Affinage

USP29

Ubiquitin carboxyl-terminal hydrolase 29 · UniProt Q9HBJ7

Length
922 aa
Mass
104.2 kDa
Annotated
2026-04-28
24 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP29 is a deubiquitinase that stabilizes a broad spectrum of substrates by removing K48-linked (and in some cases K63-linked) polyubiquitin chains, thereby regulating DNA damage checkpoints, innate immunity, epithelial-mesenchymal transition, metabolic reprogramming, and ferroptosis. It deubiquitinates p53 and Claspin to support apoptosis and ATR-Chk1 signaling (PMID:21285945, PMID:24632611), stabilizes cGAS to promote type I interferon responses (PMID:32457395), and deubiquitinates HIF1α and MYC to coordinate glycolysis and glutamine catabolism in tumors (PMID:34601505, PMID:34272356). USP29 catalytic activity is positively regulated by CDK1-mediated phosphorylation, enabling TWIST1 stabilization and EMT (PMID:36782089), while its transcription is controlled by the FBP/AIMP2 complex under oxidative stress and by FUBP1 in gastric cancer (PMID:21285945, PMID:38233848).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2008 Medium

    The initial question of how USP29 transcription is controlled was addressed by identifying two conserved cis-elements (CSE1 repressor and CSE2/YY1 activator) within the bidirectional Peg3/Usp29 promoter, establishing that USP29 expression is subject to orientation-dependent transcriptional regulation.

    Evidence Promoter mutagenesis and reporter assays in cell lines

    PMID:19068137

    Open questions at the time
    • Endogenous transcription factor occupancy not confirmed by ChIP
    • Imprinting status and its effect on USP29 expression not resolved
    • No connection to physiological signals driving USP29 induction
  2. 2011 High

    USP29 was established as an active deubiquitinase with its first identified substrate: FBP and JTV1/AIMP2 co-activate USP29 transcription under oxidative stress, and USP29 directly deubiquitinates and stabilizes p53 to induce apoptosis, revealing a stress-responsive DUB–tumor suppressor axis.

    Evidence Co-immunoprecipitation, in vitro and in vivo deubiquitination assays, transcriptional reporter assays

    PMID:21285945

    Open questions at the time
    • Ubiquitin chain-linkage specificity on p53 not determined
    • Physiological in vivo validation in knockout animals not performed
  3. 2014 High

    USP29's role was extended to DNA damage checkpoint signaling by showing it deubiquitinates and stabilizes Claspin, supporting ATR-Chk1 activation and S-phase progression after replication stress.

    Evidence Reciprocal Co-IP, in vitro DUB assay, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis

    PMID:24632611

    Open questions at the time
    • Whether USP29 acts at stalled replication forks versus globally on Claspin pools is unknown
    • Relationship to other Claspin-directed DUBs not clarified
  4. 2019 Medium

    A link between USP29 and neurodegeneration was proposed: parkin loss elevates AIMP2, which upregulates USP29, leading to MYBBP1A accumulation in dopaminergic neurons, potentially contributing to Parkinson's disease pathogenesis.

    Evidence siRNA knockdown, Western blot, AIMP2 transgenic and knockdown mouse models

    PMID:31878357

    Open questions at the time
    • No in vitro DUB assay confirming direct deubiquitination of MYBBP1A
    • Causal contribution of USP29–MYBBP1A axis to dopaminergic neuron loss not established
    • Single study without independent replication
  5. 2020 High

    USP29 was established as a critical regulator of innate immunity by constitutively interacting with and deubiquitinating cGAS (K48-linked chains), stabilizing it to promote type I IFN responses; Usp29 knockout mice showed impaired antiviral defense against HSV-1.

    Evidence K48-linkage-specific ubiquitination assays, Co-IP, reconstitution, Usp29 KO mice with HSV-1 challenge

    PMID:32457395

    Open questions at the time
    • Whether USP29 regulation of cGAS is modulated by viral immune evasion strategies
    • Structural basis of USP29–cGAS interaction unknown
  6. 2020 High

    USP29 was identified as a Snail-stabilizing DUB through unbiased screening, showing it cooperates with phosphatase SCP1 to prevent Snail degradation and promote EMT and gastric/lung cancer migration, extending USP29's role to epithelial-mesenchymal transition.

    Evidence DUB cDNA library screen (79 DUBs), Co-IP, ubiquitination assay, catalytic mutant analysis, xenograft models

    PMID:32968046 PMID:32973332

    Open questions at the time
    • How SCP1 and USP29 are co-recruited to Snail is unknown
    • Whether USP29 regulation of Snail operates in normal epithelial homeostasis
  7. 2021 High

    USP29 was shown to coordinately stabilize both HIF1α and MYC, establishing it as a master regulator of tumor metabolic reprogramming (glycolysis and glutamine catabolism); systemic Usp29 knockout prolonged survival in tumor models without developmental defects, indicating therapeutic potential.

    Evidence Unbiased siRNA screen of 96 DUBs, metabolic flux analysis, Co-IP, DUB assays, Usp29 KO mice in neuroblastoma and lymphoma models

    PMID:34272356 PMID:34601505

    Open questions at the time
    • How USP29 selectively targets HIF1α versus VHL-mediated degradation pathway
    • Compensatory DUBs in Usp29 KO mice not characterized
  8. 2021 High

    USP29 was connected to NRF2-dependent anti-oxidant signaling by showing it deubiquitinates and stabilizes NRF2, driving M1-to-M2 microglia/macrophage polarization and neuroprotection after spinal cord injury.

    Evidence Co-IP, ubiquitination assay, proteomics, NRF2 KO mice, in vivo SCI model

    PMID:34562326

    Open questions at the time
    • Whether USP29 competes with Keap1/Cul3 E3 ligase for NRF2 not tested
    • Specificity of USP29 versus other NRF2-directed DUBs unclear
  9. 2022 High

    USP29's substrate repertoire was extended to viral proteins and DNA damage effectors: it stabilizes SARS-CoV-2 ORF9b (at K4/K40) to suppress innate immunity, and stabilizes SETD8 to promote H4K20me1 and 53BP1 recruitment at DNA damage sites.

    Evidence Site-directed mutagenesis of ORF9b ubiquitination sites, viral virulence assays; catalytic-mutant-dependent Co-IP with SETD8, H4K20me1 and 53BP1 focus formation assays

    PMID:35638730 PMID:36010569

    Open questions at the time
    • Whether SARS-CoV-2 actively hijacks USP29 or passively benefits from it
    • Structural determinants of USP29 substrate recognition remain unknown
  10. 2023 High

    CDK1 was identified as an upstream activator of USP29 through direct phosphorylation, which is required for USP29-mediated deubiquitination of TWIST1, thereby linking cell-cycle kinase signaling to EMT and chemoresistance in triple-negative breast cancer.

    Evidence In vitro CDK1 kinase assay on USP29, CDK1 genetic ablation and pharmacological inhibition, DUB assay for TWIST1, TNBC xenograft models

    PMID:36782089

    Open questions at the time
    • Phosphorylation site(s) on USP29 not mapped
    • Whether CDK1-dependent activation applies to all USP29 substrates or is TWIST1-specific
  11. 2024 High

    USP29's transcriptional control and substrate range were further expanded: FUBP1 directly activates USP29 transcription to stabilize Aurora kinase B (AURKB) in gastric cancer, and USP29 stabilizes ACSL5 via K48-chain removal to promote fatty acid β-oxidation and protect against hepatic steatosis.

    Evidence ChIP and luciferase for FUBP1→USP29 transcription; K48-specific DUB assays for AURKB and ACSL5; Usp29 KO and overexpression mice on HFD/HFCD

    PMID:38233848 PMID:39355870

    Open questions at the time
    • Whether FUBP1-driven transcription of USP29 is equivalent to the FBP/AIMP2-driven pathway reported earlier
    • Tissue-specific regulation of USP29 expression not systematically characterized
  12. 2025 High

    USP29 was shown to suppress ferroptosis by deubiquitinating FSP1, counteracting SMURF1-mediated K63/K193 polyubiquitination, and to regulate neuroinflammation by deubiquitinating TAK1 to inhibit M1 microglial polarization, further broadening its functional scope.

    Evidence Site-specific ubiquitination mutagenesis for FSP1, paired E3/DUB analysis, chemoresistant gastric cancer models; GST pull-down and DUB assay for TAK1, rat SCI model

    PMID:40634288 PMID:41387682

    Open questions at the time
    • How USP29 selects among its many substrates in a given cellular context is unknown
    • TAK1 study is a single report in a rat model without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include how USP29 achieves substrate selectivity among its remarkably broad substrate repertoire, what the structural basis of its catalytic domain and substrate recognition is, whether CDK1-mediated phosphorylation regulates activity toward all substrates, and how its apparently non-essential in vivo role (viable KO mice) is reconciled with its strong tumor-promoting functions.
  • No crystal or cryo-EM structure of USP29 available
  • Systematic identification of all CDK1 phosphorylation sites on USP29 lacking
  • No comprehensive substrate-specificity or ubiquitin-chain-type selectivity study

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 12 GO:0140096 catalytic activity, acting on a protein 12
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-392499 Metabolism of proteins 12 GO:0098772 molecular function regulator activity 9 R-HSA-1643685 Disease 8 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
AURKBCGASCLSPNHIF1AMYCSNAI1TP53TWIST1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 USP29 is transcriptionally induced by FBP and JTV1/AIMP2 in response to oxidative stress; USP29 binds to p53, cleaves poly-ubiquitin chains from p53, and stabilizes p53 protein, leading to apoptosis. Co-immunoprecipitation, deubiquitination assay (in vivo and in vitro), transcriptional reporter assays, cellular fractionation The EMBO journal High 21285945
2014 USP29 interacts with and deubiquitinates Claspin both in vivo and in vitro, stabilizing Claspin and thereby supporting ATR-Chk1 pathway signaling and S-phase progression; USP29 knockdown impairs Chk1 phosphorylation after DNA damage. Co-immunoprecipitation, in vivo and in vitro deubiquitination assays, siRNA knockdown with Chk1 phosphorylation readout, cell-cycle analysis Oncogene High 24632611
2020 USP29 constitutively interacts with cGAS and deconjugates K48-linked polyubiquitin chains from cGAS, stabilizing cGAS and promoting type I interferon induction and antiviral responses; USP29 knockout mice are hypersensitive to HSV-1 infection. Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), USP29 KO mice, reconstitution experiments Cell research High 32457395
2020 USP29 stabilizes Snail protein by deubiquitinating it, and cooperates with phosphatase SCP1 to simultaneously dephosphorylate and deubiquitinate Snail, preventing its degradation and promoting gastric cancer cell migration. DUB cDNA library screen (79 DUBs), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell migration assays Oncogene High 32973332
2020 USP29 deubiquitinates and stabilizes Snail1 in a catalytic activity-dependent manner, and USP29 is transcriptionally upregulated by oxidative stress induced by chemotherapy, thereby enhancing cancer stem cell-like characteristics in lung adenocarcinoma. Ubiquitination assay, catalytic mutant analysis, siRNA knockdown, xenograft mouse model Cell death & disease Medium 32968046
2021 USP29 directly deubiquitinates and stabilizes HIF1α, promoting its transcriptional activity; this stabilization upregulates hexokinase 2 (HK2) and aerobic glycolysis, contributing to Sorafenib resistance in hepatocellular carcinoma. Co-immunoprecipitation, ubiquitination assay, siRNA/CRISPR knockdown, xenograft mouse model, glycolysis metabolic assays Oncogenesis High 34272356
2021 USP29 directly deubiquitinates and stabilizes both MYC and HIF1α, coordinating metabolic reprogramming (glycolysis and glutamine catabolism) in tumor cells; systemic Usp29 knockout depletes MYC and HIF1α in vivo and prolongs survival of tumor-bearing mice without overt developmental defects. Unbiased siRNA screen (96 DUBs), metabolic flux analysis, Co-immunoprecipitation, ubiquitination assay, Usp29 KO mice, neuroblastoma and lymphoma models Oncogene High 34601505
2021 USP29 interacts with and deubiquitinates NRF2, stabilizing it and thereby regulating microglia/macrophage polarization from M1 to M2; USP29 knockdown abolishes the protective effects of melatonin-preconditioned MSC extracellular vesicles after spinal cord injury. Co-immunoprecipitation, ubiquitination assay, proteomics, shRNA knockdown, NRF2 knockout mice, in vivo SCI model Journal of pineal research High 34562326
2022 USP29 interacts with the carboxyl end of SARS-CoV-2 ORF9b, removes ubiquitin chains from ORF9b (ubiquitinated at Lys-4 and Lys-40), preventing its proteasomal degradation and thereby inhibiting type I IFN and NF-κB activation and enhancing viral virulence. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of ORF9b lysines, VSV-eGFP and SARS-CoV-2 trVLP viral virulence assays mBio High 35638730
2022 USP29 interacts with SETD8 (interaction dependent on USP29 catalytic activity), deubiquitinates SETD8 in vivo, and is required for irradiation-induced H4K20 monomethylation and 53BP1 focus formation at DNA damage sites; USP29 depletion increases cellular sensitivity to irradiation. Co-immunoprecipitation (catalytic mutant-dependent), in vivo ubiquitination assay, siRNA knockdown, H4K20me1 immunostaining, 53BP1 focus formation, irradiation survival assays Cells High 36010569
2023 CDK1 directly phosphorylates USP29, which is required for USP29 deubiquitinase activity toward TWIST1; USP29-mediated deubiquitination of TWIST1 stabilizes TWIST1 and promotes EMT, cancer stem cell functions, and chemoresistance in triple-negative breast cancer. Co-immunoprecipitation, ubiquitination assay, CDK1 kinase assay (phosphorylation of USP29), CDK1 genetic ablation and pharmacological inhibition, TNBC cell and xenograft models Advanced science High 36782089
2023 USP29 deubiquitinates and stabilizes KIAA1429 (VIRMA) via co-immunoprecipitation-confirmed interaction; stabilized KIAA1429 promotes SOX8 mRNA stability through m6A modification, facilitating colorectal cancer cell proliferation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft model Biomolecules & biomedicine Medium 36373629
2024 Transcription factor FUBP1 directly activates USP29 gene transcription (shown by ChIP and luciferase assays); USP29 then interacts with and stabilizes AURKB by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB oncogenic axis in gastric cancer. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), ChIP, luciferase reporter assay, Usp29 KO mice, xenograft model Cancer cell international High 38233848
2024 USP29 directly interacts with ACSL5 and stabilizes it by removing K48-linked ubiquitin chains, promoting fatty acid β-oxidation and protecting against MASLD; USP29 deletion exacerbates hepatic steatosis and fibrosis. Co-immunoprecipitation, K48-linked deubiquitination assay, USP29 knockout and overexpression in mice (HFD/HFCD model), in vitro hepatocyte model Clinical and molecular hepatology High 39355870
2019 USP29 deubiquitinates and stabilizes MYBBP1A; parkin loss leads to accumulation of AIMP2, which upregulates USP29 and subsequently MYBBP1A in dopaminergic neurons, linking this pathway to Parkinson's disease pathogenesis. siRNA knockdown, Western blot (MYBBP1A stabilization), in vivo AIMP2 transgenic and knockdown mouse models Journal of clinical medicine Medium 31878357
2025 USP29 interacts with TAK1, directly inhibiting TAK1 ubiquitination and phosphorylation; ELAVL1 binds USP29 mRNA and promotes its degradation, reducing USP29 levels and thereby activating TAK1 to drive M1 microglial polarization after spinal cord injury. Co-immunoprecipitation, GST pull-down, ubiquitination assay, shRNA knockdown, rat SCI model Cell death discovery Medium 40634288
2025 USP29 deubiquitinates FSP1 (ferroptosis suppressor protein 1), counteracting SMURF1-mediated K63/K193 polyubiquitination of FSP1, thereby stabilizing FSP1 and suppressing ferroptosis to facilitate chemoresistance in gastric cancer. Co-immunoprecipitation, ubiquitination assay (site-specific K63/K193 mutagenesis), pharmacological FSP1 inhibition, chemoresistant cell and mouse models Nature communications High 41387682
2008 Two conserved sequence elements (CSE1 and CSE2/YY1 binding sites) within the bidirectional Peg3/Usp29 promoter regulate Usp29 transcription: CSE1 acts as a repressor and CSE2 as an activator, with orientation-dependent effects demonstrated by promoter mutagenesis assays. Cell line-based promoter assays, serial mutagenesis of YY1 binding sites and CSE1 elements BMC molecular biology Medium 19068137

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. The EMBO journal 116 21285945
2021 Extracellular vesicles derived from melatonin-preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2. Journal of pineal research 108 34562326
2020 USP29 maintains the stability of cGAS and promotes cellular antiviral responses and autoimmunity. Cell research 72 32457395
2014 USP29 controls the stability of checkpoint adaptor Claspin by deubiquitination. Oncogene 62 24632611
2020 Deubiquitinase USP29 promotes gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein. Oncogene 57 32973332
2021 USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis. Oncogenesis 49 34272356
2023 Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 36782089
2001 Imprinting and evolution of two Kruppel-type zinc-finger genes, ZIM3 and ZNF264, located in the PEG3/USP29 imprinted domain. Genomics 39 11543637
2020 USP29 enhances chemotherapy-induced stemness in non-small cell lung cancer via stabilizing Snail1 in response to oxidative stress. Cell death & disease 35 32968046
2021 USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression. Oncogene 33 34601505
2022 The Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b. mBio 29 35638730
2023 Promotive role of USP29-mediated deubiquitination in malignant proliferation of colorectal cancer cells via the KIAA1429/SOX8 axis. Biomolecules & biomedicine 17 36373629
2008 Two evolutionarily conserved sequence elements for Peg3/Usp29 transcription. BMC molecular biology 15 19068137
2024 USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination. Clinical and molecular hepatology 12 39355870
2024 USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer. Cancer cell international 11 38233848
2019 The deubiquitinating gene Usp29 is dispensable for fertility in male mice. Science China. Life sciences 9 30919279
2019 Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson's Disease Patients. Journal of clinical medicine 9 31878357
2022 USP29 Deubiquitinates SETD8 and Regulates DNA Damage-Induced H4K20 Monomethylation and 53BP1 Focus Formation. Cells 6 36010569
2023 Identification of USP29 as a key regulator of nucleotide biosynthesis in neuroblastoma through integrative analysis of multi-omics data. Cancer biology & therapy 3 37463886
2022 Deubiquitinase USP29 correlates RORγt expression and its association with thymoma myasthenia gravis. American journal of translational research 3 36628242
2016 Transcriptional Truncation of the Long Coding Imprinted Gene Usp29. PloS one 3 27327533
2024 The emerging role of USP29 in cancer and other diseases. Cell biochemistry and function 2 38269503
2025 USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer. Nature communications 1 41387682
2025 ELAVL1-mediated USP29 mRNA degradation activates TAK1 driving M1 microglial polarization and neural stem cell differentiation dysregulation in spinal cord injury. Cell death discovery 0 40634288