulating receptor-interacting protein kinase 3 ubiquitination. EMBO reports 63 33369872
2022 USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy. Autophagy 62 35900990
2011 The co-expression of USP22 and BMI-1 may promote cancer progression and predict therapy failure in gastric carcinoma. Cell biochemistry and biophysics 62 21735131
2019 Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling. Aging 61 31689236
2023 Bone marrow mesenchymal stem cell-derived exosomal lncRNA KLF3-AS1 stabilizes Sirt1 protein to improve cerebral ischemia/reperfusion injury via miR-206/USP22 axis. Molecular medicine (Cambridge, Mass.) 60 36627572
2019 Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer. Cancer immunology research 59 31871120
2010 Silencing USP22 by asymmetric structure of interfering RNA inhibits proliferation and induces cell cycle arrest in bladder cancer cells. Molecular and cellular biochemistry 59 20824490
2022 Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms. Frontiers in immunology 58 35935969
2013 A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Molecular and cellular biology 55 23382074
2018 The H2B deubiquitinase Usp22 promotes antibody class switch recombination by facilitating non-homologous end joining. Nature communications 54 29520062
2021 Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular Carcinoma Therapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 53 33717848
2018 USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism. Blood 53 29844011
2018 Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration. The Journal of clinical investigation 53 30300140
2019 USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity. Cell death and differentiation 51 31527800
2019 USP22 Functions as an Oncogenic Driver in Prostate Cancer by Regulating Cell Proliferation and DNA Repair. Cancer research 51 31740444
2017 USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis. Frontiers in pharmacology 51 28567015
2018 USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma. Cancer letters 49 29981430
2024 EZH2 Inhibition Enhances PD-L1 Protein Stability Through USP22-Mediated Deubiquitination in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 41 38520088
2015 USP22 promotes tumor progression and induces epithelial-mesenchymal transition in lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands) 41 25907317
2014 USP22 promotes epithelial-mesenchymal transition via the FAK pathway in pancreatic cancer cells. Oncology reports 38 25070659
2019 USP22-dependent HSP90AB1 expression promotes resistance to HSP90 inhibition in mammary and colorectal cancer. Cell death & disease 37 31801945
2014 Ubiquitin-specific peptidase USP22 negatively regulates the STAT signaling pathway by deubiquitinating SIRT1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 24969755
2024 The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma. Signal transduction and targeted therapy 35 39300073
2017 USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein. Oncotarget 35 28415621
2012 USP22 nuclear expression is significantly associated with progression and unfavorable clinical outcome in human esophageal squamous cell carcinoma. Journal of cancer research and clinical oncology 35 22447106
2020 USP22 positively modulates ERα action via its deubiquitinase activity in breast cancer. Cell death and differentiation 34 32494025
2019 USP22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta. Development (Cambridge, England) 33 30718289
2016 Silencing of USP22 suppresses high glucose-induced apoptosis, ROS production and inflammation in podocytes. Molecular bioSystems 33 26953552
2010 Implication of USP22 in the regulation of BMI-1, c-Myc, p16INK4a, p14ARF, and cyclin D2 expression in primary colorectal carcinomas. Diagnostic molecular pathology : the American journal of surgical pathology, part B 33 21052002
2018 Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma. Molecular cancer research : MCR 32 29720480
2013 RNA interference-mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest. Oncology letters 32 23599781
2020 RETRACTED: BMSCs-derived exosomal microRNA-let-7a plays a protective role in diabetic nephropathy via inhibition of USP22 expression. Life sciences 31 33347877
2011 The ubiquitin hydrolase USP22 contributes to 3'-end processing of JAK-STAT-inducible genes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 22067483
2015 USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non-small cell lung cancer. Biochemical and biophysical research communications 30 25817787
2015 Expression of USP22 and Survivin is an indicator of malignant behavior in hepatocellular carcinoma. International journal of oncology 30 26497847
2014 USP22 promotes NSCLC tumorigenesis via MDMX up-regulation and subsequent p53 inhibition. International journal of molecular sciences 30 25547493
2022 Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance. Cells 29 35203285
2021 USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response. Oncogene 29 34007022
2017 USP22 drives colorectal cancer invasion and metastasis via epithelial-mesenchymal transition by activating AP4. Oncotarget 29 28427243
2017 USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt. Oncotarget 29 28445968
2021 ZRANB1 enhances stem-cell-like features and accelerates tumor progression by regulating Sox9-mediated USP22/Wnt/β-catenin pathway in colorectal cancer. Cellular signalling 28 34798260
2022 LncRNA MALAT1 Regulates USP22 Expression Through EZH2-Mediated H3K27me3 Modification to Accentuate Sepsis-Induced Myocardial Dysfunction. Cardiovascular toxicology 27 35726125
2024 Demethylzeylasteral induces PD-L1 ubiquitin-proteasome degradation and promotes antitumor immunity via targeting USP22. Acta pharmaceutica Sinica. B 26 39525573
2022 Targeting ferroptosis with miR-144-3p to attenuate pancreatic β cells dysfunction via regulating USP22/SIRT1 in type 2 diabetes. Diabetology & metabolic syndrome 25 35761309
2020 The USP22 promotes the growth of cancer cells through the DYRK1A in pancreatic ductal adenocarcinoma. Gene 25 32687947
2015 Usp22 deficiency impairs intestinal epithelial lineage specification in vivo. Oncotarget 25 26431380
2022 Long Intergenic Noncoding RNA00265 Enhances Cell Viability and Metastasis via Targeting miR-485-5p/USP22 Axis in Osteosarcoma. Frontiers in oncology 24 35692754
2020 USP22 promotes development of lung adenocarcinoma through ubiquitination and immunosuppression. Aging 24 32294625
2020 MiR-329-3p inhibits hepatocellular carcinoma cell proliferation and migration through USP22-Wnt/β-Catenin pathway. European review for medical and pharmacological sciences 24 33090397
2018 MiR-30e-5p inhibits proliferation and metastasis of nasopharyngeal carcinoma cells by target-ing USP22. European review for medical and pharmacological sciences 24 30338802
2016 MiR-101 targets USP22 to inhibit the tumorigenesis of papillary thyroid carcinoma. American journal of cancer research 23 27904772
2021 USP22 deficiency in melanoma mediates resistance to T cells through IFNγ-JAK1-STAT1 signal axis. Molecular therapy : the journal of the American Society of Gene Therapy 22 33601053
2014 USP22 is a positive regulator of NFATc2 on promoting IL2 expression. FEBS letters 22 24561192
2020 USP22 controls iNKT immunity through MED1 suppression of histone H2A monoubiquitination. The Journal of experimental medicine 21 32069354
2020 Long Non-Coding RNA SNHG16 Activates USP22 Expression to Promote Colorectal Cancer Progression by Sponging miR-132-3p. OncoTargets and therapy 21 32547062
2021 miR-140 inhibits osteosarcoma progression by impairing USP22-mediated LSD1 stabilization and promoting p21 expression. Molecular therapy. Nucleic acids 20 33868787
2021 USP22-mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression. Molecular oncology 20 34743406
2024 Hypoxic adipose stem cell-derived exosomes carrying high-abundant USP22 facilitate cutaneous wound healing through stabilizing HIF-1α and upregulating lncRNA H19. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 38738548
2020 Hypoxia-induced USP22-BMI1 axis promotes the stemness and malignancy of glioma stem cells via regulation of HIF-1α. Life sciences 18 32070708
2019 USP22 Interacts with PALB2 and Promotes Chemotherapy Resistance via Homologous Recombination of DNA Double-Strand Breaks. Molecular cancer research : MCR 18 31685642
2023 USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma. Cell death & disease 17 36906615
2020 RNF220 promotes the proliferation of leukaemic cells and reduces the degradation of the Cyclin D1 protein through USP22. Blood cells, molecules & diseases 17 32896826
2022 USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING. Cell death & disease 16 35933402
2021 USP22 Suppresses SPARC Expression in Acute Colitis and Inflammation-Associated Colorectal Cancer. Cancers 16 33920268
2021 Deubiquitination of the repressor E2F6 by USP22 facilitates AKT activation and tumor growth in hepatocellular carcinoma. Cancer letters 16 34339800
2017 USP22 down-regulation facilitates human retinoblastoma cell aging and apoptosis via inhibiting TERT/P53 pathway. European review for medical and pharmacological sciences 16 28682440
2015 The deubiquitinating enzyme activity of USP22 is necessary for regulating HeLa cell growth. Gene 15 26143114
2012 Knock-down of USP22 by small interfering RNA interference inhibits HepG2 cell proliferation and induces cell cycle arrest. Cellular and molecular biology (Noisy-le-Grand, France) 15 23217440
2012 Cloning and characterization of the human USP22 gene promoter. PloS one 15 23300749
2023 USP22 aggravated diabetic renal tubulointerstitial fibrosis progression through deubiquitinating and stabilizing Snail1. European journal of pharmacology 13 37001578
2023 RNF220 promotes gastric cancer growth and stemness via modulating the USP22/wnt/β-catenin pathway. Tissue & cell 13 37295272
2022 USP22 Contributes to Chemoresistance, Stemness, and EMT Phenotype of Triple-Negative Breast Cancer Cells by egulating the Warburg Effect via c-Myc Deubiquitination. Clinical breast cancer 13 36528490
2020 The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer. Cellular oncology (Dordrecht, Netherlands) 13 32857323
2018 Targeted eradication of gastric cancer stem cells by CD44 targeting USP22 small interfering RNA-loaded nanoliposomes. Future oncology (London, England) 13 30543303
2018 Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma. Oncology letters 13 30675271
2015 Ubiquitin-specific protease 22 (USP22) positively regulates RCAN1 protein levels through RCAN1 de-ubiquitination. Journal of cellular physiology 13 25546086
2023 Discovery of selective and potent USP22 inhibitors via structure-based virtual screening and bioassays exerting anti-tumor activity. Bioorganic chemistry 12 37769523