Affinage

USP24

Ubiquitin carboxyl-terminal hydrolase 24 · UniProt Q9UPU5

Length
2620 aa
Mass
294.4 kDa
Annotated
2026-06-11
28 papers in source corpus 21 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP24 is a large cysteine-protease deubiquitinating enzyme (DUB) that acts as a master post-translational stabilizer, removing K48-linked polyubiquitin from a broad panel of substrates to spare them from proteasomal degradation, with catalytic activity centered on Cys1695 required for its functions (PMID:38491202, PMID:40238877). Its earliest-defined roles are in the genome-stability arm: USP24 directly deubiquitinates and stabilizes p53 to enable UV-induced PUMA activation and apoptosis (PMID:25578727) and stabilizes the nucleotide excision repair factor DDB2 (PMID:23159851), while loss of USP24 destabilizes the microtubule regulator CRMP2 to cause spindle defects and aneuploidy, casting USP24 as a tumor suppressor of mitotic fidelity (PMID:33355202). USP24 also bidirectionally tunes autophagy: it restrains flux by destabilizing ULK1 (PMID:30957634), yet in other contexts stabilizes Beclin1 to drive autophagy-dependent ferroptosis (PMID:39379617) or acts through TRAF6 to control Beclin-1 turnover (PMID:41785730). In cancer and immune settings it sustains pro-tumorigenic signaling by stabilizing substrates including GSDMB (promoting STAT3 activation) (PMID:34326684), TRAF2 (driving AKT/NF-κB) (PMID:39127151), YAP1 (PMID:40287768), and the anti-ferroptotic enzyme DHODH (PMID:40715045), and it stabilizes PD-1 in CD8+ T cells downstream of an IL-6/STAT3 axis, linking it to T-cell exhaustion and lung tumorigenesis (PMID:40238877). Substrate recognition is partly encoded by a C-terminal motif that engages bromodomain-containing proteins at defined ubiquitin acceptor lysines (PMID:33257797). Beyond canonical ubiquitin, USP24 is ISG15 cross-reactive and deISGylates the RNA helicase MOV10 to negatively regulate innate IFN-β responses.

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Established USP24 as a bona fide deubiquitinase by showing it physically engages and enzymatically stabilizes a defined substrate, the NER factor DDB2.

    Evidence Yeast two-hybrid, co-IP, siRNA knockdown, and in vitro deubiquitination with purified USP24

    PMID:23159851

    Open questions at the time
    • Did not define ubiquitin linkage specificity
    • No structural basis for substrate selection
  2. 2015 High

    Placed USP24 in the DNA-damage response by demonstrating direct deubiquitination of p53 governs UV-induced apoptosis, framing USP24 as a stress-responsive stabilizer.

    Evidence In vitro deubiquitination with purified USP24, siRNA knockdown with p53 stability/apoptosis readouts, and re-expression rescue

    PMID:25578727

    Open questions at the time
    • How DNA damage triggers USP24-p53 engagement is unresolved
    • Linkage type not specified
  3. 2019 Medium

    Revealed USP24 as a regulator of autophagy and macrophage-driven inflammation, expanding it beyond DNA repair into proteostasis and immune signaling.

    Evidence siRNA knockdown in cell lines and iPSC dopaminergic neurons (ULK1/autophagy flux); knockdown in M2 macrophages/lung cancer with IL-6 and p300/β-TrCP readouts

    PMID:30266897 PMID:30957634

    Open questions at the time
    • Direct deubiquitination of ULK1 not reconstituted in vitro
    • Whether p300/β-TrCP are direct substrates not shown by in vitro assay
  4. 2020 Medium

    Defined a substrate-recognition mechanism and a genetic tumor-suppressor role, connecting molecular substrate engagement to organismal phenotype.

    Evidence C-terminus/bromodomain interaction mapping and acceptor-lysine mutagenesis; Usp24 knockout mouse with CRMP2 rescue of spindle/segregation defects

    PMID:33257797 PMID:33355202

    Open questions at the time
    • No structure of the USP24-BRD interface
    • How a single DUB selects such diverse substrates remains unexplained
  5. 2021 Medium

    Extended USP24 substrate stabilization to oncogenic effectors and drug-resistance machinery, linking its activity to cancer progression and chemoresistance.

    Evidence Mass spec/co-IP for GSDMB (STAT3); knockdown/overexpression with Rad51 and ABC-transporter readouts and inhibitor treatment

    PMID:33846536 PMID:34326684

    Open questions at the time
    • Direct vs indirect effects on Rad51 and ABC transporters not separated
    • Linkage specificity not defined
  6. 2024 Medium

    Resolved ubiquitin-linkage specificity (K48) for multiple substrates and showed USP24 controls ferroptosis and survival signaling in hepatocellular carcinoma.

    Evidence Co-IP, K48-linkage-specific ubiquitination assays, genetic rescue (Beclin1, TRAF2) and xenografts

    PMID:39127151 PMID:39379617

    Open questions at the time
    • Context-dependence of pro- vs anti-autophagy outcomes unexplained
    • Substrate competition/hierarchy not addressed
  7. 2024 Medium

    Demonstrated catalytic-dependence in vivo and integrated USP24 into autophagy-linked drug resistance and immune checkpoint control in lung cancer.

    Evidence CRISPR catalytic knockout (C1695A), USP24-i-101 inhibitor, bafilomycin epistasis, inducible EGFR-L858R mouse model

    PMID:38491202

    Open questions at the time
    • Direct vs indirect regulation of E2F4/TRAF6 not fully separated
    • PD-L1 degradation mechanism not molecularly defined here
  8. 2024 Medium

    Identified USP24 as ISG15 cross-reactive, broadening its activity beyond ubiquitin to deISGylation of MOV10 in innate immunity.

    Evidence ABPP, in vitro deISGylation with recombinant USP24, depletion with ISG15 conjugate/interactome proteomics (preprint)

    Open questions at the time
    • Preprint, not peer-reviewed
    • Physiological balance between deubiquitination and deISGylation unclear
  9. 2025 High

    Established USP24 as a checkpoint regulator by K48-deubiquitinating PD-1 downstream of IL-6/STAT3, linking its activity to T-cell exhaustion and tumor immunity.

    Evidence Co-IP, K48-ubiquitination assay, catalytic-deficient mice, USP24-i-101 and anti-CTLA4 combination in vivo

    PMID:40238877

    Open questions at the time
    • How IL-6/STAT3 transcriptionally drives USP24 mechanistically not fully mapped
    • Whether PD-1 stabilization is the dominant in vivo effect not isolated
  10. 2025 Medium

    Widened the substrate set to metabolic and growth-control effectors (DHODH, YAP1, PKA-Cα), positioning USP24 in ferroptosis resistance, proliferation, and adipocyte/metabolic signaling.

    Evidence Co-IP, deubiquitination assays, knockdown with substrate rescue, catalytic-knockout mice and RNA-seq

    PMID:40287768 PMID:40448065 PMID:40715045

    Open questions at the time
    • Linkage specificity not defined for all substrates
    • Tissue-specific substrate selection rules unknown
  11. 2026 Medium

    Connected USP24 to osteoblast differentiation and skeletal disease via STAT2 stabilization and to cardiac autophagy via the TRAF6-Beclin1 axis.

    Evidence Co-IP, deubiquitination assays, STAT2 phenocopy, rAAV silencing in a FOP mouse model; TRAF6/Beclin-1 epistasis with autophagic flux assays

    PMID:41785730 PMID:42218160

    Open questions at the time
    • Reconciliation of opposing autophagy effects across tissues not addressed
    • Direct STAT2/TRAF6 deubiquitination kinetics not reconstituted in vitro

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single large DUB achieves selectivity across this exceptionally broad substrate range, and what determines its context-dependent pro- versus anti-autophagy and pro- versus anti-ferroptosis outcomes, remains unresolved.
  • No structural model of substrate recognition beyond the BRD-binding motif
  • No systematic linkage-specificity profiling
  • Rules governing tissue-specific substrate choice unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-5357801 Programmed Cell Death 4 R-HSA-9612973 Autophagy 4 R-HSA-73894 DNA Repair 3 R-HSA-168256 Immune System 2
Partners
CRMP2DDB2GSDMBTP53TRAF2TRAF6ULK1YAP1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 USP24 directly deubiquitinates p53, stabilizing it in response to UV-induced DNA damage; purified USP24 protein cleaves ubiquitinated p53 in vitro, and USP24 depletion destabilizes p53, impairs PUMA activation, and renders cells resistant to apoptosis after UV irradiation. In vitro deubiquitination assay with purified USP24; siRNA knockdown with p53 stability and apoptosis readouts; forced re-expression rescue experiment Cell reports High 25578727
2012 USP24 interacts with DDB2 (a nucleotide excision repair factor) and stabilizes it by removing ubiquitin; USP24 knockdown decreases steady-state DDB2 levels, and purified USP24 cleaves ubiquitinated DDB2 in vitro. Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown; in vitro deubiquitination assay Cell cycle (Georgetown, Tex.) High 23159851
2019 USP24 negatively regulates autophagy by controlling ubiquitination and stability of ULK1; USP24 knockdown in cell lines and iPSC-derived dopaminergic neurons elevates ULK1 protein levels and increases autophagy flux in an MTORC1-independent, class III PtdIns3K-dependent manner. siRNA knockdown in cell lines and iPSC-derived dopaminergic neurons; autophagy flux assays; MTORC1 and PtdIns3K inhibitor epistasis Autophagy Medium 30957634
2018 USP24 stabilizes p300 and β-TrCP proteins in M2 macrophages and lung cancer cells, leading to increased histone-3 acetylation and NF-κB levels while decreasing DNMT1 and IκB, thereby increasing IL-6 transcription. siRNA knockdown; western blot for substrate levels; conditioned medium transfer assays; IL-6 rescue experiments Nature communications Medium 30266897
2021 USP24 interacts with GSDMB and prevents its proteasomal degradation (deubiquitination-mediated stabilization), and the USP24/GSDMB complex promotes STAT3 phosphorylation and activation in bladder cancer cells. Mass spectrometry; co-immunoprecipitation; western blot; USP24 inhibitor treatment International journal of biological sciences Medium 34326684
2019 USP24 stabilizes Mcl-1; WP1130 inhibits USP24 catalytic activity (molecular docking and cellular thermal shift assay), leading to Mcl-1 destabilization and apoptosis via mitochondrial transmembrane potential collapse in T-ALL cells. Molecular docking; cellular thermal shift assay (CETSA); siRNA knockdown; Mcl-1 protein level measurement; mitochondrial transmembrane potential assay Cancer cell international Medium 30911287
2020 USP24 interacts with the bromodomain (BRD) via its C-terminus and stabilizes most BRD-containing proteins by removing ubiquitin from Lys391/Lys400 of the BRD; loss of the USP24-BRD interaction motif abolishes this stabilization and USP24's effects on cancer progression. Co-immunoprecipitation; western blot for BRD protein stability; mutagenesis of ubiquitin acceptor sites (Lys391/Lys400); deletion mutant analysis Scientific reports Medium 33257797
2020 USP24 interacts with and stabilizes CRMP2; deletion of Usp24 in mice leads to CRMP2 degradation, causing spindle defects, chromosome missegregation, and aneuploidy that are rescued by CRMP2 restoration, identifying USP24 as a tumor suppressor maintaining mitotic accuracy. Usp24 knockout mouse model; genetic rescue with CRMP2 restoration; chromosome segregation and spindle defect assays Cancer research Medium 33355202
2021 USP24 represses DNA-damage repair by decreasing Rad51 expression (promoting genomic instability) and increases ABC transporter levels (P-gp, ABCG2, ezrin) to enhance Taxol efflux from cancer cells, thereby promoting drug resistance. USP24 knockdown/overexpression; western blot for Rad51 and ABC transporter levels; drug efflux assays; NCI677397 inhibitor treatment Cell death and differentiation Medium 33846536
2023 USP24 is recruited to phospho-Runx2 (pRunx2, phosphorylated at Ser28 by p38 kinase) and stabilizes pRunx2 by deubiquitination, allowing pRunx2 to assemble a NCOA3-p300-pRunx2 complex that transactivates ADAMTS genes and promotes ECM degradation in intervertebral disc degeneration. Co-immunoprecipitation; mass spectrometry; western blot; RT-qPCR; p38 inhibitor epistasis; LPS-induced chronic inflammation mouse model Biology direct Medium 37415159
2024 USP24 reduces K48-linked ubiquitination of Beclin1, thereby stabilizing it and promoting autophagy-dependent ferroptosis in hepatocellular carcinoma; effects of USP24 overexpression on HCC proliferation are partially reversed by Beclin1 silencing. Co-immunoprecipitation confirming endogenous USP24-Beclin1 interaction; ubiquitination assay (K48-linkage specific); genetic rescue with Beclin1 silencing; in vivo xenograft Communications biology Medium 39379617
2024 USP24 binds to and deubiquitinates TRAF2, preventing its degradation; stabilized TRAF2 activates the AKT/NF-κB signaling pathway to promote HCC cell survival. Co-immunoprecipitation; western blot for TRAF2 stability after USP24 manipulation; AKT/NF-κB pathway readouts Biochemical pharmacology Medium 39127151
2024 USP24 activates autophagy in both interphase and mitotic periods of lung cancer cells by inhibiting E2F4 and TRAF6, respectively; the catalytic mutant USP24C1695A abolishes this effect, and autophagy induction is required for USP24 inhibitor-mediated suppression of drug resistance and maintenance of genomic integrity and PD-L1 degradation. CRISPR-mediated catalytic knockout (USP24C1695A); USP24 inhibitor USP24-i-101; bafilomycin-A1 autophagy inhibition rescue; doxycycline-inducible EGFRL858R lung cancer mouse model Cell death and differentiation Medium 38491202
2025 USP24 removes K48-linked polyubiquitin from PD-1, stabilizing PD-1 protein in CD8+ T cells; IL-6 transcriptionally activates USP24 expression, linking the IL-6/STAT3 axis to PD-1 stabilization; USP24 catalytic-deficient (Usp24 catalytic mutant) mice show reduced PD-1 levels and attenuated lung tumorigenesis. Co-immunoprecipitation; K48-ubiquitination assay; catalytic-deficient mouse model; USP24-i-101 inhibitor treatment; anti-CTLA4 combination in vivo Science advances High 40238877
2025 USP24 directly interacts with and deubiquitinates DHODH, stabilizing it to maintain coenzyme Q reduction and protect TNBC cells from lipid peroxidation-driven ferroptosis; pharmacological USP24 inhibition synergizes with ferroptosis inducers via a DHODH-dependent pathway. Co-immunoprecipitation; deubiquitination assay; siRNA knockdown; in vitro and in vivo ferroptosis assays with DHODH rescue Cell death & disease Medium 40715045
2025 USP24 stabilizes YAP1 by directly interacting with and deubiquitinating it; USP24 depletion suppresses HCC cell proliferation and tumor growth, and these effects are rescued by YAP1 restoration. Co-immunoprecipitation; deubiquitination assay; siRNA knockdown; YAP1 rescue experiment; xenograft mouse model Cancer cell international Medium 40287768
2025 USP24 interacts with and stabilizes PKA-Cα by deubiquitination; USP24 expression is upregulated by PKA activation during adipocyte differentiation, creating a positive feedback loop that increases CREB phosphorylation and lipogenic gene expression; free fatty acids increase USP24 to activate NF-κB and TGFβ pathways driving inflammation and fibrosis. Co-immunoprecipitation; CRISPR/Cas9 catalytic knockout (USP24C1695A) mice; USP24-i-101 inhibitor; western blot; RNA-sequencing Journal of biomedical science Medium 40448065
2026 USP24 stabilizes STAT2 through deubiquitination in osteoblasts; loss of USP24 reduces osteoblast differentiation and bone formation, phenocopying STAT2 deficiency; rAAV-mediated Usp24 silencing in a FOP mouse model diminishes heterotopic ossification and reduces STAT2 protein levels. Co-immunoprecipitation; deubiquitination assay; USP24 knockout/knockdown; STAT2 knockdown phenocopy; rAAV-mediated silencing in FOP mouse model Cell death & disease Medium 42218160
2026 USP24 deubiquitinates TRAF6, stabilizing it; stabilized TRAF6 then ubiquitinates Beclin-1 to promote its degradation, thereby inhibiting autophagy in diabetic myocardial disorder; TRAF6 overexpression reverses the autophagy rescue caused by USP24 knockdown. Co-immunoprecipitation; western blot for TRAF6 and Beclin-1 levels; lentiviral knockdown/overexpression; autophagic flux assays (mRFP-GFP-LC3, TEM); genetic epistasis (TRAF6 OE reverses USP24 KD effect) Life sciences Medium 41785730
2024 USP24 is an ISG15 cross-reactive deubiquitylase; recombinant USP24 processes pro-ISG15 and cleaves ISG15-linked synthetic substrates in vitro; USP24 depletion increases ISG15 conjugates upon IFN-β stimulation; USP24 specifically deISGylates the RNA helicase MOV10, and ISGylated MOV10 enhances IFN-β production, while USP24-mediated deISGylation of MOV10 negatively regulates the innate immune response. Activity-based protein profiling (ABPP); in vitro deISGylation assay with recombinant USP24 and synthetic ISG15-substrates; USP24 depletion; total proteome, GG-peptidome, and ISG15 interactome proteomics bioRxivpreprint Medium
2023 USP24 promotes NF-κB accumulation in diabetic cardiomyopathy; USP24 knockdown reduces NF-κB levels, whereas NF-κB knockdown does not reduce USP24 expression, establishing USP24 as upstream of NF-κB; elevated NF-κB promotes FACL4 expression and ferroptosis while reducing SLC7A11 and FTH1. siRNA knockdown in H9c2 cells; PMA-mediated NF-κB re-activation rescue; western blot; in vivo HFD/STZ mouse model Free radical biology & medicine Medium 38056575
2023 USP24 interacts with SIRT7 and mediates its deubiquitination; inhibition of miR-21-5p downregulates the ubiquitination level of SIRT7 via USP24, affecting autophagy levels in hepatocellular carcinoma. Co-immunoprecipitation; western blot for SIRT7 ubiquitination Life sciences Low 37187452

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway. International journal of biological sciences 101 34326684
2018 USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy. Nature communications 98 30266897
2006 Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease. Human mutation 53 16917932
2023 Upregulation of NF-κB by USP24 aggravates ferroptosis in diabetic cardiomyopathy. Free radical biology & medicine 51 38056575
2015 The deubiquitinating enzyme USP24 is a regulator of the UV damage response. Cell reports 49 25578727
2019 The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability. Autophagy 43 30957634
2012 The deubiquitinating protein USP24 interacts with DDB2 and regulates DDB2 stability. Cell cycle (Georgetown, Tex.) 41 23159851
2023 MiR-21-5p promotes sorafenib resistance and hepatocellular carcinoma progression by regulating SIRT7 ubiquitination through USP24. Life sciences 29 37187452
2019 WP1130 reveals USP24 as a novel target in T-cell acute lymphoblastic leukemia. Cancer cell international 29 30911287
2024 USP24-i-101 targeting of USP24 activates autophagy to inhibit drug resistance acquired during cancer therapy. Cell death and differentiation 26 38491202
2021 USP24 promotes drug resistance during cancer therapy. Cell death and differentiation 26 33846536
2024 USP24 promotes autophagy-dependent ferroptosis in hepatocellular carcinoma by reducing the K48-linked ubiquitination of Beclin1. Communications biology 21 39379617
2015 Involvement of USP24 in the DNA damage response. Molecular & cellular oncology 20 27308530
2020 USP24 Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma. Cancer research 19 33355202
2023 USP24-dependent stabilization of Runx2 recruits a p300/NCOA3 complex to transactivate ADAMTS genes and promote degeneration of intervertebral disc in chronic inflammation mice. Biology direct 18 37415159
2020 USP24 stabilizes bromodomain containing proteins to promote lung cancer malignancy. Scientific reports 17 33257797
2023 NCI677397 targeting USP24-mediated induction of lipid peroxidation induces ferroptosis in drug-resistant cancer cells. Molecular oncology 15 38140768
2025 Deubiquitinase USP24 activated by IL-6/STAT3 enhances PD-1 protein stability and suppresses T cell antitumor response. Science advances 13 40238877
2012 Association analysis of single-nucleotide polymorphisms of USP24 and USP40 with Parkinson's disease in the Han Chinese population. European neurology 12 22923019
2025 The deubiquitinase USP24 suppresses ferroptosis in triple-negative breast cancer by stabilizing DHODH protein. Cell death & disease 10 40715045
2024 USP24 promotes hepatocellular carcinoma tumorigenesis through deubiquitinating and stabilizing TRAF2. Biochemical pharmacology 10 39127151
2025 USP24 upregulation stabilizes PKA-Cα to promote lipogenesis, inflammation, and fibrosis during MASH progression. Journal of biomedical science 4 40448065
2017 [Expression characteristics of the USP24 gene in the mouse testis during spermatogenesis]. Zhonghua nan ke xue = National journal of andrology 3 29738159
2025 USP24 promotes hepatocellular carcinoma progression by deubiquitinating and stabilizing YAP1. Cancer cell international 2 40287768
2026 USP24 inhibits autophagy in diabetic myocardial disorder by regulating TRAF6-mediated ubiquitination of Beclin-1. Life sciences 0 41785730
2026 A De Novo USP24 Variant as a Candidate Driver in a Neurodevelopmental Disorder: Insights from Trio-Based Whole-Exome Sequencing. International journal of molecular sciences 0 42123666
2026 USP24-dependent STAT2 stabilization mediates physiologic and pathologic bone formation. Cell death & disease 0 42218160
2025 The combination of USP24-i-101-Astemizole sensitizes the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 40233501

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