{"gene":"USP15","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1999,"finding":"Recombinant USP15 demonstrated ubiquitin-specific protease activity against engineered linear fusions of ubiquitin to beta-galactosidase and glutathione S-transferase, and can cleave the ubiquitin-proline bond. USP15 protein consists of 952 amino acids and contains conserved Cys and His boxes present in all UBP family members.","method":"In vitro deubiquitinase activity assay with recombinant protein against linear ubiquitin fusion substrates","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution, replicated in mouse ortholog paper (PMID:12532266)","pmids":["10444327"],"is_preprint":false},{"year":2005,"finding":"USP15 co-purifies with the human COP9 signalosome (CSN) complex. A novel zinc finger in USP15 is essential for cleavage of poly-ubiquitin chains; mutation of a single conserved cysteine in the Zn-binding motif abolishes poly-Ub substrate degradation and reduces tetra-Ub binding. Wild-type but not Zn-finger-mutant USP15 stabilizes the E3 ligase Rbx1 by reversing its poly/autoubiquitination.","method":"Co-purification, pulldown with tetra-Ub, site-directed mutagenesis, cotransfection ubiquitination assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with biochemical assays (pulldown, activity assay) in single lab with multiple orthogonal methods","pmids":["16005295"],"is_preprint":false},{"year":2009,"finding":"USP15 stabilizes APC (adenomatous polyposis coli) protein in the context of the COP9 signalosome-associated complex. Knockdown of USP15 or overexpression of a catalytically inactive USP15 mutant accelerates APC proteolysis, demonstrating that CSN-associated USP15 protects APC from ubiquitin-mediated degradation.","method":"siRNA knockdown, overexpression of catalytically inactive mutant, Western blot for APC stability","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal approaches (siRNA and dominant-negative mutant), single lab","pmids":["19576224"],"is_preprint":false},{"year":2009,"finding":"USP15 interacts with HPV16 E6 protein (identified by tandem affinity purification). Overexpression of USP15 increases E6 protein levels and siRNA-mediated knockdown of USP15 decreases E6 protein levels, implicating USP15 in stabilization of E6 through deubiquitylation.","method":"Tandem affinity purification, siRNA knockdown, overexpression, Western blot","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with protein stability readout, single lab","pmids":["19553310"],"is_preprint":false},{"year":2011,"finding":"USP15 is a deubiquitylating enzyme for receptor-activated SMADs (R-SMADs: SMAD1, 2, 3). USP15 primarily opposes R-SMAD monoubiquitylation at DNA-binding domains, which normally prevents promoter recognition. USP15 is required for TGF-β and BMP responses in mammalian cells and Xenopus embryos and is necessary for SMAD complex occupancy of endogenous target promoters.","method":"siRNA knockdown, overexpression, ChIP, in vitro deubiquitylation assays, Xenopus embryo knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deubiquitylation assay combined with ChIP and genetic knockdown in multiple model systems","pmids":["21947082"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the USP15 N-terminal DUSP and UBL domains at 1.5 Å resolution reveals an 80 Å elongated arrangement with the DU domains aligned in tandem, connected through a β-hairpin (DU finger) that forms an intricate hydrogen-bonding network. The UBL domain is monomeric in solution and unlikely to act as a ubiquitin mimic.","method":"X-ray crystallography, analytical ultracentrifugation, SAXS, gel filtration","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure validated by multiple biophysical methods in single study","pmids":["21848306"],"is_preprint":false},{"year":2012,"finding":"USP15 binds to the SMAD7-SMURF2 complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to enhanced TGF-β signaling. Identified via functional RNAi screen; downregulation or inhibition of USP15 decreases TGF-β activity in patient-derived orthotopic mouse glioblastoma models.","method":"Functional RNAi screen, Co-IP, in vitro deubiquitylation, orthotopic mouse model with patient-derived cells","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deubiquitylation assay plus in vivo mouse model, replicated by subsequent studies","pmids":["22344298"],"is_preprint":false},{"year":2012,"finding":"USP15 interacts with the E3 ligase BRAP/IMP through the N-terminal DUSP-UBL domain of USP15 and the coiled-coil region of BRAP. USP15 opposes BRAP autoubiquitylation and stabilizes BRAP protein through its catalytic activity. USP15 depletion destabilizes BRAP via proteasomal degradation, reduces CRAF levels, and decreases MAPK signaling amplitude in response to EGF and PDGF.","method":"Co-IP, domain mapping, catalytically inactive mutant rescue, siRNA knockdown, Western blot, EGF/PDGF stimulation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and catalytic mutant rescue, single lab","pmids":["23105109"],"is_preprint":false},{"year":2013,"finding":"USP15 stabilizes newly synthesized REST (RE1-silencing transcription factor) by antagonizing its polyubiquitylation in a catalytic-activity-dependent manner. USP15 specifically promotes de novo REST synthesis (associates with polysomes) rather than protecting pre-existing REST, and is required for rapid accumulation of newly synthesized REST at mitotic exit.","method":"siRNA screening, polysome fractionation, cycloheximide chase, ubiquitination assays, cell cycle analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (polysome fractionation, ubiquitination assay, cell cycle) in single lab","pmids":["23708518"],"is_preprint":false},{"year":2013,"finding":"USP15 specifically deubiquitinates Keap1 (not Nrf2 directly), which promotes incorporation of deubiquitinated Keap1 into the Keap1-Cul3-E3 ligase complex, enhancing complex stability and enzymatic activity. This leads to increased Nrf2 protein degradation and reduced Nrf2 target gene expression, suppressing the antioxidant response.","method":"In vitro deubiquitylation assay, co-immunoprecipitation, siRNA knockdown, Western blot, reporter gene assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitylation combined with co-IP and functional reporter assays, single lab with multiple orthogonal methods","pmids":["23727018"],"is_preprint":false},{"year":2014,"finding":"USP15 stabilizes the E3 ubiquitin ligase MDM2 through deubiquitination. USP15-stabilized MDM2 negatively regulates T cell activation by targeting NFATc2 for degradation. USP15 deficiency promotes T cell activation and enhances antitumor T cell responses. USP15 also stabilizes MDM2 in cancer cells to regulate p53 function.","method":"Co-IP, in vitro deubiquitylation assay, USP15 knockout mice, T cell activation assays, tumor challenge models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deubiquitylation assay combined with knockout mouse models and in vivo tumor challenge","pmids":["24777531"],"is_preprint":false},{"year":2014,"finding":"USP15 opposes Parkin-mediated mitophagy by counteracting Parkin-mediated mitochondrial ubiquitination. USP15 does not affect Parkin ubiquitination status or Parkin translocation to mitochondria, but specifically counteracts ubiquitination of outer mitochondrial membrane proteins. A catalytically inactive version of USP15 does not oppose mitophagy. Knockdown of USP15 rescues the mitophagy defect in PD patient fibroblasts with PARK2 mutations.","method":"siRNA knockdown, catalytically inactive mutant, mitophagy assays, patient fibroblasts, Drosophila parkin RNAi rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including patient fibroblasts and Drosophila genetic rescue, single lab","pmids":["24852371"],"is_preprint":false},{"year":2014,"finding":"USP15 deubiquitylates TRIM25, preventing LUBAC-dependent K48-linked polyubiquitylation and proteasomal degradation of TRIM25. USP15 was identified as an interaction partner of TRIM25 by protein purification and mass spectrometry. Wild-type but not catalytically inactive USP15 reduces K48-linked ubiquitylation of TRIM25, stabilizes it, and enhances TRIM25- and RIG-I-dependent type I IFN production.","method":"Affinity purification, mass spectrometry, Co-IP, siRNA knockdown, overexpression of catalytically inactive mutant, IFN reporter assays, viral replication assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identification by MS plus mechanistic biochemical assays with catalytic mutant, replicated in neuroinflammation study","pmids":["24399297"],"is_preprint":false},{"year":2014,"finding":"USP15 identifies and deubiquitylates monoubiquitinated histone H2B (ubH2B). In the nucleus, USP15 indirectly associates with the ubH2B E3 ligase RNF20/RNF40, and directly associates with SART3 (TIP110/p110). SART3 acts as a histone chaperone that enhances USP15 binding to ubH2B and facilitates deubiquitination of free ubH2B histones.","method":"Affinity purification with nonhydrolyzable ubH2B mimic, Co-IP, in vitro deubiquitination assay with SART3","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — affinity purification with substrate mimic combined with in vitro activity assay and Co-IP, single lab with multiple orthogonal methods","pmids":["24526689"],"is_preprint":false},{"year":2014,"finding":"USP15 deubiquitylates ALK3/BMPR1A (BMP type I receptor) by interacting with SMAD6, an inhibitory SMAD that recruits E3 ubiquitin ligases to ALK3. USP15 reduces K48-linked polyubiquitylation of ALK3, enhances BMP-induced SMAD1 phosphorylation, and promotes BMP target gene transcription. Loss of USP15 inhibits BMP-induced osteoblast differentiation in myoblasts and modulates BMP signaling in Xenopus embryos.","method":"Co-IP, RNAi depletion, ubiquitination assay, SMAD1 phosphorylation assay, BMP target gene reporter, Xenopus embryo experiments","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, in vitro signaling) in mammalian cells and Xenopus, single lab","pmids":["24850914"],"is_preprint":false},{"year":2015,"finding":"USP15 deubiquitinates SMURF2 at Lys734, a residue required for SMURF2 catalytic activity. This results in enhanced TβR-I stability and downstream TGF-β pathway activation. Proteomic analysis identified SMURF2 as a USP15 target in addition to TβR-I.","method":"Proteomic mass spectrometry, Co-IP, in vitro deubiquitination assay, mutational analysis of Lys734","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS identification of ubiquitination site plus biochemical validation, single lab","pmids":["26435193"],"is_preprint":false},{"year":2015,"finding":"USP4, USP15, and USP11 arose by whole genome and small-scale duplications in vertebrate evolution. Viability of mice is contingent on a functional copy of either USP4 or USP15 (genetic redundancy established by cross-breeding mice with inactivating mutations in both genes).","method":"Phylogenetic and syntenic reconstruction, genetic crosses of Usp4/Usp15 mutant mice","journal":"BMC evolutionary biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis through mouse crosses, single study","pmids":["26503449"],"is_preprint":false},{"year":2016,"finding":"USP15 co-expressed with and functionally acts together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses. The USP15L749R mutation in mice dampens type I interferon responses in brain and hematopoietic cells, protecting against experimental cerebral malaria and EAE neuroinflammation.","method":"ENU-mutagenesis mouse model, immunophenotyping, RNA sequencing, in situ neuroinflammation models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic mouse model with two distinct neuroinflammation disease models and mechanistic pathway assignment","pmids":["27721430"],"is_preprint":false},{"year":2016,"finding":"TGF-β promotes translation of USP15 through activation of mTOR via the PI3K/AKT pathway. Upregulated USP15 then binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells.","method":"Co-IP, ubiquitination assay, PI3K/AKT/mTOR pathway inhibitors, Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitination assay with pathway inhibitor validation, single lab","pmids":["27893708"],"is_preprint":false},{"year":2016,"finding":"Structural basis for SART3 recruitment of USP15: crystal structures of SART3 alone and in complex with USP15 DUSP-UBL domain at 2.0 and 3.0 Å respectively reveal SART3 contains 12 HAT repeats in two subdomains, dimerizes through HAT-C concave surface, and binds USP15 in a novel bipartite mode on the HAT-C convex surface. USP15 binds SART3 ~20-fold more tightly than USP4.","method":"X-ray crystallography, isothermal titration calorimetry, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures with ITC and mutagenesis validation, single study","pmids":["27255711"],"is_preprint":false},{"year":2017,"finding":"USP15, together with its substrate-targeting factor SART3, deubiquitinates PRP31 (a U4 snRNP component). PRP31 is modified with K63-linked ubiquitin chains by the PRP19 complex. USP15-SART3 forms a complex with USP4, and this ternary complex also deubiquitinates PRP3. The ubiquitination/deubiquitination status of PRP31 regulates its interaction with U5 snRNP component PRP8, required for efficient splicing of chromosome segregation-related genes.","method":"Co-IP, in vitro deubiquitination assay, ubiquitin linkage-specific analysis, splicing assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitination plus Co-IP and functional splicing assays, single lab","pmids":["28088760"],"is_preprint":false},{"year":2017,"finding":"The long isoform of USP15 (containing exon 7-encoded serine-rich stretch) preferentially recognizes and deubiquitylates mysterin/RNF213 (a large ubiquitin ligase associated with moyamoya disease), while the short isoform does not. Exon 7 skipping alters substrate specificity of USP15 isoforms, with only partially overlapping interactomes.","method":"Isoform-specific pulldown, deubiquitylation assay, mass spectrometry interactome comparison","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical assay comparing two isoforms with MS interactome, single lab","pmids":["28276505"],"is_preprint":false},{"year":2017,"finding":"USP15 interacts with and deubiquitinates SLIM1 (skeletal muscle LIM protein 1), increasing SLIM1 protein levels. Cardiac-specific overexpression of USP15 in transgenic mice induces cardiac remodeling with elevated heart weight/body weight ratios and upregulation of fetal gene markers, associated with increased endogenous SLIM1 levels.","method":"Cell-free binding, co-immunoprecipitation, in vitro deubiquitination, transgenic mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo transgenic mouse functional model, single lab","pmids":["21219870"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of the USP15 catalytic core domain reveals a canonical USP fold (finger, palm, thumb regions) but with a misaligned catalytic triad — catalytic cysteine ~10 Å from catalytic histidine, an inactive configuration. Active-site loops are flexible, creating a largely open ubiquitin tail-binding channel. USP15 displays lower monoubiquitin affinity than paralog USP4. Mitoxantrone weakly inhibits USP15 and binds the S1' site.","method":"X-ray crystallography, isothermal titration calorimetry, enzyme inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with ITC and inhibition assay in single rigorous study","pmids":["30228188"],"is_preprint":false},{"year":2018,"finding":"USP15 deubiquitylates BARD1 BRCT domain upon recruitment to DNA double-strand breaks (DSBs) by MDC1. Recruitment requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. USP15-mediated BARD1 deubiquitylation promotes BARD1-HP1γ interaction, retaining BRCA1/BARD1 at DSBs and promoting homologous recombination (HR). USP15 knockout mice exhibit genomic instability.","method":"Co-IP, phospho-mutant analysis, BARD1 deubiquitylation assay, HR assay, USP15 KO mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deubiquitylation assay combined with domain mapping, KO mice genomic instability, multiple orthogonal methods, single lab","pmids":["30874560"],"is_preprint":false},{"year":2018,"finding":"USP15 deubiquitylates topoisomerase IIα (TOP2A), and USP15 depletion leads to decreased TOP2A accumulation, formation of anaphase chromosome bridges, and micronuclei indicating genome instability. Both USP15 isoforms move from cytoplasm to nucleus at prophase; isoform-1 is phosphorylated on S229 at mitotic entry and an S229D phospho-mimetic cannot rescue TOP2A accumulation or the micronuclei phenotype, demonstrating isoform-specific phospho-regulation.","method":"siRNA depletion, phospho-mutant rescue, live-cell imaging, cell cycle analysis, ubiquitination assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, ubiquitination assay, phospho-mimetic rescue) in single lab","pmids":["29429988"],"is_preprint":false},{"year":2018,"finding":"HPV16 E6 oncoprotein forms a complex with TRIM25 and USP15 in human cells. In the presence of E6, K48-linked ubiquitination of TRIM25 is markedly increased and TRIM25 degradation is enhanced, and E6 inhibits TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS.","method":"Co-IP, ubiquitination assay, CRISPR-Cas9 knockout in keratinocytes, IFN reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and CRISPR genetic validation, single lab","pmids":["29263274"],"is_preprint":false},{"year":2019,"finding":"Ubiquitin variants (UbVs) targeting either the USP15 catalytic domain or each of three adaptor domains (including the DUSP domain) inhibit USP15 catalytic activity. A linear dimer UbV targeting both DUSP and catalytic domains shows enhanced specificity. Crystal structures show three distinct UbVs bind the catalytic domain and lock the active site in a closed, inactive conformation; one UbV forms an unusual strand-swapped dimer binding two DUSP domains simultaneously. In cells, UbVs inhibit deubiquitination of SMURF2 and TRIM25 substrates.","method":"Protein engineering (UbVs), X-ray crystallography, cell-based deubiquitination assays, TGF-β pathway assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of inhibitor complexes combined with cell-based substrate deubiquitination assays, single rigorous study","pmids":["30713027"],"is_preprint":false},{"year":2019,"finding":"The ER-located E3 ligase Hrd1 interacts with USP15 and ubiquitinates it. Unlike classical Hrd1 substrates, USP15 is not degraded but loses its deubiquitinating activity toward IκBα, resulting in excessive NF-κB activation. This represents a non-canonical Hrd1 function linking ER-plasma membrane signaling during bacterial TLR4 responses.","method":"E3 ligase screen (>280 ligases), Co-IP, ubiquitination assay, IκBα deubiquitination assay, macrophage-specific Hrd1 KO mice, LPS-sepsis model","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical activity assay plus in vivo KO mouse validation with epistasis experiments, single lab","pmids":["31477895"],"is_preprint":false},{"year":2019,"finding":"USP15 phosphorylation at Thr149 and Thr219 (identified by nuclear-cytoplasmic fractionation and mass spectrometry) occurs in the cytoplasm. The phosphorylation status alters interaction with SART3, leading to nuclear localization and deubiquitinating activity toward spliceosomal substrate PRP31. Treatment with CDK inhibitor purvalanol A induces nuclear translocation of USP15.","method":"Subcellular fractionation, mass spectrometry, phospho-mutant analysis, Co-IP, in vitro deubiquitination assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS identification of phosphosites combined with functional mutant analysis and localization assay, single lab","pmids":["31330151"],"is_preprint":false},{"year":2019,"finding":"USP15 deubiquitylates and stabilizes HECTD1 E3 ubiquitin ligase in glioblastoma cells. USP15 expression attenuates canonical WNT pathway activity in a manner dependent on HECTD1; depletion of USP15 reduces HECTD1 protein levels. USP15 interaction with HECTD1 was identified by mass spectrometry.","method":"Mass spectrometry protein network analysis, Co-IP, ubiquitination assay, WNT reporter assay, soft agar colony formation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based discovery with Co-IP, ubiquitination assay, and functional pathway reporter, single lab","pmids":["29299163"],"is_preprint":false},{"year":2020,"finding":"USP15 deubiquitylates and inactivates TET2 by removing K1299-linked monoubiquitin, which normally promotes TET2 activity. Deletion of Usp15 in melanoma cells stimulates chemokine expression and tumor-infiltrating lymphocyte accumulation in a TET2-dependent manner, leading to increased immunotherapy response.","method":"Co-IP, in vitro deubiquitylation assay, gene expression profiling, Usp15 KO melanoma model, immunotherapy challenge","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitylation of specific site combined with in vivo KO model and TET2 epistasis rescue, single lab","pmids":["32948596"],"is_preprint":false},{"year":2020,"finding":"USP15 potentiates NF-κB activation upon TNFα or IL-1β stimulation by stabilizing TAB2 and TAB3 through different mechanisms: (1) catalytic-activity-dependent deubiquitination of K48-linked TAB2 ubiquitin chains; (2) catalytic-activity-independent inhibition of lysosome-mediated TAB2 degradation; (3) catalytic-activity-independent inhibition of NBR1-mediated selective autophagic TAB3 degradation.","method":"Co-IP, ubiquitination assay, overexpression/knockdown of USP15, catalytically inactive mutant, NF-κB reporter, lysosome/autophagy inhibitor experiments","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal mechanistic experiments (ubiquitination, lysosome, autophagy) in single lab","pmids":["31903660"],"is_preprint":false},{"year":2020,"finding":"UBE2S recruits USP15 to TBK1 to remove K63-linked polyubiquitin chains from TBK1, thereby inhibiting TBK1 activation and type I IFN production. UBE2S-mediated inhibition of IFN is independent of its E2/E3 enzymatic activity but requires USP15 recruitment.","method":"Co-IP, ubiquitination assay (K63 linkage-specific), USP15 knockdown, viral replication assays in vitro and in vivo","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay with in vivo validation, single lab","pmids":["32814047"],"is_preprint":false},{"year":2020,"finding":"TIFAB regulates USP15 ubiquitin hydrolase activity (acts as an effector/activator of USP15). Expression of TIFAB in hematopoietic stem/progenitor cells permits USP15 signaling to substrates MDM2 and KEAP1, mitigating p53 expression. TIFAB-deficient HSPCs exhibit compromised USP15 signaling and are sensitized to hematopoietic stress by derepression of p53.","method":"Proteomics, co-IP, USP15 activity assays, genetic knockdown/overexpression in HSPCs, MLL-AF9 leukemia model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification combined with functional USP15 activity assay and leukemia model, single lab","pmids":["32101751"],"is_preprint":false},{"year":2020,"finding":"USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, in leukemia cells. USP15 is essential for HSC maintenance in vitro and in vivo (transplantation and Usp15 KO mice), and its depletion in leukemia cells impairs expansion and increases genotoxic stress.","method":"Co-IP, shRNA in vivo screen, Usp15 KO mice, transplantation assays, genotoxic stress assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying FUS interaction combined with in vivo KO model, single lab","pmids":["33378683"],"is_preprint":false},{"year":2020,"finding":"USP15 deubiquitinates CARD9, constitutively associating with it and removing TRIM62-deposited ubiquitin marks. USP15 knockdown and knockout specifically enhance CARD9-dependent C-type lectin receptor (CLR) signaling in mouse and human immune cells.","method":"Co-IP, ubiquitination assay, siRNA knockdown, CRISPR KO, CLR signaling assays","journal":"ImmunoHorizons","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and genetic KO validation in two species' immune cells, single lab","pmids":["33093067"],"is_preprint":false},{"year":2021,"finding":"USP15 deubiquitinates and stabilizes glutamine synthetase (GS) and CRL4CRBN neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4 by antagonizing CRL4CRBN-mediated ubiquitylation. USP15 is highly expressed in IMiD-resistant myeloma cells and depletion sensitizes these cells to lenalidomide.","method":"Ubiquitination assays, Western blot for substrate stability, siRNA depletion, lenalidomide sensitivity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple substrate deubiquitination assays with pharmacological validation, single lab","pmids":["34583995"],"is_preprint":false},{"year":2021,"finding":"USP15 deubiquitinates and stabilizes p53-R175H gain-of-function mutant through a lysosome-mediated pathway. USP15 is established as a selective upstream regulator of p53-R175H stability distinct from wild-type p53 regulation.","method":"Chemical genetic approach (MCB-613), siRNA knockdown, CRISPR, ubiquitination assay, lysosome pathway assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and chemical validation with ubiquitination assay, single lab","pmids":["29593334"],"is_preprint":false},{"year":2021,"finding":"USP15 deubiquitinates TUT1 (terminal uridylyl transferase 1) and causes redistribution of TUT1 from nucleolus to nucleoplasm, stabilizing U6 snRNA. Usp15 knockout mice show impaired motor ability and unconventional cerebellar formation. Inhibition of the USP15-TUT1 cascade triggers mild chronic ER stress.","method":"Co-IP, ubiquitination assay, immunofluorescence localization, Usp15 KO mice, U6 snRNA stability assay, ER stress markers","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo KO with functional RNA metabolism readout, single lab","pmids":["32839293"],"is_preprint":false},{"year":2021,"finding":"USP15 deubiquitinates and stabilizes ERα (estrogen receptor alpha) by removing K48-linked ubiquitin, promoting ERα+ breast cancer cell proliferation. USP15 knockdown reduces ERα protein levels and enhances tamoxifen antitumor activity.","method":"Co-IP, ubiquitination assay (K48 linkage-specific), siRNA knockdown, in vitro and in vivo proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay with in vivo tumor model, single lab","pmids":["33771975"],"is_preprint":false},{"year":2021,"finding":"USP15 deubiquitinates BECN1 (Beclin-1), interacting with BECN1 but not TRAF6, thereby attenuating TRAF6-BECN1 axis-driven autophagy induction. USP15-knockout lung cancer cells show increased cancer migration and invasion with enhanced autophagy in response to TLR4 stimulation.","method":"Co-IP, deubiquitination assay, CRISPR-Cas9 KO cell lines, migration/invasion assays, autophagy assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitination assay with CRISPR KO phenotypic validation, single lab","pmids":["35422093"],"is_preprint":false},{"year":2022,"finding":"USP15 interacts with and promotes cGAS activation through deubiquitylation of cGAS and promotion of cGAS dimerization and liquid condensation via the USP15 intrinsic disordered region (IDR). In the absence of DNA, USP15 drives cGAS liquid condensation preparing cGAS for rapid DNA response.","method":"Co-IP, in vitro deubiquitylation assay, liquid-liquid phase separation assay, IDR deletion mutant analysis, cGAS activation assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multiple biochemical methods (deubiquitylation, phase separation) in single lab","pmids":["36243958"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of USP15 D1D2 catalytic domain in a catalytically competent conformation shows the active site can switch between active and inactive states independently of mitoxantrone binding. Mitoxantrone contributes to crystal packing by forming a stack of 12 molecules at the S1' site rather than inducing catalytic triad misalignment.","method":"X-ray crystallography (multiple crystal structures), comparative structural analysis","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures directly resolving active/inactive conformations with structural comparison, single rigorous study","pmids":["35605756"],"is_preprint":false},{"year":2023,"finding":"USP15 interacts with and deubiquitinates PARP1 to promote its stability, stimulating DNA repair, genomic stability, and TNBC cell proliferation. ER inhibits USP15 expression at the promoter level, PR suppresses USP15 deubiquitinase activity, and HER2 abrogates the PARP1-USP15 interaction — explaining elevated PARP1 in TNBC where all three receptors are absent.","method":"Co-IP, in vitro deubiquitination assay, ChIP, USP15 activity assay in presence of PR, Co-IP in presence of HER2, TNBC cell proliferation/DNA repair assays","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical deubiquitination assay combined with three distinct mechanistic inhibition experiments and clinical context, single lab with multiple orthogonal methods","pmids":["37012401"],"is_preprint":false},{"year":2023,"finding":"The CRL3gigaxonin E3 ligase and USP15 form an opposing regulatory pathway governing destruction of neurofilament proteins NEFL and INA. USP15 antagonizes CRL3GIG-mediated ubiquitylation of NEFL and INA. A specific degron (NEFLL12) in neurofilament proteins is required for CRL3GIG binding; mutations in the GIG Kelch domain (L309R, R545C, C570Y) disrupt NEFL/INA binding causing accumulation of NF proteins as in giant axonal neuropathy.","method":"Ubiquitination assays, Co-IP, degron mapping, mutant GIG binding assays, proteasome degradation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple substrate ubiquitination assays with degron mapping and disease-relevant mutation analysis, single lab","pmids":["37903270"],"is_preprint":false},{"year":2023,"finding":"USP15 deubiquitinates SMYD3, stabilizing it and enabling H3K4me3-mediated transcriptional activation of CCL2. This promotes MDSC recruitment to tumors and immune evasion in colorectal cancer. USP15 inhibition improves anti-PD-1 efficacy in colorectal cancer models.","method":"Co-IP, deubiquitination assay, H3K4me3 ChIP, MDSC recruitment assays, orthotopic/metastatic colon tumor models, PD-1 blockade combination","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitination and ChIP with in vivo tumor model, single lab","pmids":["40323348"],"is_preprint":false},{"year":2023,"finding":"USP15 interacts with and deubiquitinates YAP1, inhibiting K48-linked ubiquitination of YAP1 and stabilizing it. USP15 also binds TAZ after hypoxia treatment. USP15 promotes PASMC proliferation and migration in a YAP1/TAZ-dependent manner, contributing to pulmonary vascular remodeling.","method":"Co-IP, ubiquitination assay (K48 linkage), USP15 knockdown (AAV-mediated in vivo), YAP1/TAZ rescue experiments, SuHx and MCT mouse models","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and linkage-specific ubiquitination assay with in vivo disease model, single lab","pmids":["36635430"],"is_preprint":false},{"year":2024,"finding":"USP15 deubiquitinates HKDC1 (a glycolytic regulator), inhibiting its ubiquitination-mediated degradation and thereby regulating glucose metabolism and glycolytic activity in gastric cancer cells.","method":"Co-IP, ubiquitination assay, USP15 knockdown/overexpression, glycolytic activity assays, xenograft models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay with functional metabolic readout, single lab","pmids":["39164728"],"is_preprint":false},{"year":2024,"finding":"TRIM21 E3 ligase and USP15 antagonistically regulate ACSL4 protein stability in gastrointestinal stromal tumors (GISTs); TRIM21-mediated ubiquitination decreases ACSL4 while USP15 opposes this, and the balance determines imatinib sensitivity.","method":"Co-IP, ubiquitination assay, Western blot for ACSL4 stability, shRNA, xenograft model, GIST patient clinical data","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay with in vivo model and clinical correlation, single lab","pmids":["38182686"],"is_preprint":false}],"current_model":"USP15 is a cysteine deubiquitylase (DUB) belonging to the USP subfamily that associates constitutively with the COP9 signalosome (CSN) and the spliceosome recycling factor SART3, and acts on a broad set of substrates including TβR-I, SMURF2, R-SMADs, ALK3/BMPR1A, TRIM25, BARD1, MDM2, Keap1, PARP1, TET2, TOP2A, CARD9, TBK1, cGAS, YAP1, PRP31, H2B, and many others; its catalytic activity depends on a zinc finger motif and a catalytic triad that can adopt active or inactive conformations, and its substrate specificity and nuclear/cytoplasmic localization are regulated by phosphorylation (at Thr149/Thr219 by CDKs, and Ser678) and isoform-specific alternative splicing of exon 7, collectively placing USP15 as a central reversible-ubiquitylation switch in TGF-β/BMP signaling, innate immune/interferon responses, DNA damage repair (HR), mitophagy, splicing, and cell cycle progression."},"narrative":{"mechanistic_narrative":"USP15 is a cysteine deubiquitylase of the USP family that functions as a reversible-ubiquitylation switch across signaling, genome-maintenance, immune, and RNA-processing pathways by cleaving ubiquitin from a broad set of substrates [PMID:10444327, PMID:22344298]. Its catalytic core adopts a canonical USP fold whose catalytic triad can toggle between aligned (active) and misaligned (inactive) configurations, and an N-terminal DUSP-UBL module forms an elongated tandem arrangement that mediates substrate-targeting interactions [PMID:21848306, PMID:30228188, PMID:35605756]; a zinc-finger motif is required for poly-ubiquitin chain cleavage [PMID:16005295]. Substrate selection and nuclear/cytoplasmic distribution are governed by adaptor binding and phosphorylation: the spliceosome recycling factor SART3 recruits USP15 in a bipartite mode to deliver it to nuclear substrates, while CDK-type phosphorylation at Thr149/Thr219 and isoform-specific events control SART3 association and nuclear translocation [PMID:27255711, PMID:31330151, PMID:29429988]. In TGF-β/BMP signaling USP15 stabilizes the type I receptors TβR-I and ALK3/BMPR1A and acts on SMURF2 and receptor-activated SMADs to potentiate pathway output [PMID:21947082, PMID:22344298, PMID:24850914, PMID:26435193]. It controls innate immunity bidirectionally, stabilizing TRIM25 to enhance RIG-I-dependent type I IFN yet removing activating ubiquitin from TBK1, cGAS, and CARD9, and deubiquitylating IκBα and TAB2/TAB3 to tune NF-κB [PMID:24399297, PMID:27721430, PMID:32814047, PMID:33093067, PMID:36243958, PMID:31477895, PMID:31903660]. At DNA double-strand breaks phospho-Ser678 USP15 is recruited by MDC1 to deubiquitylate BARD1 and promote homologous recombination, and it stabilizes TOP2A and PARP1 to safeguard genomic stability, with USP15-null mice showing genomic instability [PMID:30874560, PMID:29429988, PMID:37012401]. USP15 additionally regulates oxidative-stress (Keap1/Nrf2) and p53 axes via MDM2, opposes Parkin-driven mitophagy, and participates in spliceosomal deubiquitylation of PRP31/PRP3 together with SART3 and USP15's paralog USP4 [PMID:23727018, PMID:24777531, PMID:24852371, PMID:28088760]. Mouse viability requires a functional copy of either USP15 or its paralog USP4, indicating genetic redundancy [PMID:26503449].","teleology":[{"year":1999,"claim":"Established that USP15 is a bona fide ubiquitin-specific protease, defining its core enzymatic identity.","evidence":"in vitro deubiquitinase assay with recombinant protein against linear ubiquitin fusion substrates","pmids":["10444327"],"confidence":"High","gaps":["No physiological substrate identified","Chain-linkage preference not addressed","No structural basis for catalysis"]},{"year":2005,"claim":"Linked USP15 to the COP9 signalosome and showed a zinc-finger motif is required for poly-ubiquitin chain cleavage and for stabilizing an E3 ligase, moving beyond minimal substrates to E3-protective roles.","evidence":"co-purification, tetra-Ub pulldown, Zn-finger mutagenesis, cotransfection ubiquitination assay (Rbx1)","pmids":["16005295"],"confidence":"High","gaps":["Endogenous CSN-dependent substrate repertoire unmapped","Stoichiometry within CSN unknown"]},{"year":2011,"claim":"Defined USP15 as a positive regulator of TGF-β/BMP signaling by reversing R-SMAD monoubiquitylation required for promoter occupancy, and resolved the elongated DUSP-UBL architecture.","evidence":"in vitro deubiquitylation, ChIP, knockdown in cells and Xenopus; X-ray/SAXS of DUSP-UBL","pmids":["21947082","21848306"],"confidence":"High","gaps":["How DUSP-UBL selects SMAD substrates unresolved","Catalytic-domain structure not yet solved"]},{"year":2012,"claim":"Showed USP15 acts at the receptor level of TGF-β signaling by deubiquitylating TβR-I via the SMAD7-SMURF2 complex, with in vivo relevance to glioblastoma.","evidence":"RNAi screen, Co-IP, in vitro deubiquitylation, patient-derived orthotopic mouse model; plus BRAP/MAPK study","pmids":["22344298","23105109"],"confidence":"High","gaps":["Direct vs SMURF2-mediated effect on receptor not fully separated","Selectivity among receptor-complex components unclear"]},{"year":2013,"claim":"Expanded USP15 substrates into oxidative-stress and transcription control, deubiquitylating Keap1 to suppress Nrf2 and stabilizing newly synthesized REST.","evidence":"in vitro deubiquitylation, Co-IP, reporter assays, polysome fractionation, cycloheximide chase","pmids":["23727018","23708518"],"confidence":"High","gaps":["Mechanism coupling USP15 to translation/polysomes unknown","Cell-type specificity of Keap1 effect not defined"]},{"year":2014,"claim":"Demonstrated broad regulatory reach — stabilizing MDM2 to restrain T-cell/p53 responses, opposing Parkin mitophagy, stabilizing TRIM25 for IFN, deubiquitylating histone H2B via SART3, and targeting ALK3 in BMP signaling — establishing USP15 as a multi-pathway DUB.","evidence":"in vitro deubiquitylation, KO mice, mitophagy and patient-fibroblast assays, MS, SART3 in vitro assays, Xenopus","pmids":["24777531","24852371","24399297","24526689","24850914"],"confidence":"High","gaps":["Determinants of substrate choice across pathways unknown","Whether one localization pool serves all substrates unclear"]},{"year":2015,"claim":"Refined the TGF-β mechanism by identifying SMURF2 Lys734 deubiquitylation, and established USP4/USP15 genetic redundancy required for mouse viability.","evidence":"proteomic MS, site-directed mutagenesis, in vitro deubiquitylation; Usp4/Usp15 mouse crosses","pmids":["26435193","26503449"],"confidence":"Medium","gaps":["Degree of substrate overlap with USP4 not catalogued","Tissue-specific redundancy unresolved"]},{"year":2016,"claim":"Connected USP15 activity to physiology and disease in vivo, showing a hypomorphic mutation dampens type I IFN and protects against neuroinflammation, and that TGF-β drives USP15 translation to stabilize p53.","evidence":"ENU mouse model, RNA-seq, neuroinflammation models; Co-IP, pathway inhibitors","pmids":["27721430","27893708"],"confidence":"High","gaps":["Direct substrate driving IFN phenotype in vivo not pinpointed","Generality of TGF-β→mTOR→USP15 axis untested"]},{"year":2017,"claim":"Established the structural and regulatory logic of SART3-mediated targeting and isoform/phospho control, and defined spliceosomal substrates PRP31/PRP3.","evidence":"crystal structures with ITC/mutagenesis; isoform-specific pulldowns; in vitro deubiquitylation of PRP31/PRP3 with USP4/SART3","pmids":["27255711","28276505","28088760"],"confidence":"High","gaps":["Functional consequence of exon-7 isoform switch in vivo limited","How splicing-substrate deubiquitylation integrates with cell cycle unclear"]},{"year":2018,"claim":"Resolved that the catalytic core has an intrinsically misaligned (inactive) triad with low monoubiquitin affinity, and placed USP15 directly in DNA-damage repair via MDC1-recruited, phospho-S678-dependent BARD1 deubiquitylation and TOP2A stabilization.","evidence":"X-ray crystallography, ITC, inhibition assay; Co-IP, phospho-mutant analysis, HR assays, KO mice; imaging and ubiquitination assays","pmids":["30228188","30874560","29429988","29593334"],"confidence":"High","gaps":["What triggers triad activation on substrate not defined","Kinase responsible for S678/S229 phosphorylation in repair not identified"]},{"year":2019,"claim":"Defined inhibitor-accessible conformational control via ubiquitin variants, mapped phospho-regulated nuclear targeting through SART3, and uncovered non-canonical Hrd1 ubiquitination that inactivates USP15 toward IκBα.","evidence":"UbV engineering with crystal structures and cell assays; fractionation/MS phospho-mutant analysis; E3 screen, KO mice, sepsis model","pmids":["30713027","31330151","31477895","29299163"],"confidence":"High","gaps":["In vivo kinase(s) for Thr149/Thr219 not established","Physiological scope of Hrd1-mediated USP15 inactivation unclear"]},{"year":2020,"claim":"Broadened immune and stem-cell roles, showing USP15 deubiquitylates TET2, CARD9, TBK1, and stabilizes TAB2/TAB3 and FUS, with TIFAB acting as an activator of USP15 toward MDM2/KEAP1.","evidence":"in vitro deubiquitylation, KO models, linkage-specific ubiquitination assays, proteomics, leukemia/transplantation models","pmids":["32948596","33093067","32814047","31903660","33378683","32101751","32839293"],"confidence":"Medium","gaps":["How a single DUB achieves opposing IFN outcomes mechanistically unresolved","Effector-driven (TIFAB) activation generality untested"]},{"year":2021,"claim":"Extended USP15 to additional disease-relevant substrates including CRL4CRBN neosubstrates, mutant p53-R175H, ERα, BECN1, and TUT1, linking it to drug resistance, autophagy, and RNA metabolism.","evidence":"ubiquitination/deubiquitination assays, knockdown/KO, lenalidomide/tamoxifen sensitivity, KO mice with U6 snRNA readout","pmids":["34583995","29593334","33771975","35422093","32839293"],"confidence":"Medium","gaps":["Catalytic vs scaffold contributions not separated for several substrates","Direct vs indirect deubiquitylation not always established"]},{"year":2022,"claim":"Showed USP15 promotes cGAS activation not only by deubiquitylation but by driving cGAS liquid condensation through its intrinsic disordered region, adding a phase-separation dimension to its function.","evidence":"Co-IP, in vitro deubiquitylation, LLPS assays, IDR deletion mutants, cGAS activation assays","pmids":["36243958"],"confidence":"Medium","gaps":["Single-lab finding awaiting independent confirmation","Quantitative role of IDR vs catalysis in vivo unclear"]},{"year":2023,"claim":"Established the active/inactive triad switch as ligand-independent and consolidated genome-stability and tumor-immune roles via PARP1 stabilization (regulated by ER/PR/HER2), SMYD3-driven chemokine induction, neurofilament regulation opposing CRL3gigaxonin, and YAP1/TAZ stabilization.","evidence":"multiple crystal structures; Co-IP, deubiquitination assays, ChIP, degron mapping, tumor and disease models","pmids":["35605756","37012401","40323348","37903270","36635430"],"confidence":"High","gaps":["What endogenously switches the triad state unresolved","Substrate-specific conformational requirements unmapped"]},{"year":2024,"claim":"Continued substrate expansion into cancer metabolism and drug sensitivity, deubiquitylating HKDC1 and antagonizing TRIM21 on ACSL4.","evidence":"Co-IP, ubiquitination assays, metabolic/glycolysis readouts, xenografts, clinical correlation","pmids":["39164728","38182686"],"confidence":"Medium","gaps":["Direct binding vs indirect stabilization not fully resolved","In vivo significance beyond tumor models unknown"]},{"year":null,"claim":"What governs USP15 substrate selectivity and the active/inactive catalytic-triad switch across its many pathways remains the central open question.","evidence":"no single study reconciles substrate choice with conformational state and phospho/adaptor regulation","pmids":[],"confidence":"Medium","gaps":["No unifying model linking phosphorylation, SART3/adaptor binding, and triad activation to substrate choice","Endogenous trigger of triad alignment unknown","Relative weight of catalytic vs scaffold/IDR functions per substrate undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,6,9,12,24,31]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,23,43]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,15,34]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25,29]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,24,25,29]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[39]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,14,47]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,17,33,36,42]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[24,25,44]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[20,29,39]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,15,37]}],"complexes":["COP9 signalosome (CSN)","USP15-SART3-USP4 spliceosomal complex"],"partners":["SART3","SMURF2","TRIM25","MDM2","BARD1","CARD9","TBK1","USP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4E8","full_name":"Ubiquitin carboxyl-terminal hydrolase 15","aliases":["Deubiquitinating enzyme 15","Ubiquitin thioesterase 15","Ubiquitin-specific-processing protease 15","Unph-2","Unph4"],"length_aa":981,"mass_kda":112.4,"function":"Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:16005295, PubMed:17318178, PubMed:19576224, PubMed:19826004, PubMed:21947082, PubMed:22344298, PubMed:24852371). Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:33093067). May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP (PubMed:16005295, PubMed:17318178, PubMed:19576224, PubMed:19826004). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Acts as a negative regulator of antifungal immunity by mediating 'Lys-27'-linked deubiquitination of CARD9, thereby inactivating CARD9 (PubMed:33093067) (Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9Y4E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP15","classification":"Not Classified","n_dependent_lines":42,"n_total_lines":1208,"dependency_fraction":0.0347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"PSMD12","stoichiometry":0.2},{"gene":"PSMD6","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/USP15","total_profiled":1310},"omim":[{"mim_id":"610900","title":"CHARGED MULTIVESICULAR BODY PROTEIN 5; CHMP5","url":"https://www.omim.org/entry/610900"},{"mim_id":"604731","title":"UBIQUITIN-SPECIFIC PROTEASE 15; USP15","url":"https://www.omim.org/entry/604731"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":166.2}],"url":"https://www.proteinatlas.org/search/USP15"},"hgnc":{"alias_symbol":["KIAA0529","UNPH4"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y4E8","domains":[{"cath_id":"3.30.2230.10","chopping":"8-129","consensus_level":"high","plddt":85.5336,"start":8,"end":129},{"cath_id":"3.10.20.90","chopping":"133-212","consensus_level":"high","plddt":84.7736,"start":133,"end":212},{"cath_id":"3.10.20","chopping":"559-576_585-617_711-767","consensus_level":"medium","plddt":75.4693,"start":559,"end":767}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4E8-F1-predicted_aligned_error_v6.png","plddt_mean":75.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP15","jax_strain_url":"https://www.jax.org/strain/search?query=USP15"},"sequence":{"accession":"Q9Y4E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4E8"}},"corpus_meta":[{"pmid":"22344298","id":"PMC_22344298","title":"USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma.","date":"2012","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22344298","citation_count":347,"is_preprint":false},{"pmid":"24852371","id":"PMC_24852371","title":"The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24852371","citation_count":265,"is_preprint":false},{"pmid":"24777531","id":"PMC_24777531","title":"USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses.","date":"2014","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24777531","citation_count":210,"is_preprint":false},{"pmid":"21947082","id":"PMC_21947082","title":"USP15 is a deubiquitylating enzyme for receptor-activated SMADs.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21947082","citation_count":165,"is_preprint":false},{"pmid":"24399297","id":"PMC_24399297","title":"The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24399297","citation_count":139,"is_preprint":false},{"pmid":"29263274","id":"PMC_29263274","title":"The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29263274","citation_count":126,"is_preprint":false},{"pmid":"16005295","id":"PMC_16005295","title":"The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1.","date":"2005","source":"Current biology : 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/30874560","citation_count":93,"is_preprint":false},{"pmid":"24526689","id":"PMC_24526689","title":"The U4/U6 recycling factor SART3 has histone chaperone activity and associates with USP15 to regulate H2B deubiquitination.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24526689","citation_count":83,"is_preprint":false},{"pmid":"27721430","id":"PMC_27721430","title":"USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27721430","citation_count":75,"is_preprint":false},{"pmid":"27893708","id":"PMC_27893708","title":"TGF-β upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 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spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/38019020","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50930,"output_tokens":12440,"usd":0.169695,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23668,"output_tokens":5753,"usd":0.131082,"stage2_stop_reason":"end_turn"},"total_usd":0.300777,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Recombinant USP15 demonstrated ubiquitin-specific protease activity against engineered linear fusions of ubiquitin to beta-galactosidase and glutathione S-transferase, and can cleave the ubiquitin-proline bond. USP15 protein consists of 952 amino acids and contains conserved Cys and His boxes present in all UBP family members.\",\n      \"method\": \"In vitro deubiquitinase activity assay with recombinant protein against linear ubiquitin fusion substrates\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution, replicated in mouse ortholog paper (PMID:12532266)\",\n      \"pmids\": [\"10444327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"USP15 co-purifies with the human COP9 signalosome (CSN) complex. A novel zinc finger in USP15 is essential for cleavage of poly-ubiquitin chains; mutation of a single conserved cysteine in the Zn-binding motif abolishes poly-Ub substrate degradation and reduces tetra-Ub binding. Wild-type but not Zn-finger-mutant USP15 stabilizes the E3 ligase Rbx1 by reversing its poly/autoubiquitination.\",\n      \"method\": \"Co-purification, pulldown with tetra-Ub, site-directed mutagenesis, cotransfection ubiquitination assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with biochemical assays (pulldown, activity assay) in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16005295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP15 stabilizes APC (adenomatous polyposis coli) protein in the context of the COP9 signalosome-associated complex. Knockdown of USP15 or overexpression of a catalytically inactive USP15 mutant accelerates APC proteolysis, demonstrating that CSN-associated USP15 protects APC from ubiquitin-mediated degradation.\",\n      \"method\": \"siRNA knockdown, overexpression of catalytically inactive mutant, Western blot for APC stability\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal approaches (siRNA and dominant-negative mutant), single lab\",\n      \"pmids\": [\"19576224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP15 interacts with HPV16 E6 protein (identified by tandem affinity purification). Overexpression of USP15 increases E6 protein levels and siRNA-mediated knockdown of USP15 decreases E6 protein levels, implicating USP15 in stabilization of E6 through deubiquitylation.\",\n      \"method\": \"Tandem affinity purification, siRNA knockdown, overexpression, Western blot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with protein stability readout, single lab\",\n      \"pmids\": [\"19553310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP15 is a deubiquitylating enzyme for receptor-activated SMADs (R-SMADs: SMAD1, 2, 3). USP15 primarily opposes R-SMAD monoubiquitylation at DNA-binding domains, which normally prevents promoter recognition. USP15 is required for TGF-β and BMP responses in mammalian cells and Xenopus embryos and is necessary for SMAD complex occupancy of endogenous target promoters.\",\n      \"method\": \"siRNA knockdown, overexpression, ChIP, in vitro deubiquitylation assays, Xenopus embryo knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deubiquitylation assay combined with ChIP and genetic knockdown in multiple model systems\",\n      \"pmids\": [\"21947082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the USP15 N-terminal DUSP and UBL domains at 1.5 Å resolution reveals an 80 Å elongated arrangement with the DU domains aligned in tandem, connected through a β-hairpin (DU finger) that forms an intricate hydrogen-bonding network. The UBL domain is monomeric in solution and unlikely to act as a ubiquitin mimic.\",\n      \"method\": \"X-ray crystallography, analytical ultracentrifugation, SAXS, gel filtration\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure validated by multiple biophysical methods in single study\",\n      \"pmids\": [\"21848306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP15 binds to the SMAD7-SMURF2 complex and deubiquitinates and stabilizes type I TGF-β receptor (TβR-I), leading to enhanced TGF-β signaling. Identified via functional RNAi screen; downregulation or inhibition of USP15 decreases TGF-β activity in patient-derived orthotopic mouse glioblastoma models.\",\n      \"method\": \"Functional RNAi screen, Co-IP, in vitro deubiquitylation, orthotopic mouse model with patient-derived cells\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deubiquitylation assay plus in vivo mouse model, replicated by subsequent studies\",\n      \"pmids\": [\"22344298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP15 interacts with the E3 ligase BRAP/IMP through the N-terminal DUSP-UBL domain of USP15 and the coiled-coil region of BRAP. USP15 opposes BRAP autoubiquitylation and stabilizes BRAP protein through its catalytic activity. USP15 depletion destabilizes BRAP via proteasomal degradation, reduces CRAF levels, and decreases MAPK signaling amplitude in response to EGF and PDGF.\",\n      \"method\": \"Co-IP, domain mapping, catalytically inactive mutant rescue, siRNA knockdown, Western blot, EGF/PDGF stimulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and catalytic mutant rescue, single lab\",\n      \"pmids\": [\"23105109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP15 stabilizes newly synthesized REST (RE1-silencing transcription factor) by antagonizing its polyubiquitylation in a catalytic-activity-dependent manner. USP15 specifically promotes de novo REST synthesis (associates with polysomes) rather than protecting pre-existing REST, and is required for rapid accumulation of newly synthesized REST at mitotic exit.\",\n      \"method\": \"siRNA screening, polysome fractionation, cycloheximide chase, ubiquitination assays, cell cycle analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (polysome fractionation, ubiquitination assay, cell cycle) in single lab\",\n      \"pmids\": [\"23708518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP15 specifically deubiquitinates Keap1 (not Nrf2 directly), which promotes incorporation of deubiquitinated Keap1 into the Keap1-Cul3-E3 ligase complex, enhancing complex stability and enzymatic activity. This leads to increased Nrf2 protein degradation and reduced Nrf2 target gene expression, suppressing the antioxidant response.\",\n      \"method\": \"In vitro deubiquitylation assay, co-immunoprecipitation, siRNA knockdown, Western blot, reporter gene assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitylation combined with co-IP and functional reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23727018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP15 stabilizes the E3 ubiquitin ligase MDM2 through deubiquitination. USP15-stabilized MDM2 negatively regulates T cell activation by targeting NFATc2 for degradation. USP15 deficiency promotes T cell activation and enhances antitumor T cell responses. USP15 also stabilizes MDM2 in cancer cells to regulate p53 function.\",\n      \"method\": \"Co-IP, in vitro deubiquitylation assay, USP15 knockout mice, T cell activation assays, tumor challenge models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deubiquitylation assay combined with knockout mouse models and in vivo tumor challenge\",\n      \"pmids\": [\"24777531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP15 opposes Parkin-mediated mitophagy by counteracting Parkin-mediated mitochondrial ubiquitination. USP15 does not affect Parkin ubiquitination status or Parkin translocation to mitochondria, but specifically counteracts ubiquitination of outer mitochondrial membrane proteins. A catalytically inactive version of USP15 does not oppose mitophagy. Knockdown of USP15 rescues the mitophagy defect in PD patient fibroblasts with PARK2 mutations.\",\n      \"method\": \"siRNA knockdown, catalytically inactive mutant, mitophagy assays, patient fibroblasts, Drosophila parkin RNAi rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including patient fibroblasts and Drosophila genetic rescue, single lab\",\n      \"pmids\": [\"24852371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP15 deubiquitylates TRIM25, preventing LUBAC-dependent K48-linked polyubiquitylation and proteasomal degradation of TRIM25. USP15 was identified as an interaction partner of TRIM25 by protein purification and mass spectrometry. Wild-type but not catalytically inactive USP15 reduces K48-linked ubiquitylation of TRIM25, stabilizes it, and enhances TRIM25- and RIG-I-dependent type I IFN production.\",\n      \"method\": \"Affinity purification, mass spectrometry, Co-IP, siRNA knockdown, overexpression of catalytically inactive mutant, IFN reporter assays, viral replication assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identification by MS plus mechanistic biochemical assays with catalytic mutant, replicated in neuroinflammation study\",\n      \"pmids\": [\"24399297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP15 identifies and deubiquitylates monoubiquitinated histone H2B (ubH2B). In the nucleus, USP15 indirectly associates with the ubH2B E3 ligase RNF20/RNF40, and directly associates with SART3 (TIP110/p110). SART3 acts as a histone chaperone that enhances USP15 binding to ubH2B and facilitates deubiquitination of free ubH2B histones.\",\n      \"method\": \"Affinity purification with nonhydrolyzable ubH2B mimic, Co-IP, in vitro deubiquitination assay with SART3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — affinity purification with substrate mimic combined with in vitro activity assay and Co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24526689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP15 deubiquitylates ALK3/BMPR1A (BMP type I receptor) by interacting with SMAD6, an inhibitory SMAD that recruits E3 ubiquitin ligases to ALK3. USP15 reduces K48-linked polyubiquitylation of ALK3, enhances BMP-induced SMAD1 phosphorylation, and promotes BMP target gene transcription. Loss of USP15 inhibits BMP-induced osteoblast differentiation in myoblasts and modulates BMP signaling in Xenopus embryos.\",\n      \"method\": \"Co-IP, RNAi depletion, ubiquitination assay, SMAD1 phosphorylation assay, BMP target gene reporter, Xenopus embryo experiments\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, in vitro signaling) in mammalian cells and Xenopus, single lab\",\n      \"pmids\": [\"24850914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP15 deubiquitinates SMURF2 at Lys734, a residue required for SMURF2 catalytic activity. This results in enhanced TβR-I stability and downstream TGF-β pathway activation. Proteomic analysis identified SMURF2 as a USP15 target in addition to TβR-I.\",\n      \"method\": \"Proteomic mass spectrometry, Co-IP, in vitro deubiquitination assay, mutational analysis of Lys734\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS identification of ubiquitination site plus biochemical validation, single lab\",\n      \"pmids\": [\"26435193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP4, USP15, and USP11 arose by whole genome and small-scale duplications in vertebrate evolution. Viability of mice is contingent on a functional copy of either USP4 or USP15 (genetic redundancy established by cross-breeding mice with inactivating mutations in both genes).\",\n      \"method\": \"Phylogenetic and syntenic reconstruction, genetic crosses of Usp4/Usp15 mutant mice\",\n      \"journal\": \"BMC evolutionary biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis through mouse crosses, single study\",\n      \"pmids\": [\"26503449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP15 co-expressed with and functionally acts together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses. The USP15L749R mutation in mice dampens type I interferon responses in brain and hematopoietic cells, protecting against experimental cerebral malaria and EAE neuroinflammation.\",\n      \"method\": \"ENU-mutagenesis mouse model, immunophenotyping, RNA sequencing, in situ neuroinflammation models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic mouse model with two distinct neuroinflammation disease models and mechanistic pathway assignment\",\n      \"pmids\": [\"27721430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGF-β promotes translation of USP15 through activation of mTOR via the PI3K/AKT pathway. Upregulated USP15 then binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, PI3K/AKT/mTOR pathway inhibitors, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitination assay with pathway inhibitor validation, single lab\",\n      \"pmids\": [\"27893708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Structural basis for SART3 recruitment of USP15: crystal structures of SART3 alone and in complex with USP15 DUSP-UBL domain at 2.0 and 3.0 Å respectively reveal SART3 contains 12 HAT repeats in two subdomains, dimerizes through HAT-C concave surface, and binds USP15 in a novel bipartite mode on the HAT-C convex surface. USP15 binds SART3 ~20-fold more tightly than USP4.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures with ITC and mutagenesis validation, single study\",\n      \"pmids\": [\"27255711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP15, together with its substrate-targeting factor SART3, deubiquitinates PRP31 (a U4 snRNP component). PRP31 is modified with K63-linked ubiquitin chains by the PRP19 complex. USP15-SART3 forms a complex with USP4, and this ternary complex also deubiquitinates PRP3. The ubiquitination/deubiquitination status of PRP31 regulates its interaction with U5 snRNP component PRP8, required for efficient splicing of chromosome segregation-related genes.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, ubiquitin linkage-specific analysis, splicing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitination plus Co-IP and functional splicing assays, single lab\",\n      \"pmids\": [\"28088760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The long isoform of USP15 (containing exon 7-encoded serine-rich stretch) preferentially recognizes and deubiquitylates mysterin/RNF213 (a large ubiquitin ligase associated with moyamoya disease), while the short isoform does not. Exon 7 skipping alters substrate specificity of USP15 isoforms, with only partially overlapping interactomes.\",\n      \"method\": \"Isoform-specific pulldown, deubiquitylation assay, mass spectrometry interactome comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical assay comparing two isoforms with MS interactome, single lab\",\n      \"pmids\": [\"28276505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP15 interacts with and deubiquitinates SLIM1 (skeletal muscle LIM protein 1), increasing SLIM1 protein levels. Cardiac-specific overexpression of USP15 in transgenic mice induces cardiac remodeling with elevated heart weight/body weight ratios and upregulation of fetal gene markers, associated with increased endogenous SLIM1 levels.\",\n      \"method\": \"Cell-free binding, co-immunoprecipitation, in vitro deubiquitination, transgenic mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo transgenic mouse functional model, single lab\",\n      \"pmids\": [\"21219870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the USP15 catalytic core domain reveals a canonical USP fold (finger, palm, thumb regions) but with a misaligned catalytic triad — catalytic cysteine ~10 Å from catalytic histidine, an inactive configuration. Active-site loops are flexible, creating a largely open ubiquitin tail-binding channel. USP15 displays lower monoubiquitin affinity than paralog USP4. Mitoxantrone weakly inhibits USP15 and binds the S1' site.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, enzyme inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with ITC and inhibition assay in single rigorous study\",\n      \"pmids\": [\"30228188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP15 deubiquitylates BARD1 BRCT domain upon recruitment to DNA double-strand breaks (DSBs) by MDC1. Recruitment requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. USP15-mediated BARD1 deubiquitylation promotes BARD1-HP1γ interaction, retaining BRCA1/BARD1 at DSBs and promoting homologous recombination (HR). USP15 knockout mice exhibit genomic instability.\",\n      \"method\": \"Co-IP, phospho-mutant analysis, BARD1 deubiquitylation assay, HR assay, USP15 KO mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deubiquitylation assay combined with domain mapping, KO mice genomic instability, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30874560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP15 deubiquitylates topoisomerase IIα (TOP2A), and USP15 depletion leads to decreased TOP2A accumulation, formation of anaphase chromosome bridges, and micronuclei indicating genome instability. Both USP15 isoforms move from cytoplasm to nucleus at prophase; isoform-1 is phosphorylated on S229 at mitotic entry and an S229D phospho-mimetic cannot rescue TOP2A accumulation or the micronuclei phenotype, demonstrating isoform-specific phospho-regulation.\",\n      \"method\": \"siRNA depletion, phospho-mutant rescue, live-cell imaging, cell cycle analysis, ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, ubiquitination assay, phospho-mimetic rescue) in single lab\",\n      \"pmids\": [\"29429988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HPV16 E6 oncoprotein forms a complex with TRIM25 and USP15 in human cells. In the presence of E6, K48-linked ubiquitination of TRIM25 is markedly increased and TRIM25 degradation is enhanced, and E6 inhibits TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS.\",\n      \"method\": \"Co-IP, ubiquitination assay, CRISPR-Cas9 knockout in keratinocytes, IFN reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and CRISPR genetic validation, single lab\",\n      \"pmids\": [\"29263274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ubiquitin variants (UbVs) targeting either the USP15 catalytic domain or each of three adaptor domains (including the DUSP domain) inhibit USP15 catalytic activity. A linear dimer UbV targeting both DUSP and catalytic domains shows enhanced specificity. Crystal structures show three distinct UbVs bind the catalytic domain and lock the active site in a closed, inactive conformation; one UbV forms an unusual strand-swapped dimer binding two DUSP domains simultaneously. In cells, UbVs inhibit deubiquitination of SMURF2 and TRIM25 substrates.\",\n      \"method\": \"Protein engineering (UbVs), X-ray crystallography, cell-based deubiquitination assays, TGF-β pathway assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of inhibitor complexes combined with cell-based substrate deubiquitination assays, single rigorous study\",\n      \"pmids\": [\"30713027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ER-located E3 ligase Hrd1 interacts with USP15 and ubiquitinates it. Unlike classical Hrd1 substrates, USP15 is not degraded but loses its deubiquitinating activity toward IκBα, resulting in excessive NF-κB activation. This represents a non-canonical Hrd1 function linking ER-plasma membrane signaling during bacterial TLR4 responses.\",\n      \"method\": \"E3 ligase screen (>280 ligases), Co-IP, ubiquitination assay, IκBα deubiquitination assay, macrophage-specific Hrd1 KO mice, LPS-sepsis model\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical activity assay plus in vivo KO mouse validation with epistasis experiments, single lab\",\n      \"pmids\": [\"31477895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP15 phosphorylation at Thr149 and Thr219 (identified by nuclear-cytoplasmic fractionation and mass spectrometry) occurs in the cytoplasm. The phosphorylation status alters interaction with SART3, leading to nuclear localization and deubiquitinating activity toward spliceosomal substrate PRP31. Treatment with CDK inhibitor purvalanol A induces nuclear translocation of USP15.\",\n      \"method\": \"Subcellular fractionation, mass spectrometry, phospho-mutant analysis, Co-IP, in vitro deubiquitination assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS identification of phosphosites combined with functional mutant analysis and localization assay, single lab\",\n      \"pmids\": [\"31330151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP15 deubiquitylates and stabilizes HECTD1 E3 ubiquitin ligase in glioblastoma cells. USP15 expression attenuates canonical WNT pathway activity in a manner dependent on HECTD1; depletion of USP15 reduces HECTD1 protein levels. USP15 interaction with HECTD1 was identified by mass spectrometry.\",\n      \"method\": \"Mass spectrometry protein network analysis, Co-IP, ubiquitination assay, WNT reporter assay, soft agar colony formation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based discovery with Co-IP, ubiquitination assay, and functional pathway reporter, single lab\",\n      \"pmids\": [\"29299163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP15 deubiquitylates and inactivates TET2 by removing K1299-linked monoubiquitin, which normally promotes TET2 activity. Deletion of Usp15 in melanoma cells stimulates chemokine expression and tumor-infiltrating lymphocyte accumulation in a TET2-dependent manner, leading to increased immunotherapy response.\",\n      \"method\": \"Co-IP, in vitro deubiquitylation assay, gene expression profiling, Usp15 KO melanoma model, immunotherapy challenge\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitylation of specific site combined with in vivo KO model and TET2 epistasis rescue, single lab\",\n      \"pmids\": [\"32948596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP15 potentiates NF-κB activation upon TNFα or IL-1β stimulation by stabilizing TAB2 and TAB3 through different mechanisms: (1) catalytic-activity-dependent deubiquitination of K48-linked TAB2 ubiquitin chains; (2) catalytic-activity-independent inhibition of lysosome-mediated TAB2 degradation; (3) catalytic-activity-independent inhibition of NBR1-mediated selective autophagic TAB3 degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay, overexpression/knockdown of USP15, catalytically inactive mutant, NF-κB reporter, lysosome/autophagy inhibitor experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal mechanistic experiments (ubiquitination, lysosome, autophagy) in single lab\",\n      \"pmids\": [\"31903660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBE2S recruits USP15 to TBK1 to remove K63-linked polyubiquitin chains from TBK1, thereby inhibiting TBK1 activation and type I IFN production. UBE2S-mediated inhibition of IFN is independent of its E2/E3 enzymatic activity but requires USP15 recruitment.\",\n      \"method\": \"Co-IP, ubiquitination assay (K63 linkage-specific), USP15 knockdown, viral replication assays in vitro and in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay with in vivo validation, single lab\",\n      \"pmids\": [\"32814047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TIFAB regulates USP15 ubiquitin hydrolase activity (acts as an effector/activator of USP15). Expression of TIFAB in hematopoietic stem/progenitor cells permits USP15 signaling to substrates MDM2 and KEAP1, mitigating p53 expression. TIFAB-deficient HSPCs exhibit compromised USP15 signaling and are sensitized to hematopoietic stress by derepression of p53.\",\n      \"method\": \"Proteomics, co-IP, USP15 activity assays, genetic knockdown/overexpression in HSPCs, MLL-AF9 leukemia model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification combined with functional USP15 activity assay and leukemia model, single lab\",\n      \"pmids\": [\"32101751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, in leukemia cells. USP15 is essential for HSC maintenance in vitro and in vivo (transplantation and Usp15 KO mice), and its depletion in leukemia cells impairs expansion and increases genotoxic stress.\",\n      \"method\": \"Co-IP, shRNA in vivo screen, Usp15 KO mice, transplantation assays, genotoxic stress assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying FUS interaction combined with in vivo KO model, single lab\",\n      \"pmids\": [\"33378683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP15 deubiquitinates CARD9, constitutively associating with it and removing TRIM62-deposited ubiquitin marks. USP15 knockdown and knockout specifically enhance CARD9-dependent C-type lectin receptor (CLR) signaling in mouse and human immune cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA knockdown, CRISPR KO, CLR signaling assays\",\n      \"journal\": \"ImmunoHorizons\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and genetic KO validation in two species' immune cells, single lab\",\n      \"pmids\": [\"33093067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP15 deubiquitinates and stabilizes glutamine synthetase (GS) and CRL4CRBN neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4 by antagonizing CRL4CRBN-mediated ubiquitylation. USP15 is highly expressed in IMiD-resistant myeloma cells and depletion sensitizes these cells to lenalidomide.\",\n      \"method\": \"Ubiquitination assays, Western blot for substrate stability, siRNA depletion, lenalidomide sensitivity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple substrate deubiquitination assays with pharmacological validation, single lab\",\n      \"pmids\": [\"34583995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP15 deubiquitinates and stabilizes p53-R175H gain-of-function mutant through a lysosome-mediated pathway. USP15 is established as a selective upstream regulator of p53-R175H stability distinct from wild-type p53 regulation.\",\n      \"method\": \"Chemical genetic approach (MCB-613), siRNA knockdown, CRISPR, ubiquitination assay, lysosome pathway assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and chemical validation with ubiquitination assay, single lab\",\n      \"pmids\": [\"29593334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP15 deubiquitinates TUT1 (terminal uridylyl transferase 1) and causes redistribution of TUT1 from nucleolus to nucleoplasm, stabilizing U6 snRNA. Usp15 knockout mice show impaired motor ability and unconventional cerebellar formation. Inhibition of the USP15-TUT1 cascade triggers mild chronic ER stress.\",\n      \"method\": \"Co-IP, ubiquitination assay, immunofluorescence localization, Usp15 KO mice, U6 snRNA stability assay, ER stress markers\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo KO with functional RNA metabolism readout, single lab\",\n      \"pmids\": [\"32839293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP15 deubiquitinates and stabilizes ERα (estrogen receptor alpha) by removing K48-linked ubiquitin, promoting ERα+ breast cancer cell proliferation. USP15 knockdown reduces ERα protein levels and enhances tamoxifen antitumor activity.\",\n      \"method\": \"Co-IP, ubiquitination assay (K48 linkage-specific), siRNA knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay with in vivo tumor model, single lab\",\n      \"pmids\": [\"33771975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP15 deubiquitinates BECN1 (Beclin-1), interacting with BECN1 but not TRAF6, thereby attenuating TRAF6-BECN1 axis-driven autophagy induction. USP15-knockout lung cancer cells show increased cancer migration and invasion with enhanced autophagy in response to TLR4 stimulation.\",\n      \"method\": \"Co-IP, deubiquitination assay, CRISPR-Cas9 KO cell lines, migration/invasion assays, autophagy assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitination assay with CRISPR KO phenotypic validation, single lab\",\n      \"pmids\": [\"35422093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP15 interacts with and promotes cGAS activation through deubiquitylation of cGAS and promotion of cGAS dimerization and liquid condensation via the USP15 intrinsic disordered region (IDR). In the absence of DNA, USP15 drives cGAS liquid condensation preparing cGAS for rapid DNA response.\",\n      \"method\": \"Co-IP, in vitro deubiquitylation assay, liquid-liquid phase separation assay, IDR deletion mutant analysis, cGAS activation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple biochemical methods (deubiquitylation, phase separation) in single lab\",\n      \"pmids\": [\"36243958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of USP15 D1D2 catalytic domain in a catalytically competent conformation shows the active site can switch between active and inactive states independently of mitoxantrone binding. Mitoxantrone contributes to crystal packing by forming a stack of 12 molecules at the S1' site rather than inducing catalytic triad misalignment.\",\n      \"method\": \"X-ray crystallography (multiple crystal structures), comparative structural analysis\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures directly resolving active/inactive conformations with structural comparison, single rigorous study\",\n      \"pmids\": [\"35605756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP15 interacts with and deubiquitinates PARP1 to promote its stability, stimulating DNA repair, genomic stability, and TNBC cell proliferation. ER inhibits USP15 expression at the promoter level, PR suppresses USP15 deubiquitinase activity, and HER2 abrogates the PARP1-USP15 interaction — explaining elevated PARP1 in TNBC where all three receptors are absent.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, ChIP, USP15 activity assay in presence of PR, Co-IP in presence of HER2, TNBC cell proliferation/DNA repair assays\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical deubiquitination assay combined with three distinct mechanistic inhibition experiments and clinical context, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37012401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The CRL3gigaxonin E3 ligase and USP15 form an opposing regulatory pathway governing destruction of neurofilament proteins NEFL and INA. USP15 antagonizes CRL3GIG-mediated ubiquitylation of NEFL and INA. A specific degron (NEFLL12) in neurofilament proteins is required for CRL3GIG binding; mutations in the GIG Kelch domain (L309R, R545C, C570Y) disrupt NEFL/INA binding causing accumulation of NF proteins as in giant axonal neuropathy.\",\n      \"method\": \"Ubiquitination assays, Co-IP, degron mapping, mutant GIG binding assays, proteasome degradation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple substrate ubiquitination assays with degron mapping and disease-relevant mutation analysis, single lab\",\n      \"pmids\": [\"37903270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP15 deubiquitinates SMYD3, stabilizing it and enabling H3K4me3-mediated transcriptional activation of CCL2. This promotes MDSC recruitment to tumors and immune evasion in colorectal cancer. USP15 inhibition improves anti-PD-1 efficacy in colorectal cancer models.\",\n      \"method\": \"Co-IP, deubiquitination assay, H3K4me3 ChIP, MDSC recruitment assays, orthotopic/metastatic colon tumor models, PD-1 blockade combination\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitination and ChIP with in vivo tumor model, single lab\",\n      \"pmids\": [\"40323348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP15 interacts with and deubiquitinates YAP1, inhibiting K48-linked ubiquitination of YAP1 and stabilizing it. USP15 also binds TAZ after hypoxia treatment. USP15 promotes PASMC proliferation and migration in a YAP1/TAZ-dependent manner, contributing to pulmonary vascular remodeling.\",\n      \"method\": \"Co-IP, ubiquitination assay (K48 linkage), USP15 knockdown (AAV-mediated in vivo), YAP1/TAZ rescue experiments, SuHx and MCT mouse models\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and linkage-specific ubiquitination assay with in vivo disease model, single lab\",\n      \"pmids\": [\"36635430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP15 deubiquitinates HKDC1 (a glycolytic regulator), inhibiting its ubiquitination-mediated degradation and thereby regulating glucose metabolism and glycolytic activity in gastric cancer cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, USP15 knockdown/overexpression, glycolytic activity assays, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay with functional metabolic readout, single lab\",\n      \"pmids\": [\"39164728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM21 E3 ligase and USP15 antagonistically regulate ACSL4 protein stability in gastrointestinal stromal tumors (GISTs); TRIM21-mediated ubiquitination decreases ACSL4 while USP15 opposes this, and the balance determines imatinib sensitivity.\",\n      \"method\": \"Co-IP, ubiquitination assay, Western blot for ACSL4 stability, shRNA, xenograft model, GIST patient clinical data\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay with in vivo model and clinical correlation, single lab\",\n      \"pmids\": [\"38182686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP15 is a cysteine deubiquitylase (DUB) belonging to the USP subfamily that associates constitutively with the COP9 signalosome (CSN) and the spliceosome recycling factor SART3, and acts on a broad set of substrates including TβR-I, SMURF2, R-SMADs, ALK3/BMPR1A, TRIM25, BARD1, MDM2, Keap1, PARP1, TET2, TOP2A, CARD9, TBK1, cGAS, YAP1, PRP31, H2B, and many others; its catalytic activity depends on a zinc finger motif and a catalytic triad that can adopt active or inactive conformations, and its substrate specificity and nuclear/cytoplasmic localization are regulated by phosphorylation (at Thr149/Thr219 by CDKs, and Ser678) and isoform-specific alternative splicing of exon 7, collectively placing USP15 as a central reversible-ubiquitylation switch in TGF-β/BMP signaling, innate immune/interferon responses, DNA damage repair (HR), mitophagy, splicing, and cell cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP15 is a cysteine deubiquitylase of the USP family that functions as a reversible-ubiquitylation switch across signaling, genome-maintenance, immune, and RNA-processing pathways by cleaving ubiquitin from a broad set of substrates [#0, #6]. Its catalytic core adopts a canonical USP fold whose catalytic triad can toggle between aligned (active) and misaligned (inactive) configurations, and an N-terminal DUSP-UBL module forms an elongated tandem arrangement that mediates substrate-targeting interactions [#5, #23, #43]; a zinc-finger motif is required for poly-ubiquitin chain cleavage [#1]. Substrate selection and nuclear/cytoplasmic distribution are governed by adaptor binding and phosphorylation: the spliceosome recycling factor SART3 recruits USP15 in a bipartite mode to deliver it to nuclear substrates, while CDK-type phosphorylation at Thr149/Thr219 and isoform-specific events control SART3 association and nuclear translocation [#19, #29, #25]. In TGF-\\u03b2/BMP signaling USP15 stabilizes the type I receptors T\\u03b2R-I and ALK3/BMPR1A and acts on SMURF2 and receptor-activated SMADs to potentiate pathway output [#4, #6, #14, #15]. It controls innate immunity bidirectionally, stabilizing TRIM25 to enhance RIG-I-dependent type I IFN yet removing activating ubiquitin from TBK1, cGAS, and CARD9, and deubiquitylating I\\u03baB\\u03b1 and TAB2/TAB3 to tune NF-\\u03baB [#12, #17, #33, #36, #42, #28, #32]. At DNA double-strand breaks phospho-Ser678 USP15 is recruited by MDC1 to deubiquitylate BARD1 and promote homologous recombination, and it stabilizes TOP2A and PARP1 to safeguard genomic stability, with USP15-null mice showing genomic instability [#24, #25, #44]. USP15 additionally regulates oxidative-stress (Keap1/Nrf2) and p53 axes via MDM2, opposes Parkin-driven mitophagy, and participates in spliceosomal deubiquitylation of PRP31/PRP3 together with SART3 and USP15's paralog USP4 [#9, #10, #11, #20]. Mouse viability requires a functional copy of either USP15 or its paralog USP4, indicating genetic redundancy [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that USP15 is a bona fide ubiquitin-specific protease, defining its core enzymatic identity.\",\n      \"evidence\": \"in vitro deubiquitinase assay with recombinant protein against linear ubiquitin fusion substrates\",\n      \"pmids\": [\"10444327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified\", \"Chain-linkage preference not addressed\", \"No structural basis for catalysis\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked USP15 to the COP9 signalosome and showed a zinc-finger motif is required for poly-ubiquitin chain cleavage and for stabilizing an E3 ligase, moving beyond minimal substrates to E3-protective roles.\",\n      \"evidence\": \"co-purification, tetra-Ub pulldown, Zn-finger mutagenesis, cotransfection ubiquitination assay (Rbx1)\",\n      \"pmids\": [\"16005295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous CSN-dependent substrate repertoire unmapped\", \"Stoichiometry within CSN unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined USP15 as a positive regulator of TGF-\\u03b2/BMP signaling by reversing R-SMAD monoubiquitylation required for promoter occupancy, and resolved the elongated DUSP-UBL architecture.\",\n      \"evidence\": \"in vitro deubiquitylation, ChIP, knockdown in cells and Xenopus; X-ray/SAXS of DUSP-UBL\",\n      \"pmids\": [\"21947082\", \"21848306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DUSP-UBL selects SMAD substrates unresolved\", \"Catalytic-domain structure not yet solved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed USP15 acts at the receptor level of TGF-\\u03b2 signaling by deubiquitylating T\\u03b2R-I via the SMAD7-SMURF2 complex, with in vivo relevance to glioblastoma.\",\n      \"evidence\": \"RNAi screen, Co-IP, in vitro deubiquitylation, patient-derived orthotopic mouse model; plus BRAP/MAPK study\",\n      \"pmids\": [\"22344298\", \"23105109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs SMURF2-mediated effect on receptor not fully separated\", \"Selectivity among receptor-complex components unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded USP15 substrates into oxidative-stress and transcription control, deubiquitylating Keap1 to suppress Nrf2 and stabilizing newly synthesized REST.\",\n      \"evidence\": \"in vitro deubiquitylation, Co-IP, reporter assays, polysome fractionation, cycloheximide chase\",\n      \"pmids\": [\"23727018\", \"23708518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling USP15 to translation/polysomes unknown\", \"Cell-type specificity of Keap1 effect not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated broad regulatory reach \\u2014 stabilizing MDM2 to restrain T-cell/p53 responses, opposing Parkin mitophagy, stabilizing TRIM25 for IFN, deubiquitylating histone H2B via SART3, and targeting ALK3 in BMP signaling \\u2014 establishing USP15 as a multi-pathway DUB.\",\n      \"evidence\": \"in vitro deubiquitylation, KO mice, mitophagy and patient-fibroblast assays, MS, SART3 in vitro assays, Xenopus\",\n      \"pmids\": [\"24777531\", \"24852371\", \"24399297\", \"24526689\", \"24850914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate choice across pathways unknown\", \"Whether one localization pool serves all substrates unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the TGF-\\u03b2 mechanism by identifying SMURF2 Lys734 deubiquitylation, and established USP4/USP15 genetic redundancy required for mouse viability.\",\n      \"evidence\": \"proteomic MS, site-directed mutagenesis, in vitro deubiquitylation; Usp4/Usp15 mouse crosses\",\n      \"pmids\": [\"26435193\", \"26503449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degree of substrate overlap with USP4 not catalogued\", \"Tissue-specific redundancy unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected USP15 activity to physiology and disease in vivo, showing a hypomorphic mutation dampens type I IFN and protects against neuroinflammation, and that TGF-\\u03b2 drives USP15 translation to stabilize p53.\",\n      \"evidence\": \"ENU mouse model, RNA-seq, neuroinflammation models; Co-IP, pathway inhibitors\",\n      \"pmids\": [\"27721430\", \"27893708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate driving IFN phenotype in vivo not pinpointed\", \"Generality of TGF-\\u03b2\\u2192mTOR\\u2192USP15 axis untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the structural and regulatory logic of SART3-mediated targeting and isoform/phospho control, and defined spliceosomal substrates PRP31/PRP3.\",\n      \"evidence\": \"crystal structures with ITC/mutagenesis; isoform-specific pulldowns; in vitro deubiquitylation of PRP31/PRP3 with USP4/SART3\",\n      \"pmids\": [\"27255711\", \"28276505\", \"28088760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of exon-7 isoform switch in vivo limited\", \"How splicing-substrate deubiquitylation integrates with cell cycle unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved that the catalytic core has an intrinsically misaligned (inactive) triad with low monoubiquitin affinity, and placed USP15 directly in DNA-damage repair via MDC1-recruited, phospho-S678-dependent BARD1 deubiquitylation and TOP2A stabilization.\",\n      \"evidence\": \"X-ray crystallography, ITC, inhibition assay; Co-IP, phospho-mutant analysis, HR assays, KO mice; imaging and ubiquitination assays\",\n      \"pmids\": [\"30228188\", \"30874560\", \"29429988\", \"29593334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What triggers triad activation on substrate not defined\", \"Kinase responsible for S678/S229 phosphorylation in repair not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined inhibitor-accessible conformational control via ubiquitin variants, mapped phospho-regulated nuclear targeting through SART3, and uncovered non-canonical Hrd1 ubiquitination that inactivates USP15 toward I\\u03baB\\u03b1.\",\n      \"evidence\": \"UbV engineering with crystal structures and cell assays; fractionation/MS phospho-mutant analysis; E3 screen, KO mice, sepsis model\",\n      \"pmids\": [\"30713027\", \"31330151\", \"31477895\", \"29299163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo kinase(s) for Thr149/Thr219 not established\", \"Physiological scope of Hrd1-mediated USP15 inactivation unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened immune and stem-cell roles, showing USP15 deubiquitylates TET2, CARD9, TBK1, and stabilizes TAB2/TAB3 and FUS, with TIFAB acting as an activator of USP15 toward MDM2/KEAP1.\",\n      \"evidence\": \"in vitro deubiquitylation, KO models, linkage-specific ubiquitination assays, proteomics, leukemia/transplantation models\",\n      \"pmids\": [\"32948596\", \"33093067\", \"32814047\", \"31903660\", \"33378683\", \"32101751\", \"32839293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single DUB achieves opposing IFN outcomes mechanistically unresolved\", \"Effector-driven (TIFAB) activation generality untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended USP15 to additional disease-relevant substrates including CRL4CRBN neosubstrates, mutant p53-R175H, ER\\u03b1, BECN1, and TUT1, linking it to drug resistance, autophagy, and RNA metabolism.\",\n      \"evidence\": \"ubiquitination/deubiquitination assays, knockdown/KO, lenalidomide/tamoxifen sensitivity, KO mice with U6 snRNA readout\",\n      \"pmids\": [\"34583995\", \"29593334\", \"33771975\", \"35422093\", \"32839293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic vs scaffold contributions not separated for several substrates\", \"Direct vs indirect deubiquitylation not always established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed USP15 promotes cGAS activation not only by deubiquitylation but by driving cGAS liquid condensation through its intrinsic disordered region, adding a phase-separation dimension to its function.\",\n      \"evidence\": \"Co-IP, in vitro deubiquitylation, LLPS assays, IDR deletion mutants, cGAS activation assays\",\n      \"pmids\": [\"36243958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding awaiting independent confirmation\", \"Quantitative role of IDR vs catalysis in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the active/inactive triad switch as ligand-independent and consolidated genome-stability and tumor-immune roles via PARP1 stabilization (regulated by ER/PR/HER2), SMYD3-driven chemokine induction, neurofilament regulation opposing CRL3gigaxonin, and YAP1/TAZ stabilization.\",\n      \"evidence\": \"multiple crystal structures; Co-IP, deubiquitination assays, ChIP, degron mapping, tumor and disease models\",\n      \"pmids\": [\"35605756\", \"37012401\", \"40323348\", \"37903270\", \"36635430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What endogenously switches the triad state unresolved\", \"Substrate-specific conformational requirements unmapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Continued substrate expansion into cancer metabolism and drug sensitivity, deubiquitylating HKDC1 and antagonizing TRIM21 on ACSL4.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, metabolic/glycolysis readouts, xenografts, clinical correlation\",\n      \"pmids\": [\"39164728\", \"38182686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding vs indirect stabilization not fully resolved\", \"In vivo significance beyond tumor models unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What governs USP15 substrate selectivity and the active/inactive catalytic-triad switch across its many pathways remains the central open question.\",\n      \"evidence\": \"no single study reconciles substrate choice with conformational state and phospho/adaptor regulation\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking phosphorylation, SART3/adaptor binding, and triad activation to substrate choice\", \"Endogenous trigger of triad alignment unknown\", \"Relative weight of catalytic vs scaffold/IDR functions per substrate undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 6, 9, 12, 24, 31]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 23, 43]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 15, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25, 29]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 24, 25, 29]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 14, 47]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 17, 33, 36, 42]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [24, 25, 44]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [20, 29, 39]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 15, 37]}\n    ],\n    \"complexes\": [\"COP9 signalosome (CSN)\", \"USP15-SART3-USP4 spliceosomal complex\"],\n    \"partners\": [\"SART3\", \"SMURF2\", \"TRIM25\", \"MDM2\", \"BARD1\", \"CARD9\", \"TBK1\", \"USP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}