Affinage

USP36

Ubiquitin carboxyl-terminal hydrolase 36 · UniProt Q9P275

Length
1123 aa
Mass
122.9 kDa
Annotated
2026-04-28
51 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP36 is a nucleolar deubiquitinating enzyme with dual enzymatic functions — canonical ubiquitin hydrolase activity and non-canonical SUMO E3 ligase activity — that coordinates ribosome biogenesis, rRNA processing, and RNA metabolism. As a DUB, USP36 localizes to nucleoli via a basic amino acid motif recruited by nucleophosmin/B23, where it deubiquitinates and stabilizes nucleolar substrates including c-Myc, nucleophosmin/B23, fibrillarin, DHX33, and H2Bub1 to promote rRNA transcription, processing, and cell proliferation; it also functions as a FUBI-specific protease that cleaves FUBI-eS30, an activity required for cytoplasmic 40S ribosomal subunit maturation (PMID:19208757, PMID:25775507, PMID:34318747, PMID:29273634). As a SUMO E3 ligase, USP36 mediates SUMOylation of snoRNP components (Nop58, Nhp2, Nop56, DKC1), EXOSC10 at K583, Las1L at K565, and DGCR8, thereby regulating snoRNA binding, ITS2 rRNA processing, and pri-miRNA processing, respectively (PMID:33852194, PMID:36912080, PMID:39356143, PMID:36950067). Beyond ribosome biogenesis, USP36 stabilizes diverse substrates across multiple pathways — including PrimPol during replication stress, anti-apoptotic proteins cIAP1/survivin, ERα, and SOD2 — and its enzymatic activities are inhibited by methylmalonylation at K499, while Drosophila studies demonstrate that catalytic activity is dispensable for viability but essential for spermatogenesis (PMID:33237263, PMID:38876304, PMID:39215346, PMID:41398045, PMID:40646716).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 Medium

    Establishing that USP36 possesses deubiquitinase activity and is itself regulated by polyubiquitination provided the initial enzymatic characterization of this DUB.

    Evidence In vitro ubiquitin cleavage assay and immunoprecipitation

    PMID:15809067

    Open questions at the time
    • No physiological substrate identified
    • No cellular context or localization determined
    • Regulation of USP36 stability via its own ubiquitination not characterized
  2. 2009 High

    Demonstrating that USP36 localizes to nucleoli via a basic amino acid motif, is recruited by nucleophosmin/B23, and deubiquitinates nucleolar proteins (B23, fibrillarin) established USP36 as a nucleolar DUB regulating rRNA biogenesis.

    Evidence Dominant-negative inhibition, RNAi, deletion mutagenesis, Co-IP, and rRNA processing analysis in human cells

    PMID:19208757 PMID:19679658

    Open questions at the time
    • Structural basis of nucleolar targeting not resolved
    • Full spectrum of nucleolar substrates unknown
    • How USP36 activity is regulated remained unclear
  3. 2012 High

    Genetic studies in Drosophila revealed that loss of USP36 causes nuclear accumulation of ubiquitinated proteins including H2B and triggers p62-dependent selective autophagy, linking USP36 to ubiquitin homeostasis and autophagy regulation conserved across species.

    Evidence Drosophila loss-of-function mutants combined with RNAi in human cells and p62 epistasis

    PMID:22622177

    Open questions at the time
    • Whether autophagy activation is a direct or compensatory consequence of USP36 loss
    • Identity of critical nuclear ubiquitinated substrates beyond H2B
  4. 2015 High

    Identification of c-Myc as a direct USP36 substrate, stabilized against SCF(Fbw7γ)-mediated degradation in the nucleolus with a positive feedback loop (USP36 is a c-Myc target gene), established USP36 as a key regulator of oncogenic signaling.

    Evidence In vitro deubiquitination, reciprocal Co-IP, cycloheximide chase, reporter assays, and subcellular fractionation

    PMID:25775507

    Open questions at the time
    • How USP36-c-Myc feedback loop is terminated or restrained
    • Whether nucleolar versus nucleoplasmic c-Myc pools have distinct functional outcomes
  5. 2017 High

    Mouse knockout revealing embryonic lethality at morula-to-blastocyst transition, combined with identification of DHX33 and H2Bub1 as direct substrates, established USP36 as essential for early development, ribosome biogenesis, and epigenetic regulation.

    Evidence Conditional mouse knockout with EM, Northern blot, translation assay; in vitro deubiquitination of H2B with ChIP at p21 locus

    PMID:29273634 PMID:29274341

    Open questions at the time
    • Which substrate(s) account for the morula-blastocyst lethality
    • Genome-wide landscape of H2Bub1 changes upon USP36 loss
  6. 2020 High

    Discovery that USP36 removes K29-linked polyubiquitin chains from PrimPol during replication stress extended USP36 function beyond nucleolar/ribosomal roles to DNA damage tolerance.

    Evidence Mass spectrometry, in vitro K29-linkage-specific deubiquitination, DNA fiber assay, cisplatin/olaparib sensitivity

    PMID:33237263

    Open questions at the time
    • How USP36 is relocated or activated at replication forks
    • Whether other replication stress substrates exist
  7. 2021 High

    The paradigm-shifting discovery that USP36 acts as a non-canonical SUMO E3 ligase for snoRNP components (Nop58, Nhp2, Nop56, DKC1) revealed a dual enzymatic function — DUB and SUMO ligase — and explained its broad impact on rRNA processing and translation.

    Evidence In vitro SUMOylation reconstitution with purified components, Co-IP with SUMO2/Ubc9, rRNA processing and translation assays

    PMID:33852194

    Open questions at the time
    • Structural basis for SUMO E3 ligase activity
    • Whether DUB and SUMO ligase activities are coordinated or independent on the same substrates
  8. 2021 High

    Identification of USP36 as a FUBI-specific protease required for FUBI-eS30 cleavage and 40S maturation, confirmed by crystal structures in 2023, established a unique dual ubiquitin/ubiquitin-like substrate specificity and explained USP36's role in cytoplasmic ribosome maturation.

    Evidence In vitro cleavage with purified USP36, RNAi/CRISPRi depletion, rRNA maturation analysis; crystal structures of USP36-Fubi and USP36-Ub complexes

    PMID:34318747 PMID:37443395

    Open questions at the time
    • How USP36 transitions between nucleolar functions and cytoplasmic 40S maturation
    • Whether FUBI cleavage is rate-limiting for 40S assembly in vivo
  9. 2023 High

    Extension of the SUMO E3 ligase function to EXOSC10 (K583), DGCR8, and later Las1L (K565), with site-specific mutagenesis showing SUMOylation is required for pre-rRNA binding/processing and pri-miRNA processing, established USP36 as a central coordinator of nucleolar RNA metabolism through SUMOylation.

    Evidence Site-directed mutagenesis (K583R, K565R) with functional rescue of rRNA processing; RIP for pri-miRNA binding

    PMID:36912080 PMID:36950067 PMID:39356143

    Open questions at the time
    • Full catalog of USP36 SUMOylation substrates
    • Whether a single domain mediates all SUMO E3 ligase activities
    • Interplay between USP36 SUMOylation and opposing SENP activities in steady state
  10. 2023 High

    Discovery that ribotoxic stress activates a JNK-USP36-Snail1 axis in the nucleolus, promoting ribosome biogenesis and drug resistance, placed USP36 as a stress-responsive effector integrating kinase signaling with nucleolar function.

    Evidence Co-IP, JNK inhibition, nucleolar fractionation, rRNA analysis, in vivo tumor models

    PMID:37833415

    Open questions at the time
    • Whether JNK directly phosphorylates USP36 and at which site
    • Generalizability to other ribotoxic stress agents
  11. 2024 High

    Demonstrations that USP36 deubiquitinates anti-apoptotic proteins (cIAP1 via K11-linked, survivin via K48-linked chains), ERα, PARP1, and other substrates across cancer types broadened USP36's substrate repertoire to apoptosis, hormone signaling, and cardioprotection, with linkage-type specificity emerging as a recurring feature.

    Evidence Linkage-specific ubiquitination assays, catalytic mutant C131A validation, in vivo cardiac and xenograft models

    PMID:38307305 PMID:38876304 PMID:39215346

    Open questions at the time
    • How USP36 achieves substrate selectivity among its many targets
    • Whether linkage specificity is substrate-determined or context-dependent
  12. 2025 Medium

    Identification of methylmalonylation at K499 as an inhibitory post-translational modification of both DUB and SUMO ligase activities, combined with Drosophila evidence that catalytic activity is dispensable for growth but essential for spermatogenesis, revealed regulatory complexity and catalytic-independent functions of USP36.

    Evidence Metabolomics with K499 site-specific analysis and in vitro activity assays; CRISPR catalytic mutation in Drosophila with viability/fertility phenotyping

    PMID:40646716 PMID:41398045

    Open questions at the time
    • Structural basis of methylmalonylation-mediated inhibition
    • Identity of catalytic-independent binding partners mediating growth functions
    • Whether methylmalonylation occurs physiologically outside cancer contexts

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for USP36's dual DUB/SUMO E3 ligase activities, how substrate selectivity is achieved among its many targets, and the full scope of catalytic-independent functions implied by Drosophila genetics.
  • No full-length USP36 structure available
  • Mechanism of substrate prioritization in the nucleolus unknown
  • Catalytic-independent interaction partners not identified
  • No disease-causing germline mutations reported in humans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 11 GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005730 nucleolus 7 GO:0005634 nucleus 3
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-8953854 Metabolism of RNA 6 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
DGCR8DHX33EXOSC10FBLLAS1LMYCNPM1PRIMPOL
Complex memberships
Drosha-DGCR8 microprocessor (via DGCR8 SUMOylation)snoRNP (via SUMOylation of Nop58/Nhp2/Nop56/DKC1)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 USP36 localizes to nucleoli via a C-terminal basic amino acid stretch and deubiquitinates nucleolar proteins nucleophosmin/B23 and fibrillarin, stabilizing them against proteasomal degradation; RNAi depletion reduces rRNA transcription, processing, and nucleolar morphology, leading to reduced cell proliferation. Dominant-negative inhibition, RNAi knockdown, in vivo ubiquitination assay, microscopy, rRNA analysis Journal of cell science High 19208757
2009 A short basic amino acid motif (RGKEKKIKKFKREKRR) in the C-terminal region of USP36 serves as a nucleolar localization signal that interacts with the central acidic region of nucleophosmin/B23; knockdown of nucleophosmin/B23 reduces nucleolar USP36 and elevates fibrillarin ubiquitination, demonstrating nucleophosmin/B23 recruits USP36 to nucleoli. Deletion mutagenesis, co-immunoprecipitation, siRNA knockdown, ubiquitination assay The Journal of biological chemistry High 19679658
2005 USP36 possesses deubiquitinase activity capable of cleaving ubiquitin from substrates; it contains a PEST motif and is itself polyubiquitinated. Ubiquitin cleavage assay, structural analysis, immunoprecipitation Biochemical and biophysical research communications Medium 15809067
2011 USP36 interacts with the mitochondrial antioxidant enzyme SOD2, deubiquitinates it, and stabilizes it against proteasomal degradation, thereby extending SOD2 protein half-life. 2-DE/MALDI-TOF MS identification, co-immunoprecipitation, yeast two-hybrid, ubiquitination assay, cycloheximide chase Journal of cellular biochemistry Medium 21268071
2012 Drosophila USP36 (dUsp36) controls selective autophagy activation in a p62/SQSTM1-dependent manner; loss of dUsp36 causes nuclear accumulation of ubiquitinated proteins including histone H2B, and cytoplasmic ubiquitinated proteins are cleared by p62-dependent autophagy. This function is conserved in human cells. Genetic loss-of-function (Drosophila mutants), RNAi in human cells, autophagy assays, p62 dependency epistasis Autophagy High 22622177
2015 USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, stabilizing c-Myc and counteracting SCF(Fbw7γ)-mediated degradation specifically in the nucleolus; USP36 interacts with nucleolar Fbw7γ but not nucleoplasmic Fbw7α, yet abolishes c-Myc degradation by both isoforms. USP36 is itself a c-Myc target gene, forming a positive feedback loop. Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, cycloheximide chase, reporter assays, subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America High 25775507
2016 USP36 binds to the E3 ubiquitin ligase Nedd4-2 and regulates Nedd4-2 substrate targeting: USP36 depletion increases TrkA·Nedd4-2 complex formation and TrkA ubiquitination, enhancing NGF-mediated TrkA signaling and PC12 cell differentiation; similarly, USP36 interferes with Nedd4-2-dependent Kv7.2/3 channel regulation. USP36 acts indirectly on TrkA (not directly deubiquitinating TrkA) through regulating Nedd4-2. siRNA screen, co-immunoprecipitation, surface biotinylation, signaling assays, PC12 differentiation assay The Journal of biological chemistry High 27445338
2017 USP36 reduces ubiquitination of DEAH-box RNA helicase DHX33 and increases its stability; Usp36 knockout in mice is lethal at morula-to-blastocyst transition, with impaired ribosomal RNA synthesis and protein translation. DHX33 knockdown phenocopies USP36 loss in cancer cells. Conditional mouse knockout, ubiquitination assay, O-propargyl-puromycin incorporation, Northern blot, electron microscopy, cancer cell shRNA The Journal of biological chemistry High 29273634
2017 USP36 is a novel histone H2B deubiquitinase: it interacts with H2B and deubiquitinates H2Bub1 in cells and in vitro. Depletion of USP36 increases H2Bub1 at the p21 gene locus, induces p21 expression, and inhibits cell proliferation. Co-immunoprecipitation, in vitro deubiquitination assay, ChIP, siRNA knockdown, cell proliferation assay Biochemical and biophysical research communications High 29274341
2018 USP36 controls the cellular localization of CHD7 in neuroblastoma: loss of 6p22lncRNAs (CASC15/NBAT1) modulates USP36 localization, affecting CHD7 stability and SOX9 expression. lncRNA loss-of-function, immunofluorescence/localization assay, CHD7 stability measurements, SOX9 expression analysis Cancer cell Medium 29533783
2018 USP36 stabilizes PME-1 through its deubiquitinase activity, promoting ERK and Akt signaling pathways; USP36 depletion decreases PME-1 expression levels. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pathway signaling assays FEBS letters Medium 29577269
2019 USP36 knockdown impairs Parkin-dependent mitophagy by reducing Beclin-1 and ATG14L mRNA and protein levels; transfection of ATG14L restores mitophagy in USP36-silenced cells. USP36 knockdown also reduces H2B K120 monoubiquitination at transcriptionally active chromatin. siRNA knockdown, high-content imaging, mitophagy assay, mRNA/protein level measurements, rescue experiment with ATG14L transfection Experimental cell research Medium 31550441
2020 USP36 is deubiquitinated following DNA replication stress, upregulates, and interacts with PrimPol; USP36 removes K29-linked polyubiquitin chains from PrimPol, increasing its protein stability. Depletion of USP36 causes replication stress defects and sensitizes cells to cisplatin and olaparib. Co-immunoprecipitation, mass spectrometry, in vivo and in vitro ubiquitination assay, siRNA knockdown, DNA fiber assay, drug sensitivity assay Nucleic acids research High 33237263
2021 USP36 promotes nucleolar SUMOylation by interacting with SUMO2 and Ubc9, and directly mediates SUMOylation in cells and in vitro; specifically, USP36 promotes SUMOylation of snoRNP components Nop58, Nhp2, Nop56, and DKC1, enhancing their binding to snoRNAs. USP36 knockdown or deletion markedly impairs rRNA processing and translation. Co-immunoprecipitation, in vitro SUMOylation assay, overexpression/knockdown, rRNA processing analysis, translation assay EMBO reports High 33852194
2021 USP36 interacts with and deubiquitinates DOCK4, stabilizing it; elevated USP36/DOCK4 activates Wnt/β-catenin signaling and promotes epithelial-to-mesenchymal transition in diabetic renal tubular epithelial cells. Co-immunoprecipitation, ubiquitination assay, Western blot, EMT markers, Wnt/β-catenin signaling assay Frontiers in cell and developmental biology Medium 33968925
2021 USP36 cleaves the FUBI-eS30 fusion protein in vitro; purified USP36 processes FUBI-eS30 directly, and depletion of USP36 by RNAi or CRISPRi impairs FUBI-eS30 processing and late steps of cytoplasmic 40S maturation including 18S rRNA maturation and recycling of ribosome biogenesis factors. Differential affinity purification, in vitro cleavage assay with purified USP36, RNAi, CRISPRi, rRNA maturation analysis eLife High 34318747
2021 NBAT1/CASC15-003 lncRNAs post-translationally control MYCN protein stability through USP36, which functions as a deubiquitinase for MYCN; USP36 downregulation significantly reduces neuroblastoma tumor growth in xenograft models. Co-immunoprecipitation, immunoblotting, loss-of-function experiments, xenograft models, RNA-seq Neuro-oncology advances Medium 34056606
2022 USP36 associates with and deubiquitinates YAP, blocking K48-linked polyubiquitination and stabilizing YAP protein, thereby promoting Hippo/YAP signaling and esophageal squamous carcinoma progression; identified by DUB siRNA screening. DUB siRNA screening, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell proliferation/invasion assays Cell death & disease Medium 36470870
2023 USP36 binds EXOSC10 in the nucleolus and mediates its SUMOylation at K583, without significantly altering EXOSC10 protein levels; K583R mutation impairs EXOSC10 binding to pre-rRNAs and fails to rescue defects in rRNA processing and cell growth caused by EXOSC10 knockdown. Co-immunoprecipitation, in vivo SUMOylation assay, site-directed mutagenesis (K583R), rRNA processing analysis, rescue experiments Nucleic acids research High 36912080
2023 Crystal structures of USP36 complexed with Fubi and ubiquitin reveal its dual ubiquitin/Fubi cleavage mechanism and substrate recognition; chemoproteomics identified USP16 as a second Fubi protease. The structures explain how other deubiquitinases are excluded from Fubi recognition. Crystal structure determination, chemoproteomics, Fubi C-terminal hydrolase measurements, in vitro activity assays Nature chemical biology High 37443395
2023 USP36 interacts with and stabilizes ALKBH5 via deubiquitination in glioblastoma; USP36 depletion impairs cell proliferation, self-renewal of glioblastoma stem cells, and sensitizes them to temozolomide. The USP36-ALKBH5 axis regulates ALKBH5-mediated gene expression. Mass spectrometry, co-immunoprecipitation, in vivo and in vitro ubiquitination assays, cell proliferation, neurosphere, and intracranial tumor assays Neuro-oncology High 36239338
2023 USP36 interacts with the Drosha-DGCR8 microprocessor complex and mediates DGCR8 SUMOylation specifically by SUMO2; this SUMOylation does not affect DGCR8 levels or Drosha-DGCR8 complex formation, but promotes DGCR8 binding to pri-miRNAs. Knockdown of USP36 attenuates pri-miRNA processing and reduces mature miRNA levels. Co-immunoprecipitation, in vivo SUMOylation assay, RNA immunoprecipitation (RIP) of pri-miRNAs, qPCR for mature miRNAs, siRNA knockdown Cancer research communications High 36950067
2023 Ribotoxic stress activates the JNK-USP36 signaling axis, which stabilizes Snail1 in the nucleolus via deubiquitination; nucleolar Snail1 facilitates ribosome biogenesis and promotes tumor cell survival and resistance to homoharringtonine (HHT). Combination of HHT with JNK-USP36-Snail1 axis inhibition synergistically inhibits solid tumor growth. Co-immunoprecipitation, ubiquitination assay, JNK inhibition, nucleolar fractionation, rRNA analysis, in vivo tumor models Nature communications High 37833415
2024 USP36 interacts with and removes K11-linked ubiquitin chains from cIAP1 and K48-linked ubiquitin chains from survivin, stabilizing both anti-apoptotic proteins. USP36 disrupts XIAP-SMAC complex formation and promotes RIP1 ubiquitination, inhibiting both intrinsic and extrinsic apoptosis in colorectal cancer cells. Gene silencing, co-immunoprecipitation, ubiquitination assay (linkage-specific), apoptosis assays The Journal of biological chemistry High 38876304
2024 USP36 binds PARP1 and deubiquitinates it, increasing PARP1 protein stability in cardiomyocytes exposed to doxorubicin; the catalytically inactive mutant C131A fails to stabilize PARP1. Cardiac knockdown of USP36 by AAV9-shUSP36 preserves cardiac function in doxorubicin-treated mice. Co-immunoprecipitation, ubiquitination assay, catalytic mutant (C131A), AAV9 cardiac knockdown in mice, echocardiography Cellular signalling High 38307305
2024 USP36 deubiquitinates ERα and inhibits its K48-linked polyubiquitination, stabilizing ERα and enhancing its transcriptome; the C131A catalytic mutant fails to promote breast cancer progression. USP36 silencing destabilizes the tamoxifen-resistant ERα Y537S mutant and restores tamoxifen sensitivity. DUB siRNA library screening, co-immunoprecipitation, ubiquitination assay, catalytic mutant (C131A), xenograft models, RNA-seq, luciferase assay Journal of experimental & clinical cancer research High 39215346
2024 USP36 interacts with and stabilizes RBM28 via deubiquitination at K162 residue; elevated RBM28 binds p53 to suppress its transcriptional activity, inactivating p53 signaling and promoting colorectal cancer progression. Co-immunoprecipitation, site-specific ubiquitination assay (K162), p53 transcription reporter, cell proliferation/invasion assays, in vivo Oncogene High 39343961
2024 USP36 interacts with WDR5 and stabilizes it via deubiquitination; USP36 knockdown increases WDR5 ubiquitination and promotes its degradation, impairing osteoblast differentiation; WDR5 overexpression rescues osteogenic differentiation in USP36-deficient cells. Co-immunoprecipitation, ubiquitination assay, Western blot, Alizarin red staining, rescue experiment Journal of orthopaedic surgery and research Medium 39152465
2024 USP36 interacts with Las1L and Nol9, regulates their stability via deubiquitination, and mediates SUMOylation of Las1L at K565; the K565R mutant fails to rescue ITS2 rRNA processing defects caused by Las1L knockdown, demonstrating USP36-mediated Las1L SUMOylation is critical for pre-rRNA ITS2 processing. Co-immunoprecipitation, in vitro deubiquitination assay, in vivo SUMOylation assay, site-directed mutagenesis (K565R), rRNA processing analysis, rescue experiments Cancer research communications High 39356143
2024 USP36 interacts with and deubiquitinates MLLT3 in the nucleolus, stabilizing it and activating downstream HIF1α and Snai signaling; the germline USP36 variant K814N (rs3744797) upregulates USP36 expression by reducing m6A modification, facilitating MLLT3 stabilization and EGFR-TKI resistance. Co-immunoprecipitation, ubiquitination assay, m6A analysis, nucleolar fractionation, in vitro/in vivo proliferation and resistance assays Clinical cancer research Medium 38261467
2025 USP36 functions as a SUMO ligase for GNL3, mediating its SUMOylation; GNL3 SUMOylation is required for its interaction with the BLM-DNA2 helicase-nuclease complex and for DNA end resection in homologous recombination repair. SENP3 acts as the opposing SUMO protease for GNL3. Co-immunoprecipitation, SUMOylation assay, CRISPR mutagenesis (K196R), DNA end resection assay, RPA/RAD51 loading assay, epistasis with SENP3 bioRxivpreprint Medium bio_10.1101_2025.11.04.686352
2025 In Drosophila, a CRISPR-induced catalytic mutation in dUSP36 produces viable adults with only minor growth defects but causes male infertility, demonstrating that dUSP36 deubiquitinating activity is dispensable for cell growth but essential for spermatogenesis; USP36 functions through both catalytic-dependent and catalytic-independent mechanisms. CRISPR/Cas9 catalytic mutation, in vivo viability and fertility assays, genetic epistasis Genetics High 40646716
2025 Methylmalonylation of USP36 at K499 by MMA (methylmalonic acid) inhibits USP36-mediated deubiquitination and SUMOylation of SUFU, promoting Hedgehog signaling (GLI1 target genes) and M2 macrophage polarization in clear-cell renal cell carcinoma. Metabolomics, co-immunoprecipitation, in vitro deubiquitination/SUMOylation assays, K499 site-specific analysis, in vivo tumor models Cell death and differentiation Medium 41398045
2025 USP36 deubiquitinates and stabilizes APEX1 via cleavage of K48-linked ubiquitin chains; USP36 overexpression suppresses erastin-induced ferroptosis in melanoma cells, while USP36 deficiency increases ferroptosis. APEX1 knockdown abolishes the anti-ferroptotic effect of USP36. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), overexpression/knockdown, ferroptosis assays, xenograft model Clinical and experimental medicine Medium 41649582
2025 FBL acts as a carrier for monoubiquitinated H2A (H2Aub) in nucleolar lysosome-like structures; USP36, FBL, Midnolin, and BMI1 form a complex regulating the balance between H2A monoubiquitination and deubiquitination during glucose starvation. Knockdown of USP36 causes S-phase cell cycle arrest and reduced cell viability. Protein complex screening, co-immunoprecipitation, glucose starvation assay, cell cycle analysis, viability assay bioRxivpreprint Low bio_10.1101_2025.06.30.662258
2025 Oxidative stress (H2O2) promotes USP36 interaction with androgen receptor (AR) in prostate cancer cells; USP36 deubiquitinates and stabilizes AR, and USP36 knockdown abolishes H2O2-induced AR-PSA pathway activation. TurboID proximity biotin labeling/MS, co-immunoprecipitation, deubiquitination assay, siRNA knockdown, luciferase reporter assay Scientific reports Medium 41298501
2025 USP36 deubiquitinates and stabilizes SOD2 to preserve mitochondrial integrity in gastric cancer; resveratrol disrupts the USP36-SOD2 axis, reducing SOD2 stability, inducing mitochondrial dysfunction, and triggering autophagy and ferroptosis. Western blot, ubiquitination assay, functional assays (colony formation, Transwell), xenograft model, fluorescence staining for mitochondrial function Gastric cancer Medium 40650854
2022 PRL1 activates USP36-mediated Snail2 deubiquitination in glioblastoma; USP36 deubiquitinates Snail2, and PRL1 expression positively correlates with Snail2 levels, promoting EMT, invasion, and tumorigenicity. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, in vitro and in vivo invasion/tumorigenicity assays Frontiers in oncology Medium 35111679
2024 USP36 stabilizes KIF2C via K48-linked deubiquitination; USP36 overexpression suppresses erastin-induced ferroptosis in breast cancer cells, and KIF2C knockdown counteracts this anti-ferroptotic effect. USP36-deficient tumors show reduced proliferation and increased ferroptosis in vivo. Co-immunoprecipitation, K48-linkage ubiquitination assay, overexpression/knockdown, ferroptosis assays, xenograft model Biochemical pharmacology Medium 40744233

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc. Proceedings of the National Academy of Sciences of the United States of America 186 25775507
2018 Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis. Cancer cell 112 29533783
2009 Nucleolar structure and function are regulated by the deubiquitylating enzyme USP36. Journal of cell science 73 19208757
2012 The deubiquitinating enzyme USP36 controls selective autophagy activation by ubiquitinated proteins. Autophagy 61 22622177
2023 USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5. Neuro-oncology 44 36239338
2009 Nucleophosmin/B23 regulates ubiquitin dynamics in nucleoli by recruiting deubiquitylating enzyme USP36. The Journal of biological chemistry 44 19679658
2020 The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization. Nucleic acids research 40 33237263
2017 Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice. The Journal of biological chemistry 38 29273634
2015 Deubiquitinating c-Myc: USP36 steps up in the nucleolus. Cell cycle (Georgetown, Tex.) 35 26697836
2011 Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36. Journal of cellular biochemistry 33 21268071
2020 Oxidized low-density lipoprotein accelerates the injury of endothelial cells via circ-USP36/miR-98-5p/VCAM1 axis. IUBMB life 32 33249762
2022 USP36 facilitates esophageal squamous carcinoma progression via stabilizing YAP. Cell death & disease 31 36470870
2021 The deubiquitinase USP36 promotes snoRNP group SUMOylation and is essential for ribosome biogenesis. EMBO reports 31 33852194
2019 Ubiquitin-specific protease USP36 knockdown impairs Parkin-dependent mitophagy via downregulation of Beclin-1-associated autophagy-related ATG14L. Experimental cell research 29 31550441
2005 Deubiquitinating enzyme USP36 contains the PEST motif and is polyubiquitinated. Biochemical and biophysical research communications 28 15809067
2017 The ubiquitin-specific protease USP36 is a conserved histone H2B deubiquitinase. Biochemical and biophysical research communications 24 29274341
2023 USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress. Nature communications 23 37833415
2021 Processing of the ribosomal ubiquitin-like fusion protein FUBI-eS30/FAU is required for 40S maturation and depends on USP36. eLife 23 34318747
2008 Differential display identifies overexpression of the USP36 gene, encoding a deubiquitinating enzyme, in ovarian cancer. International journal of medical sciences 23 18566677
2023 The ubiquitin-specific protease USP36 SUMOylates EXOSC10 and promotes the nucleolar RNA exosome function in rRNA processing. Nucleic acids research 20 36912080
2023 Molecular basis for ubiquitin/Fubi cross-reactivity in USP16 and USP36. Nature chemical biology 20 37443395
2021 USP36-Mediated Deubiquitination of DOCK4 Contributes to the Diabetic Renal Tubular Epithelial Cell Injury via Wnt/β-Catenin Signaling Pathway. Frontiers in cell and developmental biology 18 33968925
2020 Circ_USP36/miR-182-5p/KLF5 axis regulates the ox-LDL-induced injury in human umbilical vein smooth muscle cells. American journal of translational research 18 33437365
2022 USP36 promotes tumor growth of non-small cell lung cancer via increasing KHK-A expression by regulating c-MYC-hnRNPH1/H2 axis. Human cell 16 35133629
2019 USP36 protects proximal tubule cells from ischemic injury by stabilizing c-Myc and SOD2. Biochemical and biophysical research communications 16 30975468
2021 Circ_USP36 Silencing Attenuates Oxidized Low-Density Lipoprotein-Induced Dysfunction in Endothelial Cells in Atherosclerosis Through Mediating miR-197-3p/ROBO1 Axis. Journal of cardiovascular pharmacology 14 34369900
2024 USP36-mediated PARP1 deubiquitination in doxorubicin-induced cardiomyopathy. Cellular signalling 13 38307305
2024 USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells. The Journal of biological chemistry 13 38876304
2021 NBAT1/CASC15-003/USP36 control MYCN expression and its downstream pathway genes in neuroblastoma. Neuro-oncology advances 13 34056606
2024 USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα. Journal of experimental & clinical cancer research : CR 12 39215346
2022 miR-140-3p/usp36 axis mediates ubiquitination to regulate PKM2 and suppressed the malignant biological behavior of breast cancer through Warburg effect. Cell cycle (Georgetown, Tex.) 12 36305548
2016 Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3). The Journal of biological chemistry 12 27445338
2024 The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond. Biomolecules 11 38785979
2023 The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8. Cancer research communications 11 36950067
2024 Cinobufotalin regulates the USP36/c-Myc axis to suppress malignant phenotypes of colon cancer cells in vitro and in vivo. Aging 10 38517383
2024 USP36 promotes colorectal cancer progression through inhibition of p53 signaling pathway via stabilizing RBM28. Oncogene 10 39343961
2022 PRL1 Promotes Glioblastoma Invasion and Tumorigenesis via Activating USP36-Mediated Snail2 Deubiquitination. Frontiers in oncology 10 35111679
2018 PME-1 is regulated by USP36 in ERK and Akt signaling pathways. FEBS letters 8 29577269
2025 Resveratrol targets mitochondrial USP36-SOD2 to induce autophagy-ferroptosis and inhibit gastric cancer progression. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 5 40650854
2024 Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non-Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 5 38261467
2024 USP36 SUMOylates Las1L and Promotes Its Function in Pre-Ribosomal RNA ITS2 Processing. Cancer research communications 4 39356143
2025 Targeting MMA-induced USP36 methylmalonylation to suppress macrophage polarization and tumor progression in clear-cell renal cell carcinoma. Cell death and differentiation 3 41398045
2024 SUMOylation regulation of ribosome biogenesis: Emerging roles for USP36. Frontiers in RNA research 3 38764604
2024 USP36 regulates the proliferation, survival, and differentiation of hFOB1.19 osteoblast. Journal of orthopaedic surgery and research 3 39152465
2024 USP36 plays an oncogenic role in colorectal cancer cells. Neoplasma 1 38215036
2026 USP36 inhibits ferroptosis of melanoma cells by stabilizing APEX1. Clinical and experimental medicine 0 41649582
2025 The deubiquitinase USP36 funtions through catalytic-dependent and catalytic-independent mechanisms in Drosophila. Genetics 0 40646716
2025 USP36 suppresses breast cancer cell ferroptosis by regulating the ubiquitination and stability of KIF2C. Biochemical pharmacology 0 40744233
2025 The role of USP36 in ribosome biogenesis and other pathophysiological processes. Frontiers in molecular biosciences 0 40909126
2025 Oxidative stress reactivates androgen receptor signaling via USP36 to drive castration resistance in prostate cancer. Scientific reports 0 41298501
2024 Bufalin: A promising therapeutic drug against the cisplatin-resistance of ovarian cancer by targeting the USP36/c-Myc axis. Biochemical and biophysical research communications 0 39067250