{"gene":"USP19","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ubiquitin chain-linkage analysis, siRNA knockdown with autophagic flux and IFN signaling readouts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, site-specific mutagenesis (K437), multiple orthogonal functional readouts in one study; independently referenced in multiple follow-up papers","pmids":["26988033"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, cell-cycle analysis, proteasome inhibitor assays, genetic rescue with p27-/- cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis rescue, multiple orthogonal methods in one study","pmids":["19015242"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, ubiquitin chain-linkage assays, overexpression of catalytic mutant, Usp19-/- mice, NF-κB reporter assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, catalytic-mutant controls, in vivo KO validation","pmids":["31127032"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, secretion assays","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods establishing pathway order (USP19 → HSC70 → DNAJC5), localization confirmed by fractionation","pmids":["29531792"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Subcellular fractionation, co-immunoprecipitation, in vitro DUB activity assays, siRNA knockdown with ERAD substrate readouts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro DUB assay, fractionation, Co-IP, multiple orthogonal methods in one study; negative ERAD result explicitly established","pmids":["24356957"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, caspase activation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro DUB assay and Co-IP performed, but in vivo stabilization mechanism is deubiquitinase-independent and not fully defined","pmids":["21849505"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, catalytic mutant overexpression, hypoxia response assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with catalytic mutant control, functional hypoxia readout, single lab","pmids":["22128162"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, proximity ligation assay, GTPase activity assay, siRNA knockdown with mitochondrial morphology readouts","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, in vitro GTPase assay, localization at contact sites confirmed, multiple functional readouts","pmids":["33978709"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, CMA inhibition (HSPA8/LAMP2A knockdown), siRNA knockdown, macrophage-specific KO mice, VSV infection model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic validation (CMA component KD), in vivo KO model, multiple orthogonal methods","pmids":["34436957"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Adenoviral overexpression of isoforms, siRNA knockdown, catalytic mutant, thapsigargin rescue, USP19-/- mice, myoblast fusion assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific dissection, catalytic mutant controls, chemical rescue, in vivo KO validation","pmids":["25568336"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, domain-mapping pulldowns, overexpression/knockdown, aggregation assays in cell models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional aggregation assay, single lab","pmids":["26808260"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, domain-deletion mapping, overexpression/knockdown, aggregation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mapping, functional rescue, single lab","pmids":["29093475"],"is_preprint":false},{"year":2020,"finding":"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.","method":"NMR structure determination, domain interaction assays, DUB activity assays, cell-based polyQ aggregation readout","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structures with functional validation (DUB activity assay and cell assay), single lab","pmids":["33094816"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, proteasome inhibitor assays, ubiquitination assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus Co-IP plus degradation assay, single lab","pmids":["23500468"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, K48 linkage-specific analysis, proteasome inhibitor assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro DUB assay with linkage specificity, single lab","pmids":["27827840"],"is_preprint":false},{"year":2019,"finding":"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.","method":"siRNA screening, co-immunoprecipitation, shRNA stable depletion, xenograft tumor model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo xenograft, catalytic-active USP19 required for stabilization, single lab","pmids":["30700749"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, ubiquitin linkage analysis, nuclear translocation assay (IR treatment), DNA damage readouts (γH2AX, bridge formation)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with linkage specificity, localization experiment tied to functional consequence, single lab","pmids":["27517492"],"is_preprint":false},{"year":2017,"finding":"USP19 suppresses type I IFN signaling by targeting TRAF3 and reducing its K63-linked ubiquitination; USP19 expression is induced by EV71 infection.","method":"Co-immunoprecipitation, ubiquitination assay, IFN signaling reporter assays","journal":"Future microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitin assay with linkage specificity, single lab","pmids":["28391724"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, ROS measurements, Usp19-/- mice with alum/chitin challenge","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assays, in vivo KO validation, multiple orthogonal functional readouts","pmids":["33097834"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, deubiquitination assays, USP19 KO cell lines, proteasomal subunit expression readouts","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO cell validation, functional gene expression readout, single lab","pmids":["35613680"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, site-specific ubiquitination assay (K313), in vitro differentiation assays, USP19-deficient mice in autoimmune models","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination (K313), Co-IP, in vivo KO model, multiple functional readouts","pmids":["34135062"],"is_preprint":false},{"year":2023,"finding":"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.","method":"DUB siRNA library screen, co-immunoprecipitation, site-specific ubiquitination assay, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — screen-to-validation workflow, site-specific ubiquitin mapping, in vivo confirmation, single lab","pmids":["37832781"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, phosphorylation site mapping (T103), in vivo colorectal cancer models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation-ubiquitination crosstalk mapping, in vivo tumor models, single lab","pmids":["34965422"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, site-specific ubiquitination assay (K525), phosphorylation assay (Raptor S792), autophagic flux readouts","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific mapping, pathway epistasis via Raptor phosphorylation, single lab","pmids":["39627360"],"is_preprint":false},{"year":2024,"finding":"USP19 deubiquitinates MGMT, preventing its degradation; depletion of USP19 reduces MGMT levels and sensitizes glioblastoma cells to temozolomide, rescued by MGMT overexpression.","method":"DUB panel screen, co-immunoprecipitation, deubiquitination assay, colony formation/tumor growth assays, genetic rescue","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, genetic rescue, single lab","pmids":["38644551"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays with linkage and site specificity, siRNA knockdown, IFN signaling reporter","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination of USP19 (K489/490/610), Co-IP of USP19-MAVS, single lab","pmids":["38483060"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Proteomics/co-immunoprecipitation, deubiquitination assay, Ca2+ flux assay, in vivo tumor model","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, Ca2+ functional readout, single lab","pmids":["37700495"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Isoform-specific overexpression/knockdown, co-immunoprecipitation, cell surface receptor quantification, SMAD signaling assays, migration/extravasation assays","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific dissection, Co-IP, catalytic-independent mechanism established for USP19-ER, multiple functional readouts, single lab","pmids":["36646950"],"is_preprint":false},{"year":2022,"finding":"USP19 deubiquitinates survivin, extending its half-life and stabilizing it; USP19 depletion causes cytokinesis failure and mitotic defects, and reduces tumor growth in xenograft.","method":"Co-immunoprecipitation, ubiquitination/half-life assay, CRISPR KO, mitotic phenotype analysis, xenograft","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination/half-life assay, CRISPR KO with defined mitotic phenotype, single lab","pmids":["35918893"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, half-life assay, PAH enzymatic activity measurement","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, enzymatic activity readout, single lab","pmids":["35449354"],"is_preprint":false},{"year":2023,"finding":"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.","method":"USP19 KO mice, α-syn PFF injection model, immunoprecipitation of pSyn species, anti-ubiquitin staining, primary neuron culture with PFF","journal":"NPJ Parkinson's disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model, biochemical IP of ubiquitinated species, primary neuron experiments, single lab","pmids":["38017009"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR/Cas9 sgRNA library screen, co-immunoprecipitation, ubiquitination assay, co-culture T cell cytotoxicity assay, in vivo CRC model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen to mechanistic validation, Co-IP, ubiquitination linkage assay, in vivo model, single lab","pmids":["40020887"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Ubiquitin enzyme screening, co-immunoprecipitation, deubiquitination assay (K63 linkage), SLC7A11-dependent rescue in vivo","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific deubiquitination assay, in vivo genetic rescue, single lab","pmids":["39574305"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation (ubiquitination assay), luciferase/ChIP assay, SAH mouse model, microglial polarization readouts","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP ubiquitination assay, ChIP/luciferase for downstream pathway, in vivo mouse model, single lab","pmids":["37672892"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation (protein-protein interaction database-guided), deubiquitination assay, p53-MDM2 co-IP disruption assay, siRNA knockdown","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, mechanistic p53-MDM2 disruption assay, single lab","pmids":["42193933"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Western blotting, actinomycin D chase, ubiquitination assay, AAV-mediated USP19 overexpression in trigeminal neuralgia mouse model, FUS siRNA rescue","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination/stability assay, in vivo AAV model, genetic rescue with FUS KD, single lab","pmids":["41400721"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation/mass spectrometry, deubiquitination assay, adenovirus-based USP19 manipulation, genetic rescue with PARK7","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification, deubiquitination assay, functional epistasis rescue, single lab","pmids":["39240655"],"is_preprint":false},{"year":2025,"finding":"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.","method":"ChIP assay, dual-luciferase reporter, co-immunoprecipitation, ubiquitination assay, xenograft model","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP/luciferase for transcriptional regulation, Co-IP and ubiquitination assay for deubiquitination, genetic rescue, single lab","pmids":["40020513"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Promoter reporter constructs, ChIP assay (ERα at hERE), siRNA knockdown in vivo, muscle mass/fiber size measurement","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay establishing direct ERα binding, in vivo siRNA knockdown with physiological readout, single lab","pmids":["25901042"],"is_preprint":false},{"year":2018,"finding":"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.","method":"USP19 KO mice, fasting/glucocorticoid treatment, protein expression analysis, adenoviral GR restoration (epistasis), glucose tolerance assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO, genetic epistasis rescue with GR restoration, multiple signaling readouts, single lab","pmids":["29901692"],"is_preprint":false},{"year":2026,"finding":"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.","method":"CHX stability assay, ubiquitination assay, ChIP assay, luciferase reporter, siRNA knockdown, ELISA, flow cytometry","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP/luciferase for transcriptional link, ubiquitination/stability assay, functional M1 polarization readout, single lab","pmids":["41882442"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Proteomic-peptide phage display, peptide arrays, affinity measurements","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — large-scale screen identifying SLiM binding for USP19 auxiliary domains, but USP19-specific functional validation is limited in the abstract","pmids":["bio_10.1101_2025.09.22.676098"],"is_preprint":true}],"current_model":"USP19 is a deubiquitinating enzyme expressed as two major splice isoforms (ER-anchored USP19-ER and cytoplasmic USP19-CY) that remove specific polyubiquitin chain linkages (K11, K27, K48, K63) from a broad array of substrates—including Beclin-1, TAK1, FUNDC1, KPC1, HIF-1α, c-IAP1/2, NLRP3, TBK1, YAP, ME1, NEK9, survivin, HDAC1/2, TRAF3, MAVS, RORγt, SLC7A11, MGMT, and others—to regulate autophagy, innate immune signaling, mitochondrial dynamics, muscle atrophy, cell cycle progression, and protein quality control; its activity is auto-inhibited by intramolecular CS-domain interactions with the catalytic USP domain and is activated by HSP90 binding to the CS2 domain, while its own stability is controlled by SIAH1/2-mediated ubiquitination and proteasomal degradation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2008,"claim":"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","pmids":["19015242"],"confidence":"High","gaps":["Ubiquitin chain linkage on KPC1 not defined","Whether stabilization requires catalysis not fully resolved"]},{"year":2011,"claim":"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","pmids":["21849505","22128162"],"confidence":"Medium","gaps":["The deubiquitinase-independent stabilization mechanism is not molecularly defined","Single-lab observations"]},{"year":2013,"claim":"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","pmids":["23500468"],"confidence":"Medium","gaps":["Physiological conditions triggering SIAH-mediated turnover not established","Chain linkage not defined at this stage"]},{"year":2013,"claim":"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","pmids":["24356957"],"confidence":"High","gaps":["Structural detail of auto-inhibition not yet defined here","Physiological cytosolic substrates not enumerated"]},{"year":2015,"claim":"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","pmids":["25568336","25901042"],"confidence":"High","gaps":["Catalytic substrate(s) underlying CHOP suppression not identified","Mechanism of sex-specific transcriptional control beyond ERα binding unclear"]},{"year":2016,"claim":"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","pmids":["26988033"],"confidence":"High","gaps":["How USP19 selects K11 chains at K437 not defined","Relationship between autophagy and IFN roles not fully separated"]},{"year":2017,"claim":"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","pmids":["27517492","28391724"],"confidence":"Medium","gaps":["Signal driving nuclear translocation undefined","Single-lab observations for both substrates"]},{"year":2018,"claim":"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","pmids":["29901692","29531792"],"confidence":"High","gaps":["Direct GR substrate relationship vs indirect not resolved","How USP19 enzymatically acts within MAPS unclear"]},{"year":2020,"claim":"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","pmids":["33094816"],"confidence":"High","gaps":["Cellular triggers controlling the auto-inhibited–active transition not defined","Single structural study"]},{"year":2021,"claim":"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","pmids":["33978709","34436957","33097834","34135062"],"confidence":"High","gaps":["How a single DUB is partitioned across these distinct compartments unclear","Whether these roles share common regulatory inputs not established"]},{"year":2023,"claim":"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","pmids":["36646950"],"confidence":"High","gaps":["Determinants of isoform expression ratio in vivo unknown","Mechanism of catalysis-independent ER sequestration undefined"]},{"year":2024,"claim":"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","pmids":["38483060"],"confidence":"Medium","gaps":["Temporal coordination of SIAH1 induction during infection not fully mapped","Single-lab finding"]},{"year":2025,"claim":"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)","pmids":["bio_10.1101_2025.09.22.676098"],"confidence":"Low","gaps":["USP19-specific functional validation limited","Specific substrates recognized via these SLiMs not confirmed"]},{"year":null,"claim":"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.","evidence":"No single study in the corpus integrates substrate selection rules with isoform localization and HSP90-dependent activation","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,7,16,20,21,32]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,4,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,27]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,9,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,27]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,8,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8,17,18,20,25]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,13,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[27]}],"complexes":[],"partners":["HSP90","BECLIN-1","TAK1","FUNDC1","TBK1","MAVS","SIAH1","HSC70"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94966","full_name":"Ubiquitin carboxyl-terminal hydrolase 19","aliases":["Deubiquitinating enzyme 19","Ubiquitin thioesterase 19","Ubiquitin-specific-processing protease 19","Zinc finger MYND domain-containing protein 9"],"length_aa":1318,"mass_kda":145.7,"function":"Deubiquitinating enzyme that regulates the degradation of various proteins by removing ubiquitin moieties, thereby preventing their proteasomal degradation. Stabilizes RNF123, which promotes CDKN1B degradation and contributes to cell proliferation (By similarity). Decreases the levels of ubiquitinated proteins during skeletal muscle formation and acts to repress myogenesis. Modulates transcription of major myofibrillar proteins. Also involved in turnover of endoplasmic-reticulum-associated degradation (ERAD) substrates (PubMed:19465887, PubMed:24356957). Mechanistically, deubiquitinates and thereby stabilizes several E3 ligases involved in the ERAD pathway including SYVN1 or MARCHF6 (PubMed:24356957). Regulates the stability of other E3 ligases including BIRC2/c-IAP1 and BIRC3/c-IAP2 by preventing their ubiquitination (PubMed:21849505). Required for cells to mount an appropriate response to hypoxia by rescuing HIF1A from degradation in a non-catalytic manner and by mediating the deubiquitination of FUNDC1 (PubMed:22128162, PubMed:33978709). Attenuates mitochondrial damage and ferroptosis by targeting and stabilizing NADPH oxidase 4/NOX4 (PubMed:38943386). Negatively regulates TNF- and IL-1beta-triggered NF-kappa-B activation by hydrolyzing 'Lys-27'- and 'Lys-63'-linked polyubiquitin chains from MAP3K7 (PubMed:31127032). Modulates also the protein level and aggregation of polyQ-expanded huntingtin/HTT through HSP90AA1 (PubMed:33094816)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O94966/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP19","classification":"Not Classified","n_dependent_lines":83,"n_total_lines":1208,"dependency_fraction":0.06870860927152318},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"G3BP1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"HSP90AA1","stoichiometry":0.2},{"gene":"HSP90AB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/USP19","total_profiled":1310},"omim":[{"mim_id":"614472","title":"RING FINGER PROTEIN 123; RNF123","url":"https://www.omim.org/entry/614472"},{"mim_id":"614471","title":"UBIQUITIN-SPECIFIC PROTEASE 19; USP19","url":"https://www.omim.org/entry/614471"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP19"},"hgnc":{"alias_symbol":["KIAA0891","ZMYND9"],"prev_symbol":[]},"alphafold":{"accession":"O94966","domains":[{"cath_id":"2.60.40.790","chopping":"115-201","consensus_level":"medium","plddt":83.1425,"start":115,"end":201},{"cath_id":"2.60.40.790","chopping":"281-374","consensus_level":"high","plddt":88.8934,"start":281,"end":374},{"cath_id":"3.90.70.10","chopping":"499-678_1092-1214","consensus_level":"high","plddt":89.6346,"start":499,"end":1214},{"cath_id":"3.10.20.90","chopping":"681-785_836-874_987-1050","consensus_level":"medium","plddt":91.0346,"start":681,"end":1050}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94966","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94966-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94966-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP19","jax_strain_url":"https://www.jax.org/strain/search?query=USP19"},"sequence":{"accession":"O94966","fasta_url":"https://rest.uniprot.org/uniprotkb/O94966.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94966/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94966"}},"corpus_meta":[{"pmid":"33097834","id":"PMC_33097834","title":"USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy.","date":"2020","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33097834","citation_count":197,"is_preprint":false},{"pmid":"26988033","id":"PMC_26988033","title":"USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26988033","citation_count":159,"is_preprint":false},{"pmid":"31127032","id":"PMC_31127032","title":"USP19 Inhibits TNF-α- and IL-1β-Triggered NF-κB Activation by Deubiquitinating TAK1.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31127032","citation_count":111,"is_preprint":false},{"pmid":"29531792","id":"PMC_29531792","title":"DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29531792","citation_count":88,"is_preprint":false},{"pmid":"19015242","id":"PMC_19015242","title":"USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19015242","citation_count":80,"is_preprint":false},{"pmid":"15562254","id":"PMC_15562254","title":"USP19 is a ubiquitin-specific protease regulated in rat skeletal muscle during catabolic states.","date":"2004","source":"American journal of physiology. 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Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/37808166","citation_count":4,"is_preprint":false},{"pmid":"39948244","id":"PMC_39948244","title":"Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39948244","citation_count":4,"is_preprint":false},{"pmid":"35987969","id":"PMC_35987969","title":"Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35987969","citation_count":3,"is_preprint":false},{"pmid":"39389361","id":"PMC_39389361","title":"Proteomic Characterization of Ubiquitin Carboxyl-Terminal Hydrolase 19 Deficient Cells Reveals a Role for USP19 in the Secretion of Lysosomal Proteins.","date":"2024","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/39389361","citation_count":3,"is_preprint":false},{"pmid":"38967891","id":"PMC_38967891","title":"USP19 Stabilizes TAK1 to Regulate High Glucose/Free Fatty Acid-induced Dysfunction in HK-2 Cells.","date":"2024","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/38967891","citation_count":2,"is_preprint":false},{"pmid":"39240655","id":"PMC_39240655","title":"USP19 exerts a tumor-promoting role in diffuse large B cell lymphoma through stabilizing PARK7.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/39240655","citation_count":1,"is_preprint":false},{"pmid":"40020513","id":"PMC_40020513","title":"E2F1 activates USP19 to affect the stability of c-Myc to facilitate the progression of hepatocellular carcinoma.","date":"2025","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/40020513","citation_count":1,"is_preprint":false},{"pmid":"38773770","id":"PMC_38773770","title":"The contribution and mechanism of hypoxia/USP19/Beclin-1 feed-forward loop in cervical cancer.","date":"2024","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/38773770","citation_count":0,"is_preprint":false},{"pmid":"42193933","id":"PMC_42193933","title":"The USP19-DnaJC7 Axis Stabilizes p53 in Cisplatin-Treated Epithelial Ovarian Cancer.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/42193933","citation_count":0,"is_preprint":false},{"pmid":"41400721","id":"PMC_41400721","title":"USP19 restores mitochondrial function in neurons by deubiquitinating FUS to alleviate trigeminal neuralgia.","date":"2025","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/41400721","citation_count":0,"is_preprint":false},{"pmid":"41821039","id":"PMC_41821039","title":"USP19 alleviates LPS-induced acute lung injury via inhibiting TAK1 activation.","date":"2026","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/41821039","citation_count":0,"is_preprint":false},{"pmid":"42225593","id":"PMC_42225593","title":"Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging.","date":"2026","source":"The journals of gerontology. Series A, Biological sciences and medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42225593","citation_count":0,"is_preprint":false},{"pmid":"41882442","id":"PMC_41882442","title":"YY1 Transcriptionally Activates USP19 to Mediate TRAF6 Deubiquitination to Promote Microglial Inflammation and M1 Polarization in Depression Development.","date":"2026","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/41882442","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.22.676098","title":"Systematic Discovery of Motif-based Interactions of the Auxiliary Domains of USP Family Deubiquitinases","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.676098","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31139,"output_tokens":9928,"usd":0.121168,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20176,"output_tokens":4748,"usd":0.10979,"stage2_stop_reason":"end_turn"},"total_usd":0.230958,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain-linkage analysis, siRNA knockdown with autophagic flux and IFN signaling readouts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, site-specific mutagenesis (K437), multiple orthogonal functional readouts in one study; independently referenced in multiple follow-up papers\",\n      \"pmids\": [\"26988033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell-cycle analysis, proteasome inhibitor assays, genetic rescue with p27-/- cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19015242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain-linkage assays, overexpression of catalytic mutant, Usp19-/- mice, NF-κB reporter assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, catalytic-mutant controls, in vivo KO validation\",\n      \"pmids\": [\"31127032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, secretion assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods establishing pathway order (USP19 → HSC70 → DNAJC5), localization confirmed by fractionation\",\n      \"pmids\": [\"29531792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, in vitro DUB activity assays, siRNA knockdown with ERAD substrate readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro DUB assay, fractionation, Co-IP, multiple orthogonal methods in one study; negative ERAD result explicitly established\",\n      \"pmids\": [\"24356957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, caspase activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro DUB assay and Co-IP performed, but in vivo stabilization mechanism is deubiquitinase-independent and not fully defined\",\n      \"pmids\": [\"21849505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, catalytic mutant overexpression, hypoxia response assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with catalytic mutant control, functional hypoxia readout, single lab\",\n      \"pmids\": [\"22128162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, GTPase activity assay, siRNA knockdown with mitochondrial morphology readouts\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, in vitro GTPase assay, localization at contact sites confirmed, multiple functional readouts\",\n      \"pmids\": [\"33978709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CMA inhibition (HSPA8/LAMP2A knockdown), siRNA knockdown, macrophage-specific KO mice, VSV infection model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic validation (CMA component KD), in vivo KO model, multiple orthogonal methods\",\n      \"pmids\": [\"34436957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Adenoviral overexpression of isoforms, siRNA knockdown, catalytic mutant, thapsigargin rescue, USP19-/- mice, myoblast fusion assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific dissection, catalytic mutant controls, chemical rescue, in vivo KO validation\",\n      \"pmids\": [\"25568336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldowns, overexpression/knockdown, aggregation assays in cell models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional aggregation assay, single lab\",\n      \"pmids\": [\"26808260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping, overexpression/knockdown, aggregation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mapping, functional rescue, single lab\",\n      \"pmids\": [\"29093475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"NMR structure determination, domain interaction assays, DUB activity assays, cell-based polyQ aggregation readout\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structures with functional validation (DUB activity assay and cell assay), single lab\",\n      \"pmids\": [\"33094816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, proteasome inhibitor assays, ubiquitination assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus Co-IP plus degradation assay, single lab\",\n      \"pmids\": [\"23500468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, K48 linkage-specific analysis, proteasome inhibitor assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro DUB assay with linkage specificity, single lab\",\n      \"pmids\": [\"27827840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA screening, co-immunoprecipitation, shRNA stable depletion, xenograft tumor model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo xenograft, catalytic-active USP19 required for stabilization, single lab\",\n      \"pmids\": [\"30700749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin linkage analysis, nuclear translocation assay (IR treatment), DNA damage readouts (γH2AX, bridge formation)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with linkage specificity, localization experiment tied to functional consequence, single lab\",\n      \"pmids\": [\"27517492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP19 suppresses type I IFN signaling by targeting TRAF3 and reducing its K63-linked ubiquitination; USP19 expression is induced by EV71 infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, IFN signaling reporter assays\",\n      \"journal\": \"Future microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitin assay with linkage specificity, single lab\",\n      \"pmids\": [\"28391724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, ROS measurements, Usp19-/- mice with alum/chitin challenge\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assays, in vivo KO validation, multiple orthogonal functional readouts\",\n      \"pmids\": [\"33097834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assays, USP19 KO cell lines, proteasomal subunit expression readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO cell validation, functional gene expression readout, single lab\",\n      \"pmids\": [\"35613680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination assay (K313), in vitro differentiation assays, USP19-deficient mice in autoimmune models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination (K313), Co-IP, in vivo KO model, multiple functional readouts\",\n      \"pmids\": [\"34135062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"DUB siRNA library screen, co-immunoprecipitation, site-specific ubiquitination assay, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — screen-to-validation workflow, site-specific ubiquitin mapping, in vivo confirmation, single lab\",\n      \"pmids\": [\"37832781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, phosphorylation site mapping (T103), in vivo colorectal cancer models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation-ubiquitination crosstalk mapping, in vivo tumor models, single lab\",\n      \"pmids\": [\"34965422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination assay (K525), phosphorylation assay (Raptor S792), autophagic flux readouts\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific mapping, pathway epistasis via Raptor phosphorylation, single lab\",\n      \"pmids\": [\"39627360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP19 deubiquitinates MGMT, preventing its degradation; depletion of USP19 reduces MGMT levels and sensitizes glioblastoma cells to temozolomide, rescued by MGMT overexpression.\",\n      \"method\": \"DUB panel screen, co-immunoprecipitation, deubiquitination assay, colony formation/tumor growth assays, genetic rescue\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, genetic rescue, single lab\",\n      \"pmids\": [\"38644551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with linkage and site specificity, siRNA knockdown, IFN signaling reporter\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination of USP19 (K489/490/610), Co-IP of USP19-MAVS, single lab\",\n      \"pmids\": [\"38483060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics/co-immunoprecipitation, deubiquitination assay, Ca2+ flux assay, in vivo tumor model\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, Ca2+ functional readout, single lab\",\n      \"pmids\": [\"37700495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Isoform-specific overexpression/knockdown, co-immunoprecipitation, cell surface receptor quantification, SMAD signaling assays, migration/extravasation assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific dissection, Co-IP, catalytic-independent mechanism established for USP19-ER, multiple functional readouts, single lab\",\n      \"pmids\": [\"36646950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP19 deubiquitinates survivin, extending its half-life and stabilizing it; USP19 depletion causes cytokinesis failure and mitotic defects, and reduces tumor growth in xenograft.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination/half-life assay, CRISPR KO, mitotic phenotype analysis, xenograft\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination/half-life assay, CRISPR KO with defined mitotic phenotype, single lab\",\n      \"pmids\": [\"35918893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, half-life assay, PAH enzymatic activity measurement\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, enzymatic activity readout, single lab\",\n      \"pmids\": [\"35449354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"USP19 KO mice, α-syn PFF injection model, immunoprecipitation of pSyn species, anti-ubiquitin staining, primary neuron culture with PFF\",\n      \"journal\": \"NPJ Parkinson's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model, biochemical IP of ubiquitinated species, primary neuron experiments, single lab\",\n      \"pmids\": [\"38017009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 sgRNA library screen, co-immunoprecipitation, ubiquitination assay, co-culture T cell cytotoxicity assay, in vivo CRC model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen to mechanistic validation, Co-IP, ubiquitination linkage assay, in vivo model, single lab\",\n      \"pmids\": [\"40020887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Ubiquitin enzyme screening, co-immunoprecipitation, deubiquitination assay (K63 linkage), SLC7A11-dependent rescue in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific deubiquitination assay, in vivo genetic rescue, single lab\",\n      \"pmids\": [\"39574305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (ubiquitination assay), luciferase/ChIP assay, SAH mouse model, microglial polarization readouts\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP ubiquitination assay, ChIP/luciferase for downstream pathway, in vivo mouse model, single lab\",\n      \"pmids\": [\"37672892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (protein-protein interaction database-guided), deubiquitination assay, p53-MDM2 co-IP disruption assay, siRNA knockdown\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, mechanistic p53-MDM2 disruption assay, single lab\",\n      \"pmids\": [\"42193933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Western blotting, actinomycin D chase, ubiquitination assay, AAV-mediated USP19 overexpression in trigeminal neuralgia mouse model, FUS siRNA rescue\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination/stability assay, in vivo AAV model, genetic rescue with FUS KD, single lab\",\n      \"pmids\": [\"41400721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, deubiquitination assay, adenovirus-based USP19 manipulation, genetic rescue with PARK7\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification, deubiquitination assay, functional epistasis rescue, single lab\",\n      \"pmids\": [\"39240655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, co-immunoprecipitation, ubiquitination assay, xenograft model\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/luciferase for transcriptional regulation, Co-IP and ubiquitination assay for deubiquitination, genetic rescue, single lab\",\n      \"pmids\": [\"40020513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Promoter reporter constructs, ChIP assay (ERα at hERE), siRNA knockdown in vivo, muscle mass/fiber size measurement\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay establishing direct ERα binding, in vivo siRNA knockdown with physiological readout, single lab\",\n      \"pmids\": [\"25901042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"USP19 KO mice, fasting/glucocorticoid treatment, protein expression analysis, adenoviral GR restoration (epistasis), glucose tolerance assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO, genetic epistasis rescue with GR restoration, multiple signaling readouts, single lab\",\n      \"pmids\": [\"29901692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"CHX stability assay, ubiquitination assay, ChIP assay, luciferase reporter, siRNA knockdown, ELISA, flow cytometry\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/luciferase for transcriptional link, ubiquitination/stability assay, functional M1 polarization readout, single lab\",\n      \"pmids\": [\"41882442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic-peptide phage display, peptide arrays, affinity measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — large-scale screen identifying SLiM binding for USP19 auxiliary domains, but USP19-specific functional validation is limited in the abstract\",\n      \"pmids\": [\"bio_10.1101_2025.09.22.676098\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"USP19 is a deubiquitinating enzyme expressed as two major splice isoforms (ER-anchored USP19-ER and cytoplasmic USP19-CY) that remove specific polyubiquitin chain linkages (K11, K27, K48, K63) from a broad array of substrates—including Beclin-1, TAK1, FUNDC1, KPC1, HIF-1α, c-IAP1/2, NLRP3, TBK1, YAP, ME1, NEK9, survivin, HDAC1/2, TRAF3, MAVS, RORγt, SLC7A11, MGMT, and others—to regulate autophagy, innate immune signaling, mitochondrial dynamics, muscle atrophy, cell cycle progression, and protein quality control; its activity is auto-inhibited by intramolecular CS-domain interactions with the catalytic USP domain and is activated by HSP90 binding to the CS2 domain, while its own stability is controlled by SIAH1/2-mediated ubiquitination and proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2, #7, #9]. It is expressed as ER-anchored and cytoplasmic isoforms whose differential localization dictates opposing outcomes: in TGF-\\u03b2 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 [#27], and only the ER isoform inhibits myoblast differentiation by suppressing CHOP during the unfolded protein response [#9]. 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 [#12, #10, #11, #4]. Mechanistically, USP19 acts both as a classical chain-trimming DUB\\u2014removing K48-, K11-, K63- and K27-linked chains from substrates including Beclin-1, TAK1, FUNDC1, ROR\\u03b3t, YAP, and SLC7A11 [#0, #2, #7, #20, #21, #32]\\u2014and through deubiquitinase-independent stabilization of partners such as c-IAP1/2 and HIF-1\\u03b1 [#5, #6]. 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 [#8, #17, #25, #18]. Its own abundance is constrained by SIAH1/SIAH2-mediated ubiquitination and proteasomal degradation through a motif in its unique N-terminal domain [#13, #25]. USP19 is also implicated in misfolding-associated protein secretion, acting upstream of HSC70 and DNAJC5 to export cytosolic misfolded proteins [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"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\\u2013p27Kip1 axis.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, cell-cycle analysis, and genetic rescue in p27-/- cells\",\n      \"pmids\": [\"19015242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain linkage on KPC1 not defined\", \"Whether stabilization requires catalysis not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that USP19 can stabilize substrates (c-IAP1/2, HIF-1\\u03b1) independently of its catalytic activity, distinguishing chain-trimming from scaffold-like protective functions.\",\n      \"evidence\": \"Co-IP, in vitro DUB assays, catalytic-mutant overexpression, and apoptosis/hypoxia readouts with siRNA knockdown\",\n      \"pmids\": [\"21849505\", \"22128162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The deubiquitinase-independent stabilization mechanism is not molecularly defined\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, proteasome inhibitor and ubiquitination assays\",\n      \"pmids\": [\"23500468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions triggering SIAH-mediated turnover not established\", \"Chain linkage not defined at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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\\u2013catalytic domain interaction; ERAD involvement was a property of overexpression only.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, in vitro DUB activity assays, siRNA knockdown with ERAD substrate readouts\",\n      \"pmids\": [\"24356957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of auto-inhibition not yet defined here\", \"Physiological cytosolic substrates not enumerated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Adenoviral isoform overexpression, catalytic mutants, thapsigargin rescue, USP19-/- mice, ChIP for ER\\u03b1 at the Usp19 promoter\",\n      \"pmids\": [\"25568336\", \"25901042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic substrate(s) underlying CHOP suppression not identified\", \"Mechanism of sex-specific transcriptional control beyond ER\\u03b1 binding unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitin chain-linkage analysis, site-specific mutagenesis, autophagic flux and IFN signaling readouts\",\n      \"pmids\": [\"26988033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP19 selects K11 chains at K437 not defined\", \"Relationship between autophagy and IFN roles not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP with linkage-specific ubiquitin analysis, IR-induced nuclear translocation, DNA damage readouts, IFN reporter assays\",\n      \"pmids\": [\"27517492\", \"28391724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal driving nuclear translocation undefined\", \"Single-lab observations for both substrates\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"USP19 KO mice with GR restoration epistasis; subcellular fractionation, Co-IP, and secretion assays for MAPS\",\n      \"pmids\": [\"29901692\", \"29531792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GR substrate relationship vs indirect not resolved\", \"How USP19 enzymatically acts within MAPS unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"NMR solution structures of CS1, CS2, UbL domains with domain-interaction and DUB activity assays\",\n      \"pmids\": [\"33094816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular triggers controlling the auto-inhibited\\u2013active transition not defined\", \"Single structural study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded USP19's mitochondrial and immune repertoire, defining FUNDC1 deubiquitination at ER\\u2013mitochondria contacts for hypoxia-induced fission, TBK1 degradation via chaperone-mediated autophagy, NLRP3 stabilization tied to M2 polarization, and ROR\\u03b3t K313 editing controlling Th17 cells.\",\n      \"evidence\": \"Co-IP, linkage/site-specific ubiquitination assays, GTPase and CMA component knockdowns, and multiple Usp19-/- mouse models\",\n      \"pmids\": [\"33978709\", \"34436957\", \"33097834\", \"34135062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single DUB is partitioned across these distinct compartments unclear\", \"Whether these roles share common regulatory inputs not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established isoform-determined directionality in TGF-\\u03b2 signaling, with the cytoplasmic isoform stabilizing T\\u03b2RI to promote EMT and the ER isoform inhibiting signaling in a deubiquitination-independent manner.\",\n      \"evidence\": \"Isoform-specific overexpression/knockdown, Co-IP, cell-surface receptor quantification, SMAD and migration assays\",\n      \"pmids\": [\"36646950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of isoform expression ratio in vivo unknown\", \"Mechanism of catalysis-independent ER sequestration undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, site- and linkage-specific ubiquitination assays, siRNA knockdown, IFN reporters\",\n      \"pmids\": [\"38483060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Temporal coordination of SIAH1 induction during infection not fully mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the auxiliary CS and UBL domains as SLiM-based protein interaction modules contributing to substrate recognition across the USP family.\",\n      \"evidence\": \"Proteomic-peptide phage display, peptide arrays, and affinity measurements (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.22.676098\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"USP19-specific functional validation limited\", \"Specific substrates recognized via these SLiMs not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No single study in the corpus integrates substrate selection rules with isoform localization and HSP90-dependent activation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 7, 16, 20, 21, 32]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 4, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 9, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 27]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 8, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8, 17, 18, 20, 25]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 13, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSP90\", \"Beclin-1\", \"TAK1\", \"FUNDC1\", \"TBK1\", \"MAVS\", \"SIAH1\", \"HSC70\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}