Affinage

USP19

Ubiquitin carboxyl-terminal hydrolase 19 · UniProt O94966

Length
1318 aa
Mass
145.7 kDa
Annotated
2026-06-11
60 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP19 is a deubiquitinating enzyme that functions as a hub for protein stability control, removing distinct polyubiquitin linkages from numerous substrates to govern autophagy, innate immune signaling, mitochondrial dynamics, muscle mass, and cell proliferation (PMID:26988033, PMID:31127032, PMID:33978709, PMID:25568336). It is expressed as ER-anchored and cytoplasmic isoforms whose differential localization dictates opposing outcomes: in TGF-β signaling the cytoplasmic isoform stabilizes the type I receptor at the plasma membrane to promote SMAD signaling and EMT, while the ER isoform sequesters the receptor in the ER independently of catalysis (PMID:36646950), and only the ER isoform inhibits myoblast differentiation by suppressing CHOP during the unfolded protein response (PMID:25568336). Catalytically, USP19 is auto-inhibited by intramolecular folding of its tandem CS domains back onto the C-terminal USP catalytic core, an arrangement defined by NMR structures; HSP90 binding to the CS2 domain relieves this inhibition and activates DUB activity, while HSP90 also serves to recruit USP19 to clients such as polyglutamine-expanded huntingtin and ataxin-3 (PMID:33094816, PMID:26808260, PMID:29093475, PMID:24356957). Mechanistically, USP19 acts both as a classical chain-trimming DUB—removing K48-, K11-, K63- and K27-linked chains from substrates including Beclin-1, TAK1, FUNDC1, RORγt, YAP, and SLC7A11 (PMID:26988033, PMID:31127032, PMID:33978709, PMID:34135062, PMID:37832781, PMID:39574305)—and through deubiquitinase-independent stabilization of partners such as c-IAP1/2 and HIF-1α (PMID:21849505, PMID:22128162). In innate immunity it broadly dampens type I IFN signaling by acting on TBK1 (via chaperone-mediated autophagy), TRAF3, and MAVS, and modulates inflammasome and macrophage polarization through NLRP3 (PMID:34436957, PMID:28391724, PMID:38483060, PMID:33097834). Its own abundance is constrained by SIAH1/SIAH2-mediated ubiquitination and proteasomal degradation through a motif in its unique N-terminal domain (PMID:23500468, PMID:38483060). USP19 is also implicated in misfolding-associated protein secretion, acting upstream of HSC70 and DNAJC5 to export cytosolic misfolded proteins (PMID:29531792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2008 High

    Established USP19 as a cell-cycle regulator by showing it controls a degradation cascade rather than acting alone, linking its DUB activity to proliferation through the KPC1–p27Kip1 axis.

    Evidence Co-IP, siRNA knockdown, cell-cycle analysis, and genetic rescue in p27-/- cells

    PMID:19015242

    Open questions at the time
    • Ubiquitin chain linkage on KPC1 not defined
    • Whether stabilization requires catalysis not fully resolved
  2. 2011 Medium

    Revealed that USP19 can stabilize substrates (c-IAP1/2, HIF-1α) independently of its catalytic activity, distinguishing chain-trimming from scaffold-like protective functions.

    Evidence Co-IP, in vitro DUB assays, catalytic-mutant overexpression, and apoptosis/hypoxia readouts with siRNA knockdown

    PMID:21849505 PMID:22128162

    Open questions at the time
    • The deubiquitinase-independent stabilization mechanism is not molecularly defined
    • Single-lab observations
  3. 2013 Medium

    Defined how USP19 abundance is itself controlled, identifying SIAH1/2 binding to its unique N-terminal domain as the route for its ubiquitination and proteasomal turnover.

    Evidence Yeast two-hybrid, Co-IP, proteasome inhibitor and ubiquitination assays

    PMID:23500468

    Open questions at the time
    • Physiological conditions triggering SIAH-mediated turnover not established
    • Chain linkage not defined at this stage
  4. 2013 High

    Resolved the basis of USP19 auto-regulation, showing endogenous USP19 is largely cytosolic, binds Hsp90 via its catalytic domain, and is auto-inhibited by intramolecular TMD–catalytic domain interaction; ERAD involvement was a property of overexpression only.

    Evidence Subcellular fractionation, Co-IP, in vitro DUB activity assays, siRNA knockdown with ERAD substrate readouts

    PMID:24356957

    Open questions at the time
    • Structural detail of auto-inhibition not yet defined here
    • Physiological cytosolic substrates not enumerated
  5. 2015 High

    Demonstrated isoform-specific and sex-specific control of muscle mass, showing only the ER-localized isoform inhibits myoblast fusion via CHOP/UPR suppression, and that estrogen drives Usp19 transcription in female muscle.

    Evidence Adenoviral isoform overexpression, catalytic mutants, thapsigargin rescue, USP19-/- mice, ChIP for ERα at the Usp19 promoter

    PMID:25568336 PMID:25901042

    Open questions at the time
    • Catalytic substrate(s) underlying CHOP suppression not identified
    • Mechanism of sex-specific transcriptional control beyond ERα binding unclear
  6. 2016 High

    Connected USP19 to autophagy and innate immunity through linkage-specific deubiquitination of Beclin-1 at K437, providing the first substrate with a mapped site and dual functional output.

    Evidence Co-IP, ubiquitin chain-linkage analysis, site-specific mutagenesis, autophagic flux and IFN signaling readouts

    PMID:26988033

    Open questions at the time
    • How USP19 selects K11 chains at K437 not defined
    • Relationship between autophagy and IFN roles not fully separated
  7. 2017 Medium

    Broadened USP19's roles into DNA damage response and IFN control, showing nuclear translocation after irradiation with HDAC1/2 K63-chain editing, and TRAF3 K63-chain removal that suppresses type I IFN.

    Evidence Co-IP with linkage-specific ubiquitin analysis, IR-induced nuclear translocation, DNA damage readouts, IFN reporter assays

    PMID:27517492 PMID:28391724

    Open questions at the time
    • Signal driving nuclear translocation undefined
    • Single-lab observations for both substrates
  8. 2018 High

    Placed USP19 upstream of glucocorticoid receptor stability in muscle wasting and the MAPS secretion pathway upstream of HSC70/DNAJC5, integrating it into protein quality control and metabolic physiology.

    Evidence USP19 KO mice with GR restoration epistasis; subcellular fractionation, Co-IP, and secretion assays for MAPS

    PMID:29531792 PMID:29901692

    Open questions at the time
    • Direct GR substrate relationship vs indirect not resolved
    • How USP19 enzymatically acts within MAPS unclear
  9. 2020 High

    Provided the structural mechanism of USP19 regulation, showing tandem CS domains fold back to auto-inhibit the USP domain and that CS2 binding to the HSP90 NBD activates DUB activity.

    Evidence NMR solution structures of CS1, CS2, UbL domains with domain-interaction and DUB activity assays

    PMID:33094816

    Open questions at the time
    • Cellular triggers controlling the auto-inhibited–active transition not defined
    • Single structural study
  10. 2021 High

    Expanded USP19's mitochondrial and immune repertoire, defining FUNDC1 deubiquitination at ER–mitochondria contacts for hypoxia-induced fission, TBK1 degradation via chaperone-mediated autophagy, NLRP3 stabilization tied to M2 polarization, and RORγt K313 editing controlling Th17 cells.

    Evidence Co-IP, linkage/site-specific ubiquitination assays, GTPase and CMA component knockdowns, and multiple Usp19-/- mouse models

    PMID:33097834 PMID:33978709 PMID:34135062 PMID:34436957

    Open questions at the time
    • How a single DUB is partitioned across these distinct compartments unclear
    • Whether these roles share common regulatory inputs not established
  11. 2023 High

    Established isoform-determined directionality in TGF-β signaling, with the cytoplasmic isoform stabilizing TβRI to promote EMT and the ER isoform inhibiting signaling in a deubiquitination-independent manner.

    Evidence Isoform-specific overexpression/knockdown, Co-IP, cell-surface receptor quantification, SMAD and migration assays

    PMID:36646950

    Open questions at the time
    • Determinants of isoform expression ratio in vivo unknown
    • Mechanism of catalysis-independent ER sequestration undefined
  12. 2024 Medium

    Refined the regulation of USP19 itself in antiviral signaling, showing SIAH1 mediates K27-linked ubiquitination of USP19 at K489/K490/K610 to degrade it, relieving USP19-mediated MAVS K63-chain removal and IFN suppression.

    Evidence Co-IP, site- and linkage-specific ubiquitination assays, siRNA knockdown, IFN reporters

    PMID:38483060

    Open questions at the time
    • Temporal coordination of SIAH1 induction during infection not fully mapped
    • Single-lab finding
  13. 2025 Low

    Identified the auxiliary CS and UBL domains as SLiM-based protein interaction modules contributing to substrate recognition across the USP family.

    Evidence Proteomic-peptide phage display, peptide arrays, and affinity measurements (preprint)

    PMID:bio_10.1101_2025.09.22.676098

    Open questions at the time
    • USP19-specific functional validation limited
    • Specific substrates recognized via these SLiMs not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single enzyme achieves substrate selectivity and compartment-specific activity across its many reported targets, and which interactions are physiologically dominant versus context-restricted.
  • No unifying model of substrate recognition
  • Most non-immune substrates rest on single-lab Co-IP evidence
  • Relative in vivo importance of each axis 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 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3 R-HSA-1640170 Cell Cycle 2 R-HSA-162582 Signal Transduction 1
Partners
BECLIN-1FUNDC1HSC70HSP90MAVSSIAH1TAK1TBK1

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 USP19 stabilizes Beclin-1 by removing K11-linked ubiquitin chains at lysine 437, thereby promoting autophagy flux; USP19 also negatively regulates type I IFN signaling by blocking RIG-I–MAVS interaction in a Beclin-1-dependent manner. Co-immunoprecipitation, ubiquitin chain-linkage analysis, siRNA knockdown with autophagic flux and IFN signaling readouts The EMBO journal High 26988033
2008 USP19 interacts with and stabilizes the ubiquitin ligase KPC1 by deubiquitination, thereby lowering p27Kip1 levels and promoting G1-to-S phase progression; depletion of USP19 accumulates p27Kip1 and slows proliferation, which is rescued by KPC1 overexpression or p27 knockout. Co-immunoprecipitation, siRNA knockdown, cell-cycle analysis, proteasome inhibitor assays, genetic rescue with p27-/- cells Molecular and cellular biology High 19015242
2019 USP19 deubiquitinates TAK1 by removing K63- and K27-linked polyubiquitin chains in a TNF-α– and IL-1β–dependent manner, impairing TAK1 kinase activity and disrupting the TAK1–TAB2/3 complex, thereby inhibiting NF-κB activation; enzymatically inactive USP19 mutant has no effect. Co-immunoprecipitation, ubiquitin chain-linkage assays, overexpression of catalytic mutant, Usp19-/- mice, NF-κB reporter assays Journal of immunology High 31127032
2018 USP19 acts upstream of HSC70 and DNAJC5 in the misfolding-associated protein secretion (MAPS) pathway; as a membrane-associated protein preferentially localized to late endosomes/lysosomes, DNAJC5 chaperones MAPS client proteins (including misfolded cytosolic proteins) to the cell exterior. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, secretion assays Cell discovery High 29531792
2013 Endogenous USP19 is predominantly cytosolic and binds Hsp90 via its catalytic domain; USP19's transmembrane domain is partially retained in the cytosol through intramolecular interaction with its own catalytic domain, resulting in auto-inhibition of deubiquitinating activity. Overexpressed USP19 interacts with Derlin-1 and ERAD factors, but endogenous USP19 depletion has no significant effect on ERAD. Subcellular fractionation, co-immunoprecipitation, in vitro DUB activity assays, siRNA knockdown with ERAD substrate readouts The Journal of biological chemistry High 24356957
2011 USP19 interacts with c-IAP1 and c-IAP2; knockdown reduces c-IAP levels and enhances TNFα-induced apoptosis in a c-IAP-dependent manner. USP19 stabilizes c-IAPs primarily through deubiquitinase-independent mechanisms in vivo, though it can remove ubiquitin from c-IAPs in vitro. USP19 self-association facilitates its own stabilization via its DUB activity. Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, caspase activation assays The Journal of biological chemistry Medium 21849505
2011 USP19 interacts with HIF-1α and rescues it from proteasomal degradation independently of its catalytic activity; cells lacking USP19 fail to mount a proper hypoxic transcriptional response. Co-immunoprecipitation, catalytic mutant overexpression, hypoxia response assays, siRNA knockdown The Journal of biological chemistry Medium 22128162
2021 USP19, an ER-resident deubiquitinase, accumulates at ER–mitochondria contact sites under hypoxia and deubiquitinates FUNDC1, which facilitates Drp1 oligomerization and Drp1 GTP-binding/hydrolysis, thereby promoting hypoxia-induced mitochondrial fission. Co-immunoprecipitation, proximity ligation assay, GTPase activity assay, siRNA knockdown with mitochondrial morphology readouts The Journal of cell biology High 33978709
2021 USP19 promotes TBK1 degradation via chaperone-mediated autophagy (CMA) by interacting with TBK1 and facilitating its delivery to lysosomes through HSPA8/HSC70 and LAMP2A; USP19 deficiency elevates TBK1 and enhances type-I IFN signaling after viral infection. Co-immunoprecipitation, CMA inhibition (HSPA8/LAMP2A knockdown), siRNA knockdown, macrophage-specific KO mice, VSV infection model Autophagy High 34436957
2015 Only the ER-localized isoform of USP19 (USP19-ER) inhibits myoblast differentiation and fusion; USP19-ER suppresses CHOP induction during the unfolded protein response (UPR), and this inhibition requires USP19 catalytic activity. Mild ER stress (thapsigargin) reverses the fusion defect caused by USP19-ER overexpression. USP19-/- mice show enhanced muscle regeneration with elevated CHOP. Adenoviral overexpression of isoforms, siRNA knockdown, catalytic mutant, thapsigargin rescue, USP19-/- mice, myoblast fusion assays Molecular biology of the cell High 25568336
2016 The cytoplasmic isoform USP19_b (containing an EEVD motif) directly interacts with HSP90 via its N-terminal CS/P23 domains and upregulates polyglutamine-expanded ataxin-3 and huntingtin protein levels, promoting their aggregation; HSP90 mediates the effect of USP19 on polyQ substrate triage. Co-immunoprecipitation, domain-mapping pulldowns, overexpression/knockdown, aggregation assays in cell models PloS one Medium 26808260
2017 HSP90 binds the N-terminal amphipathic α-helix of huntingtin (Htt-N90) ahead of the polyQ tract; USP19 upregulates Htt-N90 protein levels and promotes aggregation, and disruption of the Htt-N90–HSP90 interaction attenuates the effect of USP19, indicating that HSP90 recruits USP19 to modulate Htt stability. Co-immunoprecipitation, domain-deletion mapping, overexpression/knockdown, aggregation assays Scientific reports Medium 29093475
2020 NMR solution structures of USP19 CS1, CS2, and UbL domains show that the tandem CS domains fold back intramolecularly to interact with the C-terminal USP domain (CS1 with embedded UbL; CS2 with CH2 catalytic core), causing auto-inhibition; CS2 specifically binds the NBD domain of HSP90, which activates USP19 DUB activity. NMR structure determination, domain interaction assays, DUB activity assays, cell-based polyQ aggregation readout The Biochemical journal High 33094816
2013 SIAH1 and SIAH2 ubiquitin ligases interact with USP19 via a SIAH-consensus binding motif in the unique N-terminal domain of USP19, promoting USP19 ubiquitylation and proteasome-dependent degradation. Yeast two-hybrid screen, co-immunoprecipitation, proteasome inhibitor assays, ubiquitination assays Biochemical and biophysical research communications Medium 23500468
2016 USP19 deubiquitinates HRD1 (an ERAD E3 ubiquitin ligase) by removing K48-linked ubiquitin chains, rescuing it from proteasomal degradation and stabilizing its steady-state levels. Co-immunoprecipitation, in vitro deubiquitination assay, K48 linkage-specific analysis, proteasome inhibitor assays International journal of molecular sciences Medium 27827840
2019 USP19 binds to the N-terminal EWS region of the EWS-FLI1 fusion oncoprotein and regulates its deubiquitination, stabilizing the fusion protein but not wild-type EWSR1 or FLI1; USP19 depletion reduces EWS-FLI1 levels and inhibits Ewing sarcoma cell growth in vitro and tumor growth in vivo. siRNA screening, co-immunoprecipitation, shRNA stable depletion, xenograft tumor model Scientific reports Medium 30700749
2017 USP19 physically interacts with HDAC1/2 and specifically removes K63-linked ubiquitin chains from HDAC1/2; USP19 translocates to the nucleus upon ionizing radiation, and is required for normal DNA damage response and prevention of anaphase bridge formation. Co-immunoprecipitation, ubiquitin linkage analysis, nuclear translocation assay (IR treatment), DNA damage readouts (γH2AX, bridge formation) Oncotarget Medium 27517492
2017 USP19 suppresses type I IFN signaling by targeting TRAF3 and reducing its K63-linked ubiquitination; USP19 expression is induced by EV71 infection. Co-immunoprecipitation, ubiquitination assay, IFN signaling reporter assays Future microbiology Medium 28391724
2021 USP19 inhibits NLRP3 inflammasome activation by increasing autophagy flux and decreasing mitochondrial ROS; separately, USP19 cleaves polyubiquitin chains from NLRP3, stabilizing it; USP19-stabilized NLRP3 directly associates with IRF4 and prevents its p62-mediated selective autophagic degradation, thereby promoting M2-like macrophage polarization. Usp19-/- mice show decreased M2 polarization and increased IL-1β. Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, ROS measurements, Usp19-/- mice with alum/chitin challenge Cellular & molecular immunology High 33097834
2022 USP19 deubiquitinates Nrf1 after its p97-mediated retrotranslocation from the ER membrane, removing ubiquitin moieties to prevent proteasomal degradation; USP19-/- cells show decreased Nrf1 abundance and reduced nuclear entry of active Nrf1, leading to downregulation of proteasomal subunit genes. Co-immunoprecipitation, deubiquitination assays, USP19 KO cell lines, proteasomal subunit expression readouts Biochimica et biophysica acta. Molecular cell research Medium 35613680
2021 USP19 removes K63-linked ubiquitin from RORγt at lysine 313, preventing SRC3 coactivator recruitment and thereby suppressing pathogenic Th17 cell differentiation; USP19-deficient mice show enhanced Th17-mediated autoimmune pathogenesis. Co-immunoprecipitation, site-specific ubiquitination assay (K313), in vitro differentiation assays, USP19-deficient mice in autoimmune models Journal of immunology High 34135062
2023 USP19 stabilizes YAP at K76 and K90 by removing K48- and K11-linked ubiquitin chains, identified via DUB siRNA library screen; USP19 knockdown reduces YAP protein and target gene expression and inhibits HCC proliferation and migration. DUB siRNA library screen, co-immunoprecipitation, site-specific ubiquitination assay, in vivo xenograft Cancer letters Medium 37832781
2021 USP19 exacerbates lipogenesis by deubiquitinating and stabilizing ME1 (malic enzyme 1), antagonizing RNF1-mediated ME1 degradation; ERK2 phosphorylation of ME1 at T103 enhances ME1 interaction with USP19 to prevent its polyubiquitination. Co-immunoprecipitation, ubiquitination assay, phosphorylation site mapping (T103), in vivo colorectal cancer models Cell reports Medium 34965422
2024 USP19 directly interacts with and stabilizes NEK9 via inhibition of K48-linked polyubiquitination at K525; NEK9 then phosphorylates Raptor (S792), linking USP19 to mTORC1 inhibition and autophagic cell death in pancreatic cancer cells. Co-immunoprecipitation, site-specific ubiquitination assay (K525), phosphorylation assay (Raptor S792), autophagic flux readouts Cell death and differentiation Medium 39627360
2024 USP19 deubiquitinates MGMT, preventing its degradation; depletion of USP19 reduces MGMT levels and sensitizes glioblastoma cells to temozolomide, rescued by MGMT overexpression. DUB panel screen, co-immunoprecipitation, deubiquitination assay, colony formation/tumor growth assays, genetic rescue CNS neuroscience & therapeutics Medium 38644551
2024 SIAH1 interacts with USP19 early after viral infection and mediates K27-linked ubiquitination of USP19 at residues K489, K490, and K610, targeting USP19 for proteasomal degradation. Additionally, USP19 directly interacts with MAVS and deubiquitinates its K63-linked ubiquitin chains to negatively regulate type I IFN signaling; SIAH1-mediated USP19 degradation reverses this inhibition. Co-immunoprecipitation, ubiquitination assays with linkage and site specificity, siRNA knockdown, IFN signaling reporter Journal of medical virology Medium 38483060
2023 USP19 interacts with and deubiquitinates BAG6, stabilizing it; BAG6 in turn promotes BCL2 ubiquitination and degradation, raising ER Ca2+ levels and inducing ER stress-mediated apoptosis in TNBC cells. Proteomics/co-immunoprecipitation, deubiquitination assay, Ca2+ flux assay, in vivo tumor model Clinical and translational medicine Medium 37700495
2023 USP19 cytoplasmic isoform (USP19-CY) stabilizes TGF-β type I receptor (TβRI) at the plasma membrane by direct interaction, promoting TGF-β/SMAD signaling and EMT; USP19-ER isoform sequesters TβRI in the ER and inhibits TGF-β signaling in a deubiquitination-independent manner. Isoform-specific overexpression/knockdown, co-immunoprecipitation, cell surface receptor quantification, SMAD signaling assays, migration/extravasation assays Cellular and molecular life sciences High 36646950
2022 USP19 deubiquitinates survivin, extending its half-life and stabilizing it; USP19 depletion causes cytokinesis failure and mitotic defects, and reduces tumor growth in xenograft. Co-immunoprecipitation, ubiquitination/half-life assay, CRISPR KO, mitotic phenotype analysis, xenograft Molecular therapy Medium 35918893
2022 USP19 interacts with phenylalanine hydroxylase (PAH) and prevents its polyubiquitination, extending its half-life and enhancing its enzymatic activity; overexpression of USP19 increases PAH protein and metabolic function. Co-immunoprecipitation, ubiquitination assay, half-life assay, PAH enzymatic activity measurement Cell biology and toxicology Medium 35449354
2023 USP19 inactivation in mice expressing A53T α-synuclein and injected with preformed fibrils results in decreased accumulation of phospho-synuclein aggregates, increased ubiquitination of oligomeric α-syn species (by immunoprecipitation), and reduced microglial activation; USP19 KO did not affect PFF uptake or aggregate propagation between neurons, suggesting USP19 modulates intracellular aggregate dynamics. USP19 KO mice, α-syn PFF injection model, immunoprecipitation of pSyn species, anti-ubiquitin staining, primary neuron culture with PFF NPJ Parkinson's disease Medium 38017009
2024 USP19 directly stabilizes PD-L1 by binding to its intracellular domain and preventing K48-linked ubiquitination and proteasomal degradation; USP19 deficiency enhances T cell-mediated cytotoxicity in colorectal cancer. CRISPR/Cas9 sgRNA library screen, co-immunoprecipitation, ubiquitination assay, co-culture T cell cytotoxicity assay, in vivo CRC model Pharmacological research Medium 40020887
2024 USP19 deubiquitinates SLC7A11 by removing K63-linked ubiquitin chains, preventing its degradation and thereby suppressing hepatocyte ferroptosis; USP19 overexpression reduces ischemia-reperfusion injury in a SLC7A11-dependent manner in mice. Ubiquitin enzyme screening, co-immunoprecipitation, deubiquitination assay (K63 linkage), SLC7A11-dependent rescue in vivo Advanced science Medium 39574305
2023 USP19 deubiquitinates FOXO1 (shown by co-IP in an in vitro SAH model), protecting it from degradation; FOXO1 transcriptionally activates IL-10, and the USP19/FOXO1/IL-10/IL-10R1 axis regulates microglial M1/M2 polarization. Co-immunoprecipitation (ubiquitination assay), luciferase/ChIP assay, SAH mouse model, microglial polarization readouts Redox biology Medium 37672892
2025 USP19 deubiquitinates and stabilizes DnaJC7; upregulation of USP19 and DnaJC7 disrupts the p53–MDM2 interaction, stabilizing p53 in cisplatin-treated ovarian cancer cells; USP19/DnaJC7 knockdown reduces p53 levels after cisplatin. Co-immunoprecipitation (protein-protein interaction database-guided), deubiquitination assay, p53-MDM2 co-IP disruption assay, siRNA knockdown Cells Medium 42193933
2025 USP19 deubiquitinates and stabilizes FUS; in neurons, USP19 overexpression preserves mitochondrial membrane potential, reduces mitochondrial ROS, suppresses DRP1 phosphorylation, and improves NAD+/NADH ratio; these effects are abolished by FUS knockdown, defining a USP19/FUS axis in mitochondrial homeostasis. Western blotting, actinomycin D chase, ubiquitination assay, AAV-mediated USP19 overexpression in trigeminal neuralgia mouse model, FUS siRNA rescue Experimental brain research Medium 41400721
2024 USP19 interacts with and stabilizes PARK7 (DJ-1) via deubiquitylation in DLBCL cells; PARK7 acts as a downstream effector of USP19 in regulating DLBCL cell growth. Co-immunoprecipitation/mass spectrometry, deubiquitination assay, adenovirus-based USP19 manipulation, genetic rescue with PARK7 The FEBS journal Medium 39240655
2025 USP19 transcription is activated by E2F1 (confirmed by ChIP and dual-luciferase assays); USP19 directly binds c-Myc and maintains its stability by removing ubiquitination; USP19 knockdown reduces c-Myc and suppresses HCC progression rescued by c-Myc overexpression. ChIP assay, dual-luciferase reporter, co-immunoprecipitation, ubiquitination assay, xenograft model Mutation research Medium 40020513
2015 In female mice, 17β-estradiol (E2) activates ERα binding to a half-estrogen response element (hERE) in intron 1 of the Usp19 gene to upregulate USP19 mRNA; USP19 knockdown in female (but not male) hindlimb muscle increases fiber size and ubiquitin conjugates, demonstrating female-specific regulation of muscle mass. Promoter reporter constructs, ChIP assay (ERα at hERE), siRNA knockdown in vivo, muscle mass/fiber size measurement The Journal of endocrinology Medium 25901042
2018 USP19 KO mice showed enhanced insulin signaling (lower circulating insulin, increased Akt/S6K phosphorylation in muscle) and reduced glucocorticoid receptor (GR) protein levels in muscle; restoring GR levels in USP19-deficient muscle abolished protection from myofiber atrophy, placing USP19 upstream of GR protein stability in glucocorticoid-mediated muscle wasting. USP19 KO mice, fasting/glucocorticoid treatment, protein expression analysis, adenoviral GR restoration (epistasis), glucose tolerance assays Endocrinology Medium 29901692
2026 USP19 negatively regulates TRAF6 by deubiquitinating it (stabilizing TRAF6); YY1 transcriptionally activates USP19 (confirmed by ChIP and luciferase assay), forming a YY1/USP19/TRAF6 axis that promotes microglial inflammation and M1 polarization. CHX stability assay, ubiquitination assay, ChIP assay, luciferase reporter, siRNA knockdown, ELISA, flow cytometry Neurochemical research Medium 41882442
2025 The auxiliary CS (CHORD/SGT1) and UBL domains of USP19 mediate SLiM-based protein interactions, contributing to substrate recognition; identified by proteomic-peptide phage display, peptide arrays, and affinity measurements across 29 USP auxiliary domains. Proteomic-peptide phage display, peptide arrays, affinity measurements bioRxivpreprint Low bio_10.1101_2025.09.22.676098

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. Cellular & molecular immunology 197 33097834
2016 USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. The EMBO journal 159 26988033
2019 USP19 Inhibits TNF-α- and IL-1β-Triggered NF-κB Activation by Deubiquitinating TAK1. Journal of immunology (Baltimore, Md. : 1950) 111 31127032
2018 DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins. Cell discovery 88 29531792
2008 USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1. Molecular and cellular biology 80 19015242
2004 USP19 is a ubiquitin-specific protease regulated in rat skeletal muscle during catabolic states. American journal of physiology. Endocrinology and metabolism 80 15562254
2011 The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. The Journal of biological chemistry 77 21849505
2011 Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1α (HIF-1α) during hypoxia. The Journal of biological chemistry 74 22128162
2013 Characterization of the deubiquitinating activity of USP19 and its role in endoplasmic reticulum-associated degradation. The Journal of biological chemistry 55 24356957
2021 USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites. The Journal of cell biology 52 33978709
2021 USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy. Autophagy 52 34436957
2011 Cigarette smoke-induced skeletal muscle atrophy is associated with up-regulation of USP-19 via p38 and ERK MAPKs. Journal of cellular biochemistry 52 21503966
2023 The deubiquitinating enzyme USP19 facilitates hepatocellular carcinoma progression through stabilizing YAP. Cancer letters 47 37832781
2023 Low-dose LPS alleviates early brain injury after SAH by modulating microglial M1/M2 polarization via USP19/FOXO1/IL-10/IL-10R1 signaling. Redox biology 40 37672892
2009 USP19-deubiquitinating enzyme regulates levels of major myofibrillar proteins in L6 muscle cells. American journal of physiology. Endocrinology and metabolism 39 19773579
2021 USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1. Cell reports 38 34965422
2016 Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone. PloS one 37 26808260
2015 USP19 deubiquitinating enzyme inhibits muscle cell differentiation by suppressing unfolded-protein response signaling. Molecular biology of the cell 37 25568336
2020 USP19 Enhances MMP2/MMP9-Mediated Tumorigenesis in Gastric Cancer. OncoTargets and therapy 34 32904569
2016 The BECN1-USP19 axis plays a role in the crosstalk between autophagy and antiviral immune responses. Autophagy 34 27096686
2017 HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19. Scientific reports 33 29093475
2019 USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth. Scientific reports 32 30700749
2015 Female-specific regulation of skeletal muscle mass by USP19 in young mice. The Journal of endocrinology 31 25901042
2018 The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice. Diabetologia 29 30386869
2017 USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability. Oncotarget 29 27517492
2016 USP19-Mediated Deubiquitination Facilitates the Stabilization of HRD1 Ubiquitin Ligase. International journal of molecular sciences 26 27827840
2011 Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. PloS one 26 21264218
2017 USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination. Future microbiology 25 28391724
2016 Deubiquitinating enzymes in skeletal muscle atrophy-An essential role for USP19. The international journal of biochemistry & cell biology 22 27475983
2018 Knockout of USP19 Deubiquitinating Enzyme Prevents Muscle Wasting by Modulating Insulin and Glucocorticoid Signaling. Endocrinology 20 29901692
2022 Dual role of deubiquitinating enzyme USP19 regulates mitotic progression and tumorigenesis by stabilizing survivin. Molecular therapy : the journal of the American Society of Gene Therapy 19 35918893
2023 Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition of breast cancer cells. Cellular and molecular life sciences : CMLS 16 36646950
2023 Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer. Clinical and translational medicine 16 37700495
2023 USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice. NPJ Parkinson's disease 14 38017009
2013 An N-terminal SIAH-interacting motif regulates the stability of the ubiquitin specific protease (USP)-19. Biochemical and biophysical research communications 13 23500468
2022 Activation of the membrane-bound Nrf1 transcription factor by USP19, a ubiquitin-specific protease C-terminally anchored in the endoplasmic reticulum. Biochimica et biophysica acta. Molecular cell research 12 35613680
2024 USP19 regulates DNA methylation damage repair and confers temozolomide resistance through MGMT stabilization. CNS neuroscience & therapeutics 10 38644551
2024 USP19 potentiates autophagic cell death via inhibiting mTOR pathway through deubiquitinating NEK9 in pancreatic cancer. Cell death and differentiation 10 39627360
2021 USP19 Suppresses Th17-Driven Pathogenesis in Autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 10 34135062
2024 SIAH1 modulates antiviral immune responses by targeting deubiquitinase USP19. Journal of medical virology 9 38483060
2024 Suppression of Hepatocyte Ferroptosis via USP19-Mediated Deubiquitination of SLC7A11 in Ischemia-Free Liver Transplantation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 8 39574305
2025 USP19 deficiency enhances T-cell-mediated antitumor immunity by promoting PD-L1 degradation in colorectal cancer. Pharmacological research 7 40020887
2023 USP19 Negatively Regulates p53 and Promotes Cervical Cancer Progression. Molecular biotechnology 6 37572221
2022 Deubiquitinase USP19 enhances phenylalanine hydroxylase protein stability and its enzymatic activity. Cell biology and toxicology 6 35449354
2020 Domain interactions reveal auto-inhibition of the deubiquitinating enzyme USP19 and its activation by HSP90 in the modulation of huntingtin aggregation. The Biochemical journal 6 33094816
2025 TIPE3 promotes drug resistance in colorectal cancer by enhancing autophagy via the USP19/Beclin1 pathway. Cell death discovery 5 40280943
2025 Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19. Cellular and molecular life sciences : CMLS 4 39948244
2024 Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein. Journal of Alzheimer's disease : JAD 4 38943386
2023 Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1. Open medicine (Warsaw, Poland) 4 37808166
2024 Proteomic Characterization of Ubiquitin Carboxyl-Terminal Hydrolase 19 Deficient Cells Reveals a Role for USP19 in the Secretion of Lysosomal Proteins. Molecular & cellular proteomics : MCP 3 39389361
2022 Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants. Scientific reports 3 35987969
2024 USP19 Stabilizes TAK1 to Regulate High Glucose/Free Fatty Acid-induced Dysfunction in HK-2 Cells. Current medical science 2 38967891
2025 E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma. Mutation research 1 40020513
2024 USP19 exerts a tumor-promoting role in diffuse large B cell lymphoma through stabilizing PARK7. The FEBS journal 1 39240655
2026 USP19 alleviates LPS-induced acute lung injury via inhibiting TAK1 activation. Biology direct 0 41821039
2026 YY1 Transcriptionally Activates USP19 to Mediate TRAF6 Deubiquitination to Promote Microglial Inflammation and M1 Polarization in Depression Development. Neurochemical research 0 41882442
2026 The USP19-DnaJC7 Axis Stabilizes p53 in Cisplatin-Treated Epithelial Ovarian Cancer. Cells 0 42193933
2026 Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging. The journals of gerontology. Series A, Biological sciences and medical sciences 0 42225593
2025 USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia. Experimental brain research 0 41400721
2024 The contribution and mechanism of hypoxia/USP19/Beclin-1 feed-forward loop in cervical cancer. Biophysical journal 0 38773770

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