Affinage

USP27X

Ubiquitin carboxyl-terminal hydrolase 27 · UniProt A6NNY8

Length
438 aa
Mass
49.6 kDa
Annotated
2026-06-11
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP27X is a deubiquitylase that controls the stability of diverse regulatory proteins by removing polyubiquitin chains to prevent their proteasomal degradation, thereby influencing epithelial-mesenchymal transition, apoptosis, cell cycle progression, innate antiviral signaling, and tumor metabolism (PMID:30341066, PMID:27013495, PMID:31534008). In cancer it acts as a pro-tumorigenic stabilizer: it deubiquitylates and stabilizes Snail1 to drive TGFβ-induced EMT, migration, invasion and chemoresistance (PMID:30341066), and it likewise stabilizes Cyclin E, the histone methyltransferase SETD3, MYC, and the glycolytic enzymes PFKFB3 to promote proliferation and aerobic glycolysis (PMID:29497124, PMID:35018513, PMID:38969771, PMID:39746496). In apoptotic signaling it removes ubiquitin from ERK-phosphorylated Bim, counteracting ERK-driven Bim degradation and sensitizing cells to pathway inhibition (PMID:27013495, PMID:31901727). In innate immunity USP27X exerts opposing effects on two nucleic-acid sensors: it removes K48-linked chains from cGAS to stabilize it and support IFN-β production against DNA virus, yet removes K63-linked chains from RIG-I to attenuate type I interferon signaling against RNA virus (PMID:31534008, PMID:32027733). Its activity is set by upstream kinases—GSK3β phosphorylates USP27X to enhance its interaction with and stabilization of CBX2, and PIM2 phosphorylates USP27X to boost MYC deubiquitylation—and its expression is transcriptionally controlled by TGFβ and by CTCF (PMID:38030604, PMID:38969771, PMID:39746496, PMID:30341066). Loss-of-function and missense variants that reduce USP27X deubiquitylating activity and protein-interaction capacity cause X-linked intellectual disability (XLID105) (PMID:38182161, PMID:40596734).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2016 High

    Established USP27X as a deubiquitylase that protects a specific substrate from degradation, by showing it binds and removes ubiquitin from ERK-phosphorylated Bim to enhance apoptosis.

    Evidence Co-IP, ubiquitination assays and gain/loss-of-function apoptosis readouts in melanoma and NSCLC cell lines

    PMID:27013495

    Open questions at the time
    • Did not define the recognition determinant linking phospho-Bim to USP27X
    • No structural basis for substrate selection
  2. 2018 High

    Defined a pro-tumorigenic role by showing USP27X deubiquitylates and stabilizes Snail1, and is itself a TGFβ-induced gene required for TGFβ-driven EMT.

    Evidence siRNA screen, reciprocal Co-IP, ubiquitination assays, migration/invasion/metastasis and chemosensitivity readouts across cell lines

    PMID:30341066

    Open questions at the time
    • Mechanism by which TGFβ induces USP27X transcription not resolved
    • Ubiquitin linkage type on Snail1 not specified
  3. 2018 Medium

    Extended the substrate range to cell cycle control by showing USP27X stabilizes Cyclin E to drive proliferation in hepatocellular carcinoma.

    Evidence Co-IP, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays and tumor IHC

    PMID:29497124

    Open questions at the time
    • Single lab
    • Linkage specificity of Cyclin E deubiquitylation not defined
  4. 2019 High

    Showed USP27X positively regulates DNA-sensing innate immunity by cleaving K48-linked chains from cGAS to stabilize it and sustain IFN-β responses.

    Evidence Usp27x-knockout mouse macrophages, reciprocal Co-IP, K48-linkage-specific ubiquitination assay, cGAMP ELISA, phospho-immunoblot and HSV-1 infection

    PMID:31534008

    Open questions at the time
    • Whether USP27X regulation of cGAS occurs in non-macrophage cells unknown
    • No structural model of the cGAS interaction
  5. 2019 Medium

    Placed USP27X downstream of a Cathepsin K/Raptor/mitochondrial ROS axis that induces its expression and thereby stabilizes Bim.

    Evidence siRNA knockdown, ROS scavenger experiments, immunoblotting and xenograft model

    PMID:31901727

    Open questions at the time
    • Single lab
    • Direct mechanism coupling ROS to USP27X expression not defined
  6. 2020 High

    Revealed a context-dependent, opposing immune role by showing USP27X removes K63-linked chains from RIG-I to dampen RNA-virus-induced type I interferon signaling.

    Evidence siRNA library screen, Co-IP, K63-linkage-specific ubiquitination assay, IFN-β reporter and immunoblot

    PMID:32027733

    Open questions at the time
    • How USP27X stabilizes cGAS yet destabilizes RIG-I signaling within the same cell is unresolved
    • No reconstitution of linkage selectivity
  7. 2022 Medium

    Identified SETD3 as a substrate, linking USP27X to epigenetic regulation and HCC tumorigenesis.

    Evidence Co-IP, ubiquitination assay, siRNA knockdown with proliferation/tumorigenesis readouts

    PMID:35018513

    Open questions at the time
    • Single lab
    • Functional consequence of SETD3 stabilization on histone methylation not measured
  8. 2023 Medium

    Showed USP27X activity is kinase-regulated, with GSK3β phosphorylating USP27X to enhance its interaction with and stabilization of CBX2.

    Evidence Mass spectrometry, Co-IP, phosphorylation and ubiquitination assays, tumorigenesis assays

    PMID:38030604

    Open questions at the time
    • Phosphosite on USP27X not mapped here
    • Single lab
  9. 2024 Medium

    Connected USP27X to tumor metabolism by showing PIM2 phosphorylation enhances its deubiquitylation of MYC to drive aerobic glycolysis.

    Evidence Co-IP, kinase assay, ubiquitination assay, glycolysis readouts and PIM2-knockout mouse validation

    PMID:38969771

    Open questions at the time
    • Single lab
    • Phosphosite mediating MYC-directed activation not defined
  10. 2024 Medium

    Demonstrated CTCF-driven transcriptional control of USP27X and stabilization of the glycolytic enzyme PFKFB3, reinforcing a metabolic-tumorigenic axis.

    Evidence Co-IP, ubiquitination assay, ChIP for CTCF promoter binding, glycolysis assays and xenograft

    PMID:39746496

    Open questions at the time
    • Single lab
    • Overlap with other USP27X transcriptional inputs (TGFβ) not integrated
  11. 2024 Medium

    Linked USP27X dysfunction to disease by showing patient variants causing X-linked intellectual disability disrupt DUB activity and protein interactions through distinct mechanisms.

    Evidence Clinical genetics across multiple families, in vitro DUB activity assays and Co-IP for 10 variants

    PMID:38182161

    Open questions at the time
    • Which neuronal substrate(s) underlie the phenotype unknown
    • No in vivo neurodevelopmental model
  12. 2025 Low

    Reinforced the loss-of-function disease mechanism with a single new missense variant impairing USP27X expression and DUB activity.

    Evidence In vitro expression and deubiquitination activity assay of mutant construct

    PMID:40596734

    Open questions at the time
    • Single lab, single variant in vitro only
    • No pathway placement beyond reduced DUB activity

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP27X selects among its many substrates and achieves opposing K48 versus K63 linkage specificity, and which substrate dysregulation drives the neurodevelopmental phenotype, remain unresolved.
  • No structural model of substrate or linkage recognition
  • Neuronal substrate underlying XLID105 unidentified
  • Reconciliation of pro- versus anti-immune roles in vivo lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1640170 Cell Cycle 1
Partners
BCL2L11CBX2CCNE1CGASDDX58MYCSETD3SNAI1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 USP27X deubiquitinates and stabilizes Snail1 protein: identified via siRNA screen, USP27X binds Snail1 and removes ubiquitin chains to prevent its proteasomal degradation, thereby promoting EMT, cell migration/invasion, and chemoresistance; USP27X expression is upregulated by TGFβ and is required for TGFβ-induced Snail1 expression and fibroblast activation. siRNA screen, co-immunoprecipitation, ubiquitination assays, knockdown/overexpression with phenotypic readouts (migration, invasion, EMT markers, cisplatin sensitivity), in vivo metastasis assay Cancer Research High 30341066
2016 USP27X deubiquitinase binds the pro-apoptotic BH3-only protein Bim upon ERK-dependent phosphorylation of Bim, removes ubiquitin chains from phosphorylated Bim to stabilize it, counteracting ERK-driven Bim degradation and enhancing apoptosis; overexpression of USP27X reduces ERK-dependent Bim ubiquitination and sensitizes cells to ERK pathway inhibition, while loss of USP27X reduces apoptosis in EGFR-inhibitor-treated NSCLC cells. Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown with apoptosis readouts (annexin V/PI staining), cell-line models (melanoma, NSCLC) EMBO Reports High 27013495
2019 USP27X interacts with the cytosolic DNA sensor cGAS and cleaves K48-linked polyubiquitin chains from cGAS, preventing its proteasomal degradation and stabilizing it; knockout of Usp27x in mouse macrophages accelerates cGAS turnover, reduces cGAMP production, decreases TBK1 and IRF3 phosphorylation, impairs IFN-β production, and impairs innate antiviral responses against HSV-1. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), Usp27x knockout mouse macrophages, cGAMP ELISA, phospho-immunoblotting, HSV-1 infection assay Journal of Immunology High 31534008
2020 USP27X negatively regulates RIG-I-mediated antiviral signaling: identified via siRNA library screen, USP27X interacts with RIG-I and removes K63-linked polyubiquitin chains from RIG-I, thereby attenuating type I interferon signaling in response to RNA viruses. siRNA library screen, co-immunoprecipitation, K63-linkage specific ubiquitination assay, overexpression/knockdown with IFN-β luciferase reporter and immunoblotting PLoS Pathogens High 32027733
2018 USP27 (USP27X) interacts with Cyclin E, negatively regulates its ubiquitination, and promotes Cyclin E protein stability, thereby driving cell cycle progression; USP27 knockdown reduces Cyclin E levels and inhibits hepatocellular carcinoma cell growth, migration, and invasion. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays, immunohistochemistry of tumor tissues Oncogene Medium 29497124
2019 Cathepsin K inhibition increases USP27X expression via mitochondrial ROS (through Raptor degradation), and elevated USP27X then stabilizes Bim by preventing its proteasomal degradation; knockdown of USP27X blocks Cathepsin K inhibition-induced Bim upregulation, linking the Cat K/Raptor/ROS/USP27X axis to Bim stabilization and enhanced apoptotic sensitivity. siRNA knockdown of USP27X, immunoblotting for Bim/Raptor/ROS, mitochondria-specific superoxide scavenger experiments, xenograft tumor model Redox Biology Medium 31901727
2022 USP27 (USP27X) specifically interacts with the histone methyltransferase SETD3, negatively regulates its ubiquitination, and enhances SETD3 protein stability; USP27 inhibition reduces SETD3 protein levels and blocks HCC cell proliferation and tumorigenesis. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation and tumorigenesis readouts Cellular and Molecular Life Sciences Medium 35018513
2023 GSK3β directly binds to and phosphorylates USP27X, and this phosphorylation enhances the interaction between USP27X and CBX2, leading to USP27X-mediated deubiquitination and stabilization of CBX2; USP27X deficiency causes CBX2 degradation and inhibits tumorigenesis, defining a GSK3β–USP27X–CBX2 regulatory axis. Mass spectrometry (identification of USP27X as CBX2 DUB), co-immunoprecipitation, overexpression/knockdown, phosphorylation assay, ubiquitination assay, tumorigenesis assays Cell Death & Disease Medium 38030604
2024 PIM2 phosphorylates USP27X, enhancing its deubiquitylase activity toward MYC; USP27X then deubiquitylates and stabilizes MYC protein, promoting HK2-mediated aerobic glycolysis and breast cancer progression; the PIM2–USP27X–MYC axis was validated in PIM2-knockout mice. Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, overexpression/knockdown with glycolysis readouts, PIM2-knockout mouse validation Oncogene Medium 38969771
2024 USP27 (USP27X) stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating HCC tumor progression; CTCF transcription factor directly binds the USP27 promoter and upregulates its expression, establishing a CTCF/USP27/PFKFB3 axis. Co-immunoprecipitation, ubiquitination assay, ChIP (CTCF binding to USP27 promoter), siRNA knockdown with glycolysis assays, in vivo xenograft Cellular Signalling Medium 39746496
2024 Disease-causing variants in USP27X associated with X-linked intellectual disability (XLID105) disrupt USP27X protein function via distinct mechanisms, including altered protein-protein interactions and reduced deubiquitylating activity; biochemical and cell biology analysis of 10 new patient variants showed these mechanisms underlie the neurodevelopmental disorder. Clinical genetics, bioinformatics, biochemical deubiquitylating activity assays, co-immunoprecipitation (protein-protein interaction analysis), cell biology assays Life Science Alliance Medium 38182161
2025 A novel missense variant c.257C>T (p.Thr86Met) in USP27X is detrimental to USP27X protein expression and deubiquitination activity in vitro, functionally linking loss of DUB activity to X-linked intellectual disability. In vitro expression assay, deubiquitination activity assay with mutant USP27X construct Journal of Human Genetics Low 40596734

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1. Cancer research 93 30341066
2019 Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling. Journal of immunology (Baltimore, Md. : 1950) 62 31534008
2018 USP27-mediated Cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis. Oncogene 49 29497124
2016 The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis. EMBO reports 49 27013495
2019 Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization. Redox biology 37 31901727
2021 Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619. Cells 30 34571917
2020 USP27X negatively regulates antiviral signaling by deubiquitinating RIG-I. PLoS pathogens 23 32027733
2022 Stabilization of SETD3 by deubiquitinase USP27 enhances cell proliferation and hepatocellular carcinoma progression. Cellular and molecular life sciences : CMLS 20 35018513
2024 SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation. Clinical and translational medicine 12 38279869
2023 Phosphorylation of USP27X by GSK3β maintains the stability and oncogenic functions of CBX2. Cell death & disease 7 38030604
2024 USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms. Life science alliance 6 38182161
2024 Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC. Oncogene 6 38969771
2024 USP27 promotes glycolysis and hepatocellular carcinoma progression by stabilizing PFKFB3 through deubiquitination. Cellular signalling 4 39746496
2024 MiR-214 promotes the antitumor effect of NK cells in colorectal cancer liver metastasis through USP27X/Bim. Cytotechnology 1 39435421
2025 A novel USP27X missense variant identified in an individual with intellectual disability. Journal of human genetics 0 40596734
2024 [Two new cases of X-linked intellectual developmental disorder-105 linked to a previously unreported pathogenic variant in the USP27X gene]. Revista de neurologia 0 39007861

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