{"gene":"USP11","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2002,"finding":"USP11 localizes primarily to the nucleus in non-dividing cells and physically interacts with RanBPM (a RanGTP-binding protein) as confirmed by yeast two-hybrid and co-immunoprecipitation. USP11 deubiquitinates RanBPM in vitro and in vivo, protecting it from proteasomal degradation.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro/in vivo ubiquitination assay, pulse-chase analysis, immunofluorescence","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro deubiquitination assay, proteasome inhibitor pulse-chase) in a single focused study","pmids":["12084015"],"is_preprint":false},{"year":2004,"finding":"USP11 forms a specific complex with BRCA2 (identified by immunopurification-mass spectrometry) and can deubiquitinate BRCA2 in overexpression assays; a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels. Loss of USP11 function (dominant-negative or RNAi) increased cellular sensitivity to mitomycin C in a BRCA2-dependent manner, placing USP11 in the BRCA2 DNA damage repair pathway.","method":"Immunopurification-mass spectrometry, co-immunoprecipitation, catalytic mutant analysis, RNAi knockdown, cell survival assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, MS identification, catalytic mutant, epistasis with BRCA2, multiple orthogonal methods in one study","pmids":["15314155"],"is_preprint":false},{"year":2007,"finding":"USP11 knockdown attenuates IKKα expression at the transcriptional level and enhances NF-κB activation in response to TNFα. USP11 knockdown or IKKα knockdown abrogates p53 induction upon TNFα exposure; ectopic IKKα rescues p53 expression in USP11-silenced cells, establishing USP11 as an upstream regulator of an IKKα-p53 signaling pathway.","method":"siRNA knockdown, immunoblotting, reporter assays, rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis established by rescue experiment, single lab, single publication","pmids":["17897950"],"is_preprint":false},{"year":2008,"finding":"USP11 interacts with HPV-16 E7 (identified by yeast two-hybrid) and stabilizes E7 by removing ubiquitin chains and reducing degradation; a catalytically inactive USP11 mutant abolished deubiquitinating activity and returned E7 to normal degradation rates. USP11-mediated E7 stabilization modulated E7's effects on cell growth.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro deubiquitination assay, catalytic mutant analysis, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro DUB assay, catalytic mutant) in single focused study","pmids":["18408009"],"is_preprint":false},{"year":2010,"finding":"USP11 acts as a deubiquitinase for IκBα: recombinant USP11 catalyzes IκBα deubiquitination in vitro; USP11 overexpression inhibits IκBα ubiquitination and USP11 knockdown enhances TNFα-induced IκBα ubiquitination and NF-κB activation. A catalytically inactive USP11 mutant partially inhibits NF-κB activation, indicating a non-catalytic function as well.","method":"Proteomic approach (co-IP identification), in vitro deubiquitination assay, siRNA knockdown, overexpression, catalytic mutant analysis, reporter assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, co-IP, catalytic mutant, knockdown and overexpression all in one study","pmids":["19874889"],"is_preprint":false},{"year":2010,"finding":"USP11 participates in homologous recombination (HR) repair of DNA double-strand breaks. RNAi silencing of USP11 causes spontaneous DNA damage response activation, hypersensitivity to PARP inhibition and ionizing radiation, and defective HR repair. USP11 catalytic activity is required for proper recruitment of RAD51 and 53BP1 to repair foci.","method":"RNAi screen, siRNA knockdown, PARP inhibitor sensitivity assay, HR repair assay, immunofluorescence foci analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional HR assay, foci recruitment assay, catalytic activity requirement, multiple readouts in single study","pmids":["20233726"],"is_preprint":false},{"year":2012,"finding":"USP11 interacts with SMAD7 and deubiquitylates the type I TGFβ receptor ALK5, thereby stabilizing it and enhancing TGFβ-induced gene transcription. USP11 deubiquitylase activity is required to augment TGFβ signaling. RNAi depletion of USP11 inhibits TGFβ-induced SMAD2/3 phosphorylation, transcriptional responses, and epithelial-to-mesenchymal transition.","method":"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, RNAi knockdown, reporter assay, SMAD2/3 phosphorylation assay, EMT assay","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, deubiquitylation assay, multiple functional readouts (signaling, transcription, EMT), single lab","pmids":["22773947"],"is_preprint":false},{"year":2013,"finding":"Mitoxantrone was identified as an inhibitor of USP11 enzymatic activity via high-throughput biochemical screening of 2,000 FDA-approved compounds; mitoxantrone inhibits USP11 activity in vitro with IC50 < 10 nM for PDA cell survival.","method":"High-throughput enzymatic screening, in vitro USP11 activity assay, cell viability assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay confirms inhibition, but mechanism of inhibition not fully characterized, single study","pmids":["23696131"],"is_preprint":false},{"year":2014,"finding":"USP11 deubiquitinates and stabilizes PML protein, counteracting PML ubiquitin ligases RNF4 and KLHL20-Cul3-Roc1. In glioma, the Notch/Hey1 pathway transcriptionally represses USP11, leading to PML destabilization; Hey1 upregulation correlates with USP11 and PML downregulation and high-grade malignancy.","method":"RNAi screening, co-immunoprecipitation, in vivo/in vitro deubiquitination assay, knockdown/overexpression, orthotopic mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi screen identification, deubiquitination assay, epistasis with RNF4/KLHL20, in vivo validation, multiple orthogonal methods","pmids":["24487962"],"is_preprint":false},{"year":2014,"finding":"USP11 forms a complex with p53, deubiquitinates p53, and stabilizes it; USP11 knockdown dramatically attenuates p53 induction in response to DNA damage stress.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, immunoblotting","journal":"Journal of Zhejiang University. Science. B","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and deubiquitination assay, single lab, limited orthogonal methods","pmids":["25471832"],"is_preprint":false},{"year":2015,"finding":"USP11 deubiquitylates γH2AX (but not canonical ubH2A-K119 or ubH2B-K120 in vitro); USP11 interacts with γH2AX both in vivo and in vitro. USP11 ablation enhances γH2AX ubiquitylation and causes misregulation and prolonged retention of 53BP1 and ubiquitin-conjugated proteins at DSB sites, with cellular hypersensitivity to γ-irradiation.","method":"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, siRNA knockdown, immunofluorescence foci analysis, clonogenic survival assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro DUB assay with substrate specificity testing, Co-IP, knockdown with functional readouts, multiple orthogonal approaches","pmids":["26507658"],"is_preprint":false},{"year":2015,"finding":"USP11 interacts with RNF4 (a SUMO-targeted ubiquitin E3 ligase) and deubiquitinates hybrid SUMO-ubiquitin chains to counteract RNF4 activity. USP11 stabilizes SUMO-enriched nuclear bodies, and in response to MMS-induced DNA damage, USP11 counteracts RNF4 to inhibit dissolution of nuclear bodies.","method":"Proteomic approach, co-immunoprecipitation, in vitro deubiquitination of SUMO-ubiquitin chains, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus in vitro DUB activity assay, single lab","pmids":["25969536"],"is_preprint":false},{"year":2015,"finding":"USP11 deubiquitylates and stabilizes cIAP2 specifically (not cIAP1), protecting it from proteasomal degradation. High USP11 expression confers resistance to Smac mimetic-induced cIAP2 degradation and apoptosis; the TNFα/JNK pathway induces USP11 expression to maintain cIAP2 stability.","method":"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, siRNA knockdown, apoptosis assay, xenograft model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, DUB assay, functional apoptosis readout, in vivo xenograft validation, multiple methods","pmids":["25613375"],"is_preprint":false},{"year":2016,"finding":"USP11 interacts with XIAP (identified by protein complex purification coupled with mass spectrometry) and deubiquitylates it, stabilizing XIAP and thereby inhibiting anoikis and apoptosis to promote mammary tumorigenesis. Leu207 on the BIR2 domain of XIAP is required for interaction with USP11.","method":"DUB screen (transformation assay), protein complex purification + MS, co-immunoprecipitation, in vitro deubiquitylation assay, mutagenesis, anoikis/apoptosis assay, tumor colony formation assay","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification, Co-IP, DUB assay, mutagenesis, multiple functional readouts in single comprehensive study","pmids":["28040451"],"is_preprint":false},{"year":2016,"finding":"USP11 deubiquitinates and stabilizes VGLL4 protein; the USP domain of USP11 and the N-terminal region of VGLL4 are required for binding. USP11 knockdown promotes cell growth and migration in a YAP-dependent manner, suggesting USP11 acts as a tumor suppressor through the VGLL4/YAP-TEAD regulatory loop.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, domain mapping, knockdown/overexpression, cell growth and migration assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with domain mapping, DUB assay, functional readout, single lab single study","pmids":["28042509"],"is_preprint":false},{"year":2016,"finding":"USP11 deubiquitinates and stabilizes TβRII (TGF-β receptor type II), promoting TGFβ-1 signaling including SMAD2/3 phosphorylation and expression of fibronectin and smooth muscle actin; inhibition or knockdown of USP11 increases TβRII ubiquitination and reduces stability.","method":"Co-immunoprecipitation, in vitro/in vivo deubiquitination assay, siRNA knockdown, overexpression, immunoblotting","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently replicated across two studies (PMID 22773947 for ALK5, this study for TβRII), Co-IP and DUB assays, multiple functional readouts","pmids":["27853171"],"is_preprint":false},{"year":2017,"finding":"USP11 positively regulates nucleotide excision repair (NER) by deubiquitinating XPC and promoting its retention at UV-induced DNA damage sites. UV irradiation induces USP11 recruitment to chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, chromatin fractionation, UV irradiation assay, NER functional assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, chromatin recruitment experiment, single lab","pmids":["29228550"],"is_preprint":false},{"year":2018,"finding":"USP11 deubiquitylates p21 in the nucleus, removing polyubiquitin chains and stabilizing p21 protein. USP11 reverses p21 polyubiquitylation mediated by SCF-SKP2, CRL4-CDT2, and APC/C-CDC20 in a cell-cycle-independent manner. Loss of USP11 causes p21 destabilization, inducing G1/S transition; DNA damage-induced p21 accumulation is abolished in USP11-depleted cells, abrogating the G2 checkpoint.","method":"Co-immunoprecipitation, in vivo and in vitro deubiquitylation assay, siRNA knockdown, cell cycle analysis, DNA damage assay, in vivo tumor model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods, multiple E3 ligases tested, in vivo tumor model, functional cell cycle readouts, comprehensive mechanistic study","pmids":["29666278"],"is_preprint":false},{"year":2018,"finding":"FASN-induced PI3K-S6Kinase signaling phosphorylates USP11, enhancing its interaction with eIF4B. USP11 stabilizes eIF4B by deubiquitination, thereby promoting oncogenic protein translation in DLBCL.","method":"Biochemical co-immunoprecipitation, mass spectrometry, pharmacological and genetic inhibition, in vitro/in vivo deubiquitination assay, translation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification of eIF4B as USP11 substrate, Co-IP, DUB assay, phosphorylation-dependent interaction confirmed, multiple orthogonal approaches","pmids":["29483509"],"is_preprint":false},{"year":2018,"finding":"USP11 deubiquitylates TβRII and stabilizes it in breast cancer cells, enhancing TGFβ downstream signaling and EMT. Modulating USP11 expression altered TβRII stability and breast cancer cell migratory capacity in vitro and metastasis in vivo.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA/overexpression, migration assay, in vivo metastasis model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — replicated TβRII deubiquitination finding from PMID 27853171; independent lab confirmation raises confidence","pmids":["29724812"],"is_preprint":false},{"year":2018,"finding":"USP11 deubiquitinates Snail and stabilizes it, promoting epithelial-to-mesenchymal transition in ovarian cancer cells.","method":"Co-immunoprecipitation, in vitro/in vivo deubiquitination assay, functional invasion/migration assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and DUB assay, single lab, single study","pmids":["30569152"],"is_preprint":false},{"year":2018,"finding":"A crystal structure of USP11 in complex with a phage-display-identified peptide revealed a previously unknown binding site in USP11's noncatalytic UBL region that is absent in paralogs USP4 and USP15. This binding site modulates USP11's function in homologous recombination-mediated DNA repair as shown by reporter assays with a binding pocket-deficient double mutant.","method":"Phage display (NGPD), isothermal titration calorimetry, X-ray crystallography, reporter assay with mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and reporter assay, paralog selectivity confirmed by ITC, multiple methods in one study","pmids":["30373771"],"is_preprint":false},{"year":2019,"finding":"PTEN transcriptionally upregulates USP11 via the PI3K/FOXO pathway; USP11 in turn deubiquitinates and stabilizes PTEN, creating a feedforward regulatory loop. Mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth, and metastasis.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, knockout mouse model, tumor assays, FOXO pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, DUB assay, in vivo Usp11 KO mouse model with tumor phenotype, pathway epistasis, multiple orthogonal methods","pmids":["30733438"],"is_preprint":false},{"year":2019,"finding":"USP11 acts as a histone deubiquitinase that catalyzes H2AK119 and H2BK120 deubiquitination. USP11 physically associates with the NuRD chromatin remodeling complex; USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and chromatin reorganization.","method":"Co-immunoprecipitation, in vitro/in vivo histone deubiquitination assay, chromatin condensation assay, DNA repair assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — histone DUB activity confirmed in vitro, NuRD complex interaction by Co-IP, functional DNA repair readouts, multiple methods","pmids":["31504778"],"is_preprint":false},{"year":2019,"finding":"USP11 stabilizes PPP1CA by deubiquitinating and protecting it from proteasomal degradation; the USP11/PPP1CA complex promotes colorectal cancer progression by activating the ERK/MAPK signaling pathway.","method":"LC-MS/MS protein interaction identification, co-immunoprecipitation, in vivo deubiquitination assay, knockdown/overexpression, in vitro and in vivo tumor assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS identification, Co-IP, DUB assay, functional tumor assays, single lab","pmids":["31521612"],"is_preprint":false},{"year":2020,"finding":"USP11 deubiquitinates ARID1A and stabilizes it; the E3 ligase TRIM32 opposes USP11 by targeting ARID1A for degradation. USP11 depletion promotes ARID1A degradation and SCC development, while TRIM32 depletion inhibits SCC by stabilizing ARID1A. Syndecan-2 (SDC2) is identified as a downstream target of both ARID1A and USP11.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, tumor proliferation/metastasis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, functional cancer readouts, single lab","pmids":["31914402"],"is_preprint":false},{"year":2020,"finding":"USP11 interacts with NF90 and deubiquitinates it, stabilizing NF90 protein levels in HCC cells; USP11-promoted HCC proliferation and metastasis is dependent on NF90.","method":"Mass spectrometry, co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, cell proliferation/metastasis assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS identification, Co-IP, DUB assay, functional rescue experiment, single lab","pmids":["32509388"],"is_preprint":false},{"year":2020,"finding":"CRL4-DCAF8 E3 ligase and USP11 oppositely regulate the stability of myeloid leukemia factors MLF1 and MLF2: DCAF8 promotes their degradation through ubiquitin-proteasome pathway while USP11 associates with MLF2 (and MLF1) and increases their stability.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP interaction shown but in vitro DUB activity not directly demonstrated, single lab, limited methods","pmids":["32703400"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates and stabilizes Beclin 1, promoting autophagy activation which in turn enhances ferroptosis after spinal cord ischemia-reperfusion injury. USP11 knockout reduces neuronal ferroptosis and improves functional recovery; autophagy inhibition weakens USP11-mediated ferroptosis.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, USP11 KO mouse model, autophagy/ferroptosis functional assays, in vitro knockdown/overexpression","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, in vivo KO model, functional epistasis, but single lab","pmids":["34839355"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates and stabilizes NRF2; USP11 depletion suppresses cell proliferation and induces ferroptotic cell death due to ROS-mediated stress, effects that are largely abrogated by NRF2 overexpression.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, overexpression rescue, cell death/proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, functional rescue, single lab, single study","pmids":["33531626"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates SPRTN metalloprotease by cleaving monoubiquitinated SPRTN in cells and in vitro. USP11 depletion impairs SPRTN deubiquitination, promotes SPRTN auto-proteolysis, causes accumulation of unrepaired DNA-protein cross-links, and hypersensitivity to DPC-inducing agents.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, DPC repair assay, formaldehyde sensitivity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro DUB assay with monoubiquitinated SPRTN substrate, Co-IP, knockdown with functional DPC repair readouts, multiple methods","pmids":["33567341"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates and stabilizes senataxin (SETX), preventing K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels, reduces R-loop dissolution, and causes accumulation of R-loops and DNA double-strand breaks. Compensatory transcriptional downregulation of the E3 ubiquitin ligase KEAP1 partially restores SETX levels in USP11 KO cells.","method":"Co-immunoprecipitation, in vivo ubiquitination analysis, USP11 KO cells, R-loop immunofluorescence, DSB assay, KEAP1 overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, KO cells with epistasis to KEAP1, functional R-loop and DSB readouts, comprehensive mechanistic study","pmids":["34526504"],"is_preprint":false},{"year":2021,"finding":"USP11 interacts with E2F1 and maintains E2F1 protein stability by removing its ubiquitin. E2F1 regulates USP11 expression at the transcriptional level, forming a positive feedback loop. This E2F1/USP11 axis promotes HCC proliferation, migration, and inhibits autophagy via ERK/mTOR pathway.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, ChIP/promoter analysis, siRNA knockdown, functional cell assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, transcriptional regulation confirmed, functional readouts, single lab","pmids":["34044068"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates KLF4 by removing K63-dependent polyubiquitination from it, thereby destabilizing KLF4 expression. USP11 depletion inhibits HCC cell growth and chemoresistance by enhancing KLF4 stability.","method":"Proteomic approach (IP/MS), co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, cell growth assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS identification, Co-IP, DUB assay with K63 linkage specificity, functional readouts, single lab","pmids":["34114341"],"is_preprint":false},{"year":2021,"finding":"USP11 restricts autophagy: USP11 KO in mammalian cells results in elevated autophagic flux. USP11 coprecipitates with autophagy-specific class III PI3K complex I and limits its interaction with NRBF2, decreasing lipid kinase activity and recruitment of WIPI proteins. USP11 also interacts with and stabilizes mTOR kinase. USP11 homolog depletion in C. elegans triggers hyperactivation of autophagy and protects against amyloid-β aggregation-induced paralysis.","method":"Co-immunoprecipitation, KO cell analysis, autophagic flux assay, PI3K activity assay, C. elegans genetic model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple substrates/interactions identified, KO phenotype, PI3K activity assay, cross-species validation, multiple orthogonal methods","pmids":["34600886"],"is_preprint":false},{"year":2021,"finding":"USP11 deubiquitinates RAE1, and USP11 is associated with the mitotic spindle. USP11 knockdown leads to multipolar spindle formation and drastically reduces cell proliferation; USP11 controls RAE1 ubiquitination at the mitotic spindle, modulating its interaction with NuMA.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, lentiviral knockdown, immunofluorescence (spindle localization), flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, spindle localization confirmed, functional multipolar spindle phenotype, single lab","pmids":["29293652"],"is_preprint":false},{"year":2021,"finding":"Mouse Usp11 stabilizes the transcription factor Sox11 via deubiquitination in the developing cerebral cortex. Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. A disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration.","method":"Usp11 knockout mouse, in vivo ubiquitination assay, immunoblotting, behavioral testing, cortical layer analysis, mutant rescue experiments","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO mouse, DUB assay, disease mutant analysis, multiple functional readouts (neurogenesis, migration, behavior)","pmids":["33579706"],"is_preprint":false},{"year":2021,"finding":"USP11 stabilizes p53 by deubiquitination and p53 transcriptionally represses KLF2, thereby activating the NF-κB pathway and promoting neuroinflammation after intracerebral hemorrhage. USP11 silencing blocks pro-inflammatory cytokine release by downregulating p53, protecting against neurological impairment.","method":"siRNA knockdown, co-immunoprecipitation, in vivo deubiquitination assay, ChIP (p53 binding to KLF2 promoter), in vivo rat ICH model","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, ChIP for pathway placement, in vivo model, single lab","pmids":["34141823"],"is_preprint":false},{"year":2022,"finding":"USP11 interacts with and deubiquitinates Sirt3, stabilizing it and thereby reducing oxidative stress-induced ferroptosis. USP11 knockout exacerbates intervertebral disc degeneration and is reversed by Sirt3 overexpression.","method":"IP/MS, co-immunoprecipitation, in vivo deubiquitination assay, Sirt3 KO mouse, USP11 KO mouse, rescue experiments","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — IP/MS identification, Co-IP, DUB assay, in vivo genetic rescue, multiple KO mouse models, comprehensive study","pmids":["37099926"],"is_preprint":false},{"year":2022,"finding":"ERK1/2 phosphorylates USP11 at Ser905, which promotes cytoplasmic localization of USP11. In the cytoplasm, USP11 colocalizes and interacts with p21, catalyzing removal of polyubiquitin chains from cytoplasmic p21 and stabilizing it. USP11-mediated stabilization of cytoplasmic p21 induces breast cancer cell proliferation.","method":"Phosphorylation mapping, co-immunoprecipitation, subcellular fractionation, in vitro/in vivo deubiquitination assay, knockdown/overexpression, cell proliferation assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phosphorylation site identified, Co-IP, DUB assay, localization experiment with functional consequence, single lab","pmids":["35414784"],"is_preprint":false},{"year":2022,"finding":"Non-mitochondrial HK2 directly interacts with CD133 and promotes binding of USP11 to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. USP11-mediated deubiquitination of CD133 enhances cancer stem cell stemness and tumor growth.","method":"Co-immunoprecipitation, mass spectrometry, in vitro/in vivo ubiquitination assay, immunofluorescence, flow cytometry","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, MS identification, DUB assay, functional stemness readouts, single lab","pmids":["35975322"],"is_preprint":false},{"year":2023,"finding":"USP11 interacts with LSH chromatin-remodeling protein and stabilizes it via deubiquitination; erastin treatment disrupts USP11-LSH interaction, increasing LSH ubiquitination and degradation. LSH binds the CYP24A1 promoter to promote its transcription, which inhibits ferroptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, ChIP analysis, siRNA knockdown, ferroptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, ChIP for pathway placement, single lab","pmids":["37414755"],"is_preprint":false},{"year":2023,"finding":"USP11 interacts with eEF1A1 and deubiquitinates it on Lys439, preventing ubiquitin-mediated degradation. Elevated eEF1A1 binds SP1, driving SP1-dependent HGF gene transcription and PI3K/AKT activation, promoting EMT and metastasis in HCC.","method":"Co-immunoprecipitation, in vivo deubiquitination assay with site-specific K439 mutant, ChIP, knockdown/overexpression, functional EMT/metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with site-specific mutant, DUB assay, pathway placement by ChIP, single lab","pmids":["37973952"],"is_preprint":false},{"year":2023,"finding":"USP11 stabilizes SMYD5 (a lysine methyltransferase) post-transcriptionally in the context of HIV-1 transcription; the Tat cofactor function of USP11 is required for SMYD5 protein level increases in cells expressing Tat. SMYD5 methylates Tat in vitro.","method":"siRNA knockdown, immunoblotting, in vitro methylation assay, co-immunoprecipitation","journal":"Cell reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence for USP11-SMYD5 stabilization; no direct DUB assay on SMYD5 by USP11 shown, single lab","pmids":["36897778"],"is_preprint":false},{"year":2024,"finding":"USP11 deubiquitinates both AR (androgen receptor) and c-Myc to increase their protein stability, and also deubiquitinates H2A-K119Ub (a repressive histone mark) on promoters of AR and c-Myc genes to increase their transcription. ChIP-seq with catalytic-inactive USP11 mutant confirmed both mechanisms.","method":"RNA-seq, ChIP-seq, catalytic-inactive mutant, co-immunoprecipitation, in vivo deubiquitination assay, knockdown/rescue, cell growth assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP-seq, catalytic mutant analysis, two distinct substrates and two distinct mechanisms (protein stabilization and histone mark), multiple orthogonal methods","pmids":["39052835"],"is_preprint":false},{"year":2024,"finding":"USP11 deubiquitinates and stabilizes DNMT3A, opposing degradation by CUL4-DCAF8 E3 ligase. USP11 also enhances DNMT3A SUMOylation by promoting DNMT3A interaction with SUMO E3 ligases, and enhances DNMT3A binding to the polycomb complex and maintains its DNA methyltransferase activity.","method":"Co-immunoprecipitation, in vivo ubiquitination/SUMOylation assays, USP11 stable expression rescue, E1 enzyme inhibition, immunoprecipitation with SUMO E3 ligases, MTase activity assay","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple assays in single preprint study, Co-IP, DUB assay, SUMOylation and enzymatic activity measurements, not yet peer-reviewed","pmids":["40161590"],"is_preprint":true},{"year":2024,"finding":"USP11 deubiquitinates E-cadherin at K738, stabilizing it. USP11 binds E-cadherin through its C-terminal region. This deubiquitinase activity of USP11 maintains luminal differentiation of mammary epithelial cells and suppresses luminal breast cancer; deubiquitinase-inactive USP11 mutant fails to support these functions.","method":"USP11 knockout mice, catalytic-inactive mutant, in vivo deubiquitination assay, site-specific K738 mutagenesis, co-immunoprecipitation, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-specific mutagenesis (K738), catalytic mutant, KO mouse model, Co-IP domain mapping, comprehensive mechanistic study","pmids":["39270819"],"is_preprint":false},{"year":2024,"finding":"USP11 depletion leads to increased MDM2 polyubiquitination and reduced MDM2 half-life, elevating p53 protein levels and p21 mRNA in a p53-dependent manner. USP11 acts as a deubiquitinase for MDM2, thereby regulating the MDM2-p53-p21 axis and cell cycle progression. USP11 depletion also promotes cellular senescence in a deubiquitinase-activity-dependent manner.","method":"siRNA knockdown, polyubiquitination assay, protein half-life analysis, immunoblotting, cell cycle analysis, senescence assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination and half-life assays, deubiquitinase-activity dependency shown, single lab, single study","pmids":["38901057"],"is_preprint":false},{"year":2024,"finding":"USP11 deubiquitinates TPIT transcription factor and stabilizes it in functioning ACTH pituitary tumors, thereby enhancing POMC transcription and ACTH secretion. USP11 knockdown reduces both POMC transcription and ACTH secretion in vitro and in vivo.","method":"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, in vivo model, POMC/ACTH secretion assay","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, knockdown with functional readout, single lab","pmids":["39910602"],"is_preprint":false},{"year":2024,"finding":"USP11 promotes angiogenesis by binding PRDX2 and removing its K63-linked polyubiquitination, facilitating PRDX2 nuclear translocation. Nuclear PRDX2 promotes concurrent nuclear translocation of c-MYC, which enhances transcription of KDR (VEGFR2) and activates VEGFR2 signaling. USP11 KO markedly inhibits angiogenesis in vivo and in vitro.","method":"Co-immunoprecipitation, in vivo deubiquitination assay (K63-linkage specificity), USP11 KO mouse model, retinal angiogenesis model, nuclear fractionation, reporter assay","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, K63-linkage DUB assay, KO mouse model, nuclear translocation experiment, single lab","pmids":["40199774"],"is_preprint":false},{"year":2025,"finding":"The UBL2 domain of USP11 directs its selectivity toward K48-linked polyubiquitin chains; removal of UBL2-IDR reduces ability to cleave K48 chains most significantly. This K48 chain selectivity function of UBL2 is not shared by paralogs USP4 and USP15. FDA-approved drugs Fenoldopam and Olanzapine were identified as selective USP11 inhibitors that act through a unique scaffold.","method":"In vitro Ub-tetramer cleavage assay, cell-based K48-ubiquitin analysis, UBL2 domain deletion/mutation, paralog comparison, AI-based virtual screening, in vitro and cell-based inhibitor assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined Ub chains, domain truncation and mutagenesis, paralog comparison, multiple orthogonal methods in one study","pmids":["41207628"],"is_preprint":false},{"year":2025,"finding":"RRM1 interacts with USP11 in the cytoplasm; ionizing radiation-induced recruitment of RRM1 to LaminB1 facilitates USP11 binding to the nuclear pore complex and nuclear translocation of USP11. In the nucleus, USP11 binds E2F1 and prevents ubiquitin-mediated E2F1 degradation, enhancing transcription of RAD51AP1 to promote homologous recombination.","method":"Co-immunoprecipitation, nuclear fractionation, NPC binding assay, in vivo ubiquitination assay, ChIP, dominant-negative RRM1 mutant, HR repair assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, nuclear translocation experiment, DUB assay, HR functional readout, single lab","pmids":["39695160"],"is_preprint":false},{"year":2025,"finding":"SPRYD3-MYCBP2 E3 ligase complex promotes ubiquitination of USP11 specifically at cysteine 318 (non-canonical ubiquitination), which promotes bipolar spindle formation and mitotic slippage in the presence of microtubule targeting drugs.","method":"Co-immunoprecipitation, ubiquitination site mapping (C318), site-directed mutagenesis, mitotic spindle assay, mitotic slippage assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — site-specific mutagenesis, functional spindle assay, novel non-canonical ubiquitination site identified, single lab","pmids":["41052634"],"is_preprint":false},{"year":2025,"finding":"USP11 deubiquitinates and stabilizes HINT3, and HINT3 interacts with BCL2. USP11 overexpression increases BCL2 levels, and HINT3 knockdown depletes BCL2, suggesting USP11 promotes endothelial apoptosis resistance in pulmonary arterial hypertension through HINT3-BCL2.","method":"Co-immunoprecipitation, in vivo ubiquitination/degradation assay, knockdown/overexpression, immunoblotting","journal":"Journal of respiratory biology and translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP interaction shown, no direct in vitro DUB assay for HINT3, indirect inference of mechanism, single lab","pmids":["40376595"],"is_preprint":false},{"year":2025,"finding":"USP11 interacts with and deubiquitinates GSK3β, modulating its Ser9 phosphorylation level and enzymatic activity, thereby impairing synaptic integrity in the prefrontal cortex under chronic stress. USP11 deficiency protects against stress-induced synaptic injury and depression-like behaviors via GSK3β/mTOR signaling.","method":"IP-MS, co-immunoprecipitation, in vivo deubiquitination assay, phosphorylation analysis, USP11 KO mouse, behavioral testing","journal":"Neurobiology of stress","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — IP-MS identification, Co-IP, DUB assay, phosphorylation measurement, KO mouse with behavioral readout, single lab","pmids":["41889422"],"is_preprint":false},{"year":2025,"finding":"USP11 interacts with and deubiquitinates PGAM5, stabilizing it in neurotoxic astrocytes after intracerebral hemorrhage. PGAM5 promotes mPTP opening and Drp1-mediated mitochondrial fission, amplifying mtDNA leakage and cGAS-STING pathway activation. Astrocyte-specific Usp11 KO suppresses neurotoxic astrocyte reactivity and improves neurological recovery.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, astrocyte-specific KO mouse, mitochondrial function assay, mtDNA quantification, cGAS-STING pathway analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, DUB assay, cell-type-specific KO, pathway placement, single lab","pmids":["41201111"],"is_preprint":false},{"year":2025,"finding":"Usp11 maintains survival of marginal zone B cells by regulating ubiquitination of Notch ligands DLL1 and JAG2; Usp11-/- mice show higher MZ B cell survival rates after total body irradiation.","method":"Co-IP, ubiquitination assay, Usp11-/- mouse model, flow cytometry, single-cell sequencing, histological analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, ubiquitination assay, KO mouse model, multiple cell analysis methods, single lab","pmids":["39904982"],"is_preprint":false},{"year":2025,"finding":"USP11 deubiquitinates OTUD5, and this mechanism implicates the OTUD5-STING signaling pathway in the inflammatory response of endothelial cells after radiation. USP11 KO mice show decreased radiation-induced pneumonitis with reduced proinflammatory cytokines.","method":"Comprehensive proteome and ubiquitinome analysis, co-immunoprecipitation, Western blot, Usp11-/- mouse model, cytokine measurement","journal":"International journal of radiation oncology, biology, physics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitinome MS, Co-IP, KO mouse, functional inflammation readouts, single lab","pmids":["38364946"],"is_preprint":false},{"year":2025,"finding":"USP11 stabilizes SFTPC (surfactant protein C) by interacting with, deubiquitinating it, and extending its half-life; USP11 stabilizes mutant SFTPC-I73T significantly more than wild-type. USP11 depletion in hiPSC-derived alveolar organoids mitigates SFTPC-I73T-induced fibrosis.","method":"CRISPR/Cas9 screen, immunoprecipitation, TUBEs assay for ubiquitination, hiPSC-derived alveolar organoids, bleomycin mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genome-wide CRISPR screen, Co-IP, TUBEs ubiquitination assay, organoid and in vivo model, single lab","pmids":["40225577"],"is_preprint":false},{"year":2025,"finding":"USP11 stabilizes EGFR and TRAF6 by removing K48-linked ubiquitin chains, preventing their proteasomal degradation; this potentiates both EGFR and Toll-like receptor signaling in colorectal cancer cells.","method":"Co-immunoprecipitation, in vivo K48-ubiquitination assay, USP11 KO and overexpression cell lines, xenograft model, mitoxantrone inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, K48-specific DUB assay, KO/OE functional readouts, xenograft model, single lab","pmids":["41419456"],"is_preprint":false},{"year":2025,"finding":"USP11 deubiquitinates CK2α, stabilizing its protein level and promoting mitochondrial dysfunction. USP11 KO in mouse prefrontal cortex protects against stress-induced synaptic injury and depressive-like behaviors, effects reversed by CK2α stabilization.","method":"IP-MS, co-immunoprecipitation, in vivo deubiquitination assay, USP11 KO mouse, CK2α inhibitor (CX4945), primary neuronal cultures","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — IP-MS, Co-IP, DUB assay, KO mouse with behavioral readout, pharmacological validation, single lab","pmids":["42231570"],"is_preprint":false}],"current_model":"USP11 is an X-linked deubiquitinase (cysteine protease, USP family) that localizes primarily to the nucleus and is phosphorylated by ERK1/2 at Ser905 to redistribute to the cytoplasm; its non-catalytic UBL2 domain confers selectivity for K48-linked polyubiquitin chains and provides a unique peptide-binding interface absent in paralogs USP4/USP15. USP11 stabilizes a broad array of substrates by deubiquitination—including BRCA2, p21, p53, MDM2, IκBα, ALK5/TβRII, PML, XIAP, cIAP2, NRF2, RAE1, Sox11, E-cadherin, senataxin, SPRTN, eIF4B, AR, c-Myc, H2AK119ub, γH2AX, Beclin-1, PTEN, VGLL4, and many others—and thereby regulates multiple cellular processes including DNA double-strand break repair by homologous recombination, NER, DNA-protein cross-link repair, R-loop homeostasis, autophagy, ferroptosis, NF-κB and TGFβ signaling, cell cycle progression, mitotic spindle integrity, cortical neurogenesis, and cancer cell survival and metastasis."},"narrative":{"mechanistic_narrative":"USP11 is an X-linked ubiquitin-specific protease (cysteine-protease deubiquitinase) that controls the stability and activity of a broad set of nuclear and cytoplasmic regulatory proteins, thereby governing DNA damage repair, cell-cycle progression, chromatin organization, and growth-factor signaling [PMID:15314155, PMID:29666278]. Its substrate selectivity is structurally encoded: a noncatalytic UBL2 domain bearing a peptide-binding interface absent from paralogs USP4/USP15 directs USP11 toward K48-linked polyubiquitin chains and modulates its DNA-repair function [PMID:30373771, PMID:41207628]. In the genome-maintenance arena, USP11 acts in BRCA2-dependent homologous recombination and is required for proper RAD51/53BP1 focus formation [PMID:15314155, PMID:20233726]; it deubiquitinates the DNA-damage substrates γH2AX, SPRTN, and senataxin to terminate repair signaling, resolve DNA-protein cross-links, and clear R-loops, and supports nucleotide excision repair by stabilizing XPC [PMID:26507658, PMID:33567341, PMID:34526504, PMID:29228550]. As a histone deubiquitinase acting on H2AK119ub/H2BK120ub in concert with the NuRD complex, USP11 couples chromatin reorganization to repair termination and also regulates transcription of target loci such as AR and c-Myc [PMID:31504778, PMID:39052835]. USP11 is a central rheostat of cell-cycle and tumor-suppressor circuits, stabilizing p21, p53, PTEN, and VGLL4 while also deubiquitinating MDM2 within the MDM2–p53–p21 axis [PMID:29666278, PMID:30733438, PMID:28042509, PMID:38901057]. It amplifies TGFβ signaling by stabilizing the receptors ALK5 and TβRII to drive SMAD2/3 activation and EMT [PMID:22773947, PMID:27853171], and it tunes NF-κB signaling through IκBα and IKKα [PMID:19874889, PMID:17897950]. USP11 further restrains autophagy by limiting class III PI3K complex activity and stabilizing mTOR, while stabilizing Beclin-1, NRF2, and Sirt3 to modulate autophagic flux and ferroptosis [PMID:34600886, PMID:34839355, PMID:33531626, PMID:37099926]. ERK1/2 phosphorylation at Ser905 redistributes USP11 to the cytoplasm to stabilize cytoplasmic p21, linking signaling input to subcellular substrate choice [PMID:35414784]. In vivo, Usp11 stabilizes the transcription factor Sox11 to support cortical neurogenesis and neuronal migration, with a disease-associated mutant failing to rescue these functions [PMID:33579706].","teleology":[{"year":2002,"claim":"Established USP11 as a functional deubiquitinase with a defined nuclear substrate, answering whether the enzyme protects specific proteins from proteasomal turnover.","evidence":"Y2H, Co-IP, in vitro/in vivo deubiquitination and pulse-chase of RanBPM","pmids":["12084015"],"confidence":"High","gaps":["Did not define chain-linkage specificity","No structural basis for substrate recognition"]},{"year":2004,"claim":"Placed USP11 in the BRCA2 DNA-damage repair pathway, addressing whether the enzyme has a genome-maintenance role beyond isolated substrate stabilization.","evidence":"Immunopurification-MS, reciprocal Co-IP, catalytic mutant, RNAi, mitomycin C survival in BRCA2-dependent manner","pmids":["15314155"],"confidence":"High","gaps":["Direct repair substrate within the pathway not defined","Mechanism of recruitment to damage sites unknown"]},{"year":2010,"claim":"Demonstrated that USP11 catalytic activity is required for homologous recombination and proper RAD51/53BP1 focus formation, establishing a direct functional requirement in DSB repair.","evidence":"RNAi, HR reporter assay, PARP inhibitor/IR sensitivity, immunofluorescence foci","pmids":["20233726"],"confidence":"High","gaps":["Repair substrate deubiquitinated at foci not yet identified","Distinction between HR and NHEJ roles unclear"]},{"year":2010,"claim":"Defined USP11 as a deubiquitinase of IκBα and a regulator of NF-κB, with evidence for both catalytic and non-catalytic functions in signaling.","evidence":"Recombinant in vitro DUB assay, knockdown/overexpression, catalytic mutant, NF-κB reporter","pmids":["19874889","17897950"],"confidence":"High","gaps":["Molecular basis of the non-catalytic NF-κB function unresolved","Relationship between IKKα transcriptional and IκBα post-translational roles unclear"]},{"year":2012,"claim":"Showed USP11 amplifies TGFβ signaling by deubiquitinating and stabilizing the receptor ALK5, establishing a receptor-level mechanism for promoting EMT.","evidence":"Reciprocal Co-IP with SMAD7, in vitro/in vivo DUB assay, SMAD2/3 phosphorylation and EMT readouts","pmids":["22773947"],"confidence":"High","gaps":["Whether SMAD7 recruits USP11 to the receptor not fully resolved"]},{"year":2014,"claim":"Extended USP11 substrate range to tumor-suppressor and apoptotic regulators (PML, p53), and showed transcriptional repression of USP11 by Notch/Hey1 links it to glioma malignancy.","evidence":"RNAi screen, Co-IP, in vivo/in vitro DUB assays, orthotopic mouse model (PML); Co-IP and DUB assay (p53)","pmids":["24487962","25471832"],"confidence":"High","gaps":["p53 finding rests on limited orthogonal methods","Competition between USP11 and the RNF4/KLHL20 ligases not quantified"]},{"year":2016,"claim":"Consolidated USP11 as a stabilizer of apoptosis inhibitors and growth regulators (cIAP2, XIAP, VGLL4, TβRII), connecting it to apoptosis resistance and YAP/TGFβ axes in cancer.","evidence":"Co-IP/MS, in vitro/in vivo DUB assays, mutagenesis (XIAP BIR2 Leu207), domain mapping, anoikis/apoptosis and xenograft assays","pmids":["25613375","28040451","28042509","27853171"],"confidence":"High","gaps":["Determinants of substrate selectivity (e.g. cIAP2 over cIAP1) not structurally explained","Tumor-suppressor vs oncogenic role appears context-dependent"]},{"year":2018,"claim":"Defined USP11 as a master stabilizer of the CDK inhibitor p21 against multiple E3 ligases, establishing direct control over G1/S transition and the G2 DNA-damage checkpoint.","evidence":"In vivo/in vitro DUB assays reversing SCF-SKP2, CRL4-CDT2, APC/C-CDC20 ubiquitylation; cell-cycle and DNA-damage analyses; in vivo tumor model","pmids":["29666278"],"confidence":"High","gaps":["How USP11 outcompetes diverse ligases on a single substrate not defined"]},{"year":2018,"claim":"Solved a crystal structure revealing a unique UBL-region peptide-binding site absent in USP4/USP15 that modulates HR repair, providing the first structural basis for paralog-selective function.","evidence":"Phage display, ITC, X-ray crystallography, reporter assay with binding-pocket double mutant","pmids":["30373771"],"confidence":"High","gaps":["Endogenous ligand of the binding pocket not identified","Link between pocket occupancy and catalytic output not resolved"]},{"year":2019,"claim":"Identified USP11 as a histone deubiquitinase acting with the NuRD complex, and as a node in a PTEN feedforward loop, integrating chromatin reorganization and PI3K/FOXO signaling.","evidence":"In vitro/in vivo histone DUB assays (H2AK119ub/H2BK120ub), Co-IP with NuRD, DNA-repair readouts; Co-IP, DUB assay and Usp11 KO mouse tumor model for PTEN","pmids":["31504778","30733438"],"confidence":"High","gaps":["Recruitment of USP11 to specific chromatin loci not defined","Apparent substrate-specificity discrepancy with earlier γH2AX-only finding [#10] unreconciled"]},{"year":2021,"claim":"Expanded the genome-maintenance role to DNA-protein cross-link repair and R-loop homeostasis through deubiquitination of SPRTN and senataxin.","evidence":"In vitro DUB assays on monoubiquitinated SPRTN and K48-ubiquitinated SETX, KO cells, DPC/R-loop/DSB functional readouts, KEAP1 epistasis","pmids":["33567341","34526504"],"confidence":"High","gaps":["Timing of USP11 action relative to substrate function not resolved","Whether these activities require chromatin recruitment cofactors unknown"]},{"year":2021,"claim":"Defined a role for USP11 in restraining autophagy and in spindle integrity and cortical neurogenesis, broadening its physiological reach to cell division and neural development.","evidence":"KO cells with autophagic-flux and PI3K activity assays, C. elegans model (autophagy); spindle localization and multipolar-spindle phenotype (RAE1); Usp11 KO mouse with Sox11 DUB assay, neurogenesis, migration and behavior","pmids":["34600886","29293652","33579706"],"confidence":"High","gaps":["Direct vs indirect effects on the class III PI3K complex not fully separated","Whether a defined Mendelian disease arises from the Sox11-linked mutant not established here"]},{"year":2022,"claim":"Established phosphorylation-controlled subcellular partitioning of USP11, linking ERK1/2 signaling to cytoplasmic substrate engagement.","evidence":"Phospho-site mapping (Ser905), subcellular fractionation, Co-IP and DUB assay of cytoplasmic p21, proliferation readout","pmids":["35414784"],"confidence":"Medium","gaps":["Single lab","How cytoplasmic vs nuclear p21 pools differ functionally not fully resolved"]},{"year":2024,"claim":"Demonstrated dual transcriptional control by USP11 (substrate protein stabilization plus histone-mark erasure at target promoters), unifying its post-translational and chromatin functions for AR and c-Myc.","evidence":"RNA-seq, ChIP-seq with catalytic-inactive mutant, Co-IP, in vivo DUB assays for AR/c-Myc protein and H2A-K119Ub at promoters","pmids":["39052835"],"confidence":"High","gaps":["Generality of the dual mechanism beyond AR/c-Myc loci untested","Recruitment specificity to these promoters not defined"]},{"year":2025,"claim":"Mapped UBL2 as the determinant of K48-linkage selectivity and identified selective small-molecule inhibitors, providing a biochemical and pharmacological handle on USP11.","evidence":"In vitro Ub-tetramer cleavage, UBL2 deletion/mutation, paralog comparison, AI-based virtual screening and inhibitor assays (Fenoldopam, Olanzapine)","pmids":["41207628"],"confidence":"High","gaps":["Structural mechanism of inhibitor binding not detailed","How K48 selectivity reconciles with reported K63-substrate activity unresolved"]},{"year":2025,"claim":"Revealed regulation of USP11 itself, including IR-induced RRM1-dependent nuclear import for E2F1-driven HR transcription and non-canonical ubiquitination at Cys318 controlling mitotic behavior.","evidence":"Co-IP, nuclear fractionation/NPC binding, ChIP, HR assay (RRM1/E2F1); ubiquitination-site mapping and spindle/slippage assays (SPRYD3-MYCBP2 at C318)","pmids":["39695160","41052634"],"confidence":"Medium","gaps":["Both rest on single-lab datasets","Functional integration of import control with cytoplasmic ERK-phospho redistribution unclear"]},{"year":null,"claim":"How USP11 achieves substrate and linkage selectivity across its very large substrate set in vivo, and how its many context-dependent oncogenic versus tumor-suppressive roles are determined, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model reconciling K48 selectivity with reported K63 substrates","Determinants directing USP11 to a given substrate in a given cell type unknown","Whether a defined human Mendelian disorder is causally linked not established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,4,6,10,17,23,30,31,44,50]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,30,50]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[10,23,44]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,17,23,51]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[39,40,51]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[35]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,5,10,16,30,31,51]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[17,35,47,52]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,6,15,19]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[23,44]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[28,34]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,17,30]}],"complexes":["NuRD complex"],"partners":["BRCA2","SMAD7","XIAP","RNF4","E2F1","P53","MDM2","RANBPM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51784","full_name":"Ubiquitin carboxyl-terminal hydrolase 11","aliases":["Deubiquitinating enzyme 11","Ubiquitin thioesterase 11","Ubiquitin-specific-processing protease 11"],"length_aa":963,"mass_kda":109.8,"function":"Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains (PubMed:12084015, PubMed:15314155, PubMed:17897950, PubMed:19874889, PubMed:20233726, PubMed:24724799, PubMed:28992046). Inhibits the degradation of target proteins by the proteasome (PubMed:12084015). Cleaves preferentially 'Lys-6' and 'Lys-63'-linked ubiquitin chains. Has lower activity with 'Lys-11' and 'Lys-33'-linked ubiquitin chains, and extremely low activity with 'Lys-27', 'Lys-29' and 'Lys-48'-linked ubiquitin chains (in vitro) (PubMed:24724799). Plays a role in the regulation of pathways leading to NF-kappa-B activation (PubMed:17897950, PubMed:19874889). Plays a role in the regulation of DNA repair after double-stranded DNA breaks (PubMed:15314155, PubMed:20233726). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Promotes cell proliferation by deubiquitinating phosphorylated E2F1 (PubMed:28992046)","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/P51784/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP11","total_profiled":1310},"omim":[{"mim_id":"300050","title":"UBIQUITIN-SPECIFIC PROTEASE 11; USP11","url":"https://www.omim.org/entry/300050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":169.4}],"url":"https://www.proteinatlas.org/search/USP11"},"hgnc":{"alias_symbol":["UHX1"],"prev_symbol":[]},"alphafold":{"accession":"P51784","domains":[{"cath_id":"3.30.2230.10","chopping":"78-192","consensus_level":"high","plddt":88.5583,"start":78,"end":192},{"cath_id":"3.10.20.90","chopping":"198-277","consensus_level":"medium","plddt":92.333,"start":198,"end":277},{"cath_id":"3.10.20.90","chopping":"495-646_716-730_739-771","consensus_level":"medium","plddt":85.643,"start":495,"end":771}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51784","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51784-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51784-F1-predicted_aligned_error_v6.png","plddt_mean":78.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP11","jax_strain_url":"https://www.jax.org/strain/search?query=USP11"},"sequence":{"accession":"P51784","fasta_url":"https://rest.uniprot.org/uniprotkb/P51784.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51784/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51784"}},"corpus_meta":[{"pmid":"34839355","id":"PMC_34839355","title":"USP11 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40736712","citation_count":0,"is_preprint":false},{"pmid":"40376595","id":"PMC_40376595","title":"USP11 Promotes Endothelial Apoptosis-Resistance in Pulmonary Arterial Hypertension by Deubiquitinating HINT3.","date":"2025","source":"Journal of respiratory biology and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40376595","citation_count":0,"is_preprint":false},{"pmid":"41461277","id":"PMC_41461277","title":"Discovery, development, and characterization of potent and selective USP11 inhibitors.","date":"2025","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/41461277","citation_count":0,"is_preprint":false},{"pmid":"41033073","id":"PMC_41033073","title":"USP11 is involved in the sensitivity of liver cancer cells to ferroptosis and taxanes through the regulation of NRF2 ubiquitin-mediated degradation.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41033073","citation_count":0,"is_preprint":false},{"pmid":"41207628","id":"PMC_41207628","title":"Non-catalytic UBL2 domain directs deubiquitinase USP11 toward K48-linked polyubiquitin chains.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41207628","citation_count":0,"is_preprint":false},{"pmid":"41889422","id":"PMC_41889422","title":"USP11 drives stress-induced synaptic structural deficits and depression-like behaviors through GSK3β/mTOR signaling.","date":"2026","source":"Neurobiology of stress","url":"https://pubmed.ncbi.nlm.nih.gov/41889422","citation_count":0,"is_preprint":false},{"pmid":"41052634","id":"PMC_41052634","title":"The E3 ubiquitin ligase SPRYD3-MYCBP2(PAM) regulates mitotic cell fate and ubiquitination of USP11 to control spindle assembly.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41052634","citation_count":0,"is_preprint":false},{"pmid":"41298816","id":"PMC_41298816","title":"The Rac1-USP11 feedback amplification loop: a radiation-activated engine driving radioresistance in hepatocellular carcinoma.","date":"2025","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41298816","citation_count":0,"is_preprint":false},{"pmid":"42231570","id":"PMC_42231570","title":"X-Linked USP11 Drives Depression-Like Behaviors by Stabilizing CK2α and Disrupting Mitochondrial Function.","date":"2026","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/42231570","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.22.676098","title":"Systematic Discovery of Motif-based Interactions of the Auxiliary Domains of USP Family Deubiquitinases","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.22.676098","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.13.659525","title":"Assessing the Suitability of Deubiquitylases As Substrates For Targeted Protein Degradation","date":"2025-06-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.659525","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":100880,"output_tokens":31132,"usd":0.57396,"retried_sync":true,"stage1_stop_reason":"max_tokens"},"stage2":{"model":"claude-opus-4-8","input_tokens":27510,"output_tokens":5729,"usd":0.140387,"stage2_stop_reason":"end_turn"},"total_usd":0.714347,"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\": 2002,\n      \"finding\": \"USP11 localizes primarily to the nucleus in non-dividing cells and physically interacts with RanBPM (a RanGTP-binding protein) as confirmed by yeast two-hybrid and co-immunoprecipitation. USP11 deubiquitinates RanBPM in vitro and in vivo, protecting it from proteasomal degradation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro/in vivo ubiquitination assay, pulse-chase analysis, immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro deubiquitination assay, proteasome inhibitor pulse-chase) in a single focused study\",\n      \"pmids\": [\"12084015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"USP11 forms a specific complex with BRCA2 (identified by immunopurification-mass spectrometry) and can deubiquitinate BRCA2 in overexpression assays; a catalytically inactive USP11 mutant had no effect on BRCA2 ubiquitination or protein levels. Loss of USP11 function (dominant-negative or RNAi) increased cellular sensitivity to mitomycin C in a BRCA2-dependent manner, placing USP11 in the BRCA2 DNA damage repair pathway.\",\n      \"method\": \"Immunopurification-mass spectrometry, co-immunoprecipitation, catalytic mutant analysis, RNAi knockdown, cell survival assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, MS identification, catalytic mutant, epistasis with BRCA2, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15314155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"USP11 knockdown attenuates IKKα expression at the transcriptional level and enhances NF-κB activation in response to TNFα. USP11 knockdown or IKKα knockdown abrogates p53 induction upon TNFα exposure; ectopic IKKα rescues p53 expression in USP11-silenced cells, establishing USP11 as an upstream regulator of an IKKα-p53 signaling pathway.\",\n      \"method\": \"siRNA knockdown, immunoblotting, reporter assays, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis established by rescue experiment, single lab, single publication\",\n      \"pmids\": [\"17897950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"USP11 interacts with HPV-16 E7 (identified by yeast two-hybrid) and stabilizes E7 by removing ubiquitin chains and reducing degradation; a catalytically inactive USP11 mutant abolished deubiquitinating activity and returned E7 to normal degradation rates. USP11-mediated E7 stabilization modulated E7's effects on cell growth.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro deubiquitination assay, catalytic mutant analysis, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, in vitro DUB assay, catalytic mutant) in single focused study\",\n      \"pmids\": [\"18408009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"USP11 acts as a deubiquitinase for IκBα: recombinant USP11 catalyzes IκBα deubiquitination in vitro; USP11 overexpression inhibits IκBα ubiquitination and USP11 knockdown enhances TNFα-induced IκBα ubiquitination and NF-κB activation. A catalytically inactive USP11 mutant partially inhibits NF-κB activation, indicating a non-catalytic function as well.\",\n      \"method\": \"Proteomic approach (co-IP identification), in vitro deubiquitination assay, siRNA knockdown, overexpression, catalytic mutant analysis, reporter assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, co-IP, catalytic mutant, knockdown and overexpression all in one study\",\n      \"pmids\": [\"19874889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"USP11 participates in homologous recombination (HR) repair of DNA double-strand breaks. RNAi silencing of USP11 causes spontaneous DNA damage response activation, hypersensitivity to PARP inhibition and ionizing radiation, and defective HR repair. USP11 catalytic activity is required for proper recruitment of RAD51 and 53BP1 to repair foci.\",\n      \"method\": \"RNAi screen, siRNA knockdown, PARP inhibitor sensitivity assay, HR repair assay, immunofluorescence foci analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional HR assay, foci recruitment assay, catalytic activity requirement, multiple readouts in single study\",\n      \"pmids\": [\"20233726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP11 interacts with SMAD7 and deubiquitylates the type I TGFβ receptor ALK5, thereby stabilizing it and enhancing TGFβ-induced gene transcription. USP11 deubiquitylase activity is required to augment TGFβ signaling. RNAi depletion of USP11 inhibits TGFβ-induced SMAD2/3 phosphorylation, transcriptional responses, and epithelial-to-mesenchymal transition.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, RNAi knockdown, reporter assay, SMAD2/3 phosphorylation assay, EMT assay\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, deubiquitylation assay, multiple functional readouts (signaling, transcription, EMT), single lab\",\n      \"pmids\": [\"22773947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mitoxantrone was identified as an inhibitor of USP11 enzymatic activity via high-throughput biochemical screening of 2,000 FDA-approved compounds; mitoxantrone inhibits USP11 activity in vitro with IC50 < 10 nM for PDA cell survival.\",\n      \"method\": \"High-throughput enzymatic screening, in vitro USP11 activity assay, cell viability assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay confirms inhibition, but mechanism of inhibition not fully characterized, single study\",\n      \"pmids\": [\"23696131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP11 deubiquitinates and stabilizes PML protein, counteracting PML ubiquitin ligases RNF4 and KLHL20-Cul3-Roc1. In glioma, the Notch/Hey1 pathway transcriptionally represses USP11, leading to PML destabilization; Hey1 upregulation correlates with USP11 and PML downregulation and high-grade malignancy.\",\n      \"method\": \"RNAi screening, co-immunoprecipitation, in vivo/in vitro deubiquitination assay, knockdown/overexpression, orthotopic mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen identification, deubiquitination assay, epistasis with RNF4/KLHL20, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"24487962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP11 forms a complex with p53, deubiquitinates p53, and stabilizes it; USP11 knockdown dramatically attenuates p53 induction in response to DNA damage stress.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, immunoblotting\",\n      \"journal\": \"Journal of Zhejiang University. Science. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and deubiquitination assay, single lab, limited orthogonal methods\",\n      \"pmids\": [\"25471832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP11 deubiquitylates γH2AX (but not canonical ubH2A-K119 or ubH2B-K120 in vitro); USP11 interacts with γH2AX both in vivo and in vitro. USP11 ablation enhances γH2AX ubiquitylation and causes misregulation and prolonged retention of 53BP1 and ubiquitin-conjugated proteins at DSB sites, with cellular hypersensitivity to γ-irradiation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, siRNA knockdown, immunofluorescence foci analysis, clonogenic survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro DUB assay with substrate specificity testing, Co-IP, knockdown with functional readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"26507658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP11 interacts with RNF4 (a SUMO-targeted ubiquitin E3 ligase) and deubiquitinates hybrid SUMO-ubiquitin chains to counteract RNF4 activity. USP11 stabilizes SUMO-enriched nuclear bodies, and in response to MMS-induced DNA damage, USP11 counteracts RNF4 to inhibit dissolution of nuclear bodies.\",\n      \"method\": \"Proteomic approach, co-immunoprecipitation, in vitro deubiquitination of SUMO-ubiquitin chains, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus in vitro DUB activity assay, single lab\",\n      \"pmids\": [\"25969536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP11 deubiquitylates and stabilizes cIAP2 specifically (not cIAP1), protecting it from proteasomal degradation. High USP11 expression confers resistance to Smac mimetic-induced cIAP2 degradation and apoptosis; the TNFα/JNK pathway induces USP11 expression to maintain cIAP2 stability.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo deubiquitylation assay, siRNA knockdown, apoptosis assay, xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, DUB assay, functional apoptosis readout, in vivo xenograft validation, multiple methods\",\n      \"pmids\": [\"25613375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP11 interacts with XIAP (identified by protein complex purification coupled with mass spectrometry) and deubiquitylates it, stabilizing XIAP and thereby inhibiting anoikis and apoptosis to promote mammary tumorigenesis. Leu207 on the BIR2 domain of XIAP is required for interaction with USP11.\",\n      \"method\": \"DUB screen (transformation assay), protein complex purification + MS, co-immunoprecipitation, in vitro deubiquitylation assay, mutagenesis, anoikis/apoptosis assay, tumor colony formation assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, Co-IP, DUB assay, mutagenesis, multiple functional readouts in single comprehensive study\",\n      \"pmids\": [\"28040451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP11 deubiquitinates and stabilizes VGLL4 protein; the USP domain of USP11 and the N-terminal region of VGLL4 are required for binding. USP11 knockdown promotes cell growth and migration in a YAP-dependent manner, suggesting USP11 acts as a tumor suppressor through the VGLL4/YAP-TEAD regulatory loop.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, domain mapping, knockdown/overexpression, cell growth and migration assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with domain mapping, DUB assay, functional readout, single lab single study\",\n      \"pmids\": [\"28042509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP11 deubiquitinates and stabilizes TβRII (TGF-β receptor type II), promoting TGFβ-1 signaling including SMAD2/3 phosphorylation and expression of fibronectin and smooth muscle actin; inhibition or knockdown of USP11 increases TβRII ubiquitination and reduces stability.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo deubiquitination assay, siRNA knockdown, overexpression, immunoblotting\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently replicated across two studies (PMID 22773947 for ALK5, this study for TβRII), Co-IP and DUB assays, multiple functional readouts\",\n      \"pmids\": [\"27853171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP11 positively regulates nucleotide excision repair (NER) by deubiquitinating XPC and promoting its retention at UV-induced DNA damage sites. UV irradiation induces USP11 recruitment to chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, chromatin fractionation, UV irradiation assay, NER functional assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, chromatin recruitment experiment, single lab\",\n      \"pmids\": [\"29228550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP11 deubiquitylates p21 in the nucleus, removing polyubiquitin chains and stabilizing p21 protein. USP11 reverses p21 polyubiquitylation mediated by SCF-SKP2, CRL4-CDT2, and APC/C-CDC20 in a cell-cycle-independent manner. Loss of USP11 causes p21 destabilization, inducing G1/S transition; DNA damage-induced p21 accumulation is abolished in USP11-depleted cells, abrogating the G2 checkpoint.\",\n      \"method\": \"Co-immunoprecipitation, in vivo and in vitro deubiquitylation assay, siRNA knockdown, cell cycle analysis, DNA damage assay, in vivo tumor model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods, multiple E3 ligases tested, in vivo tumor model, functional cell cycle readouts, comprehensive mechanistic study\",\n      \"pmids\": [\"29666278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FASN-induced PI3K-S6Kinase signaling phosphorylates USP11, enhancing its interaction with eIF4B. USP11 stabilizes eIF4B by deubiquitination, thereby promoting oncogenic protein translation in DLBCL.\",\n      \"method\": \"Biochemical co-immunoprecipitation, mass spectrometry, pharmacological and genetic inhibition, in vitro/in vivo deubiquitination assay, translation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of eIF4B as USP11 substrate, Co-IP, DUB assay, phosphorylation-dependent interaction confirmed, multiple orthogonal approaches\",\n      \"pmids\": [\"29483509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP11 deubiquitylates TβRII and stabilizes it in breast cancer cells, enhancing TGFβ downstream signaling and EMT. Modulating USP11 expression altered TβRII stability and breast cancer cell migratory capacity in vitro and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA/overexpression, migration assay, in vivo metastasis model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — replicated TβRII deubiquitination finding from PMID 27853171; independent lab confirmation raises confidence\",\n      \"pmids\": [\"29724812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP11 deubiquitinates Snail and stabilizes it, promoting epithelial-to-mesenchymal transition in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo deubiquitination assay, functional invasion/migration assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and DUB assay, single lab, single study\",\n      \"pmids\": [\"30569152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A crystal structure of USP11 in complex with a phage-display-identified peptide revealed a previously unknown binding site in USP11's noncatalytic UBL region that is absent in paralogs USP4 and USP15. This binding site modulates USP11's function in homologous recombination-mediated DNA repair as shown by reporter assays with a binding pocket-deficient double mutant.\",\n      \"method\": \"Phage display (NGPD), isothermal titration calorimetry, X-ray crystallography, reporter assay with mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and reporter assay, paralog selectivity confirmed by ITC, multiple methods in one study\",\n      \"pmids\": [\"30373771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN transcriptionally upregulates USP11 via the PI3K/FOXO pathway; USP11 in turn deubiquitinates and stabilizes PTEN, creating a feedforward regulatory loop. Mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth, and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, knockout mouse model, tumor assays, FOXO pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, DUB assay, in vivo Usp11 KO mouse model with tumor phenotype, pathway epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"30733438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP11 acts as a histone deubiquitinase that catalyzes H2AK119 and H2BK120 deubiquitination. USP11 physically associates with the NuRD chromatin remodeling complex; USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and chromatin reorganization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo histone deubiquitination assay, chromatin condensation assay, DNA repair assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — histone DUB activity confirmed in vitro, NuRD complex interaction by Co-IP, functional DNA repair readouts, multiple methods\",\n      \"pmids\": [\"31504778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP11 stabilizes PPP1CA by deubiquitinating and protecting it from proteasomal degradation; the USP11/PPP1CA complex promotes colorectal cancer progression by activating the ERK/MAPK signaling pathway.\",\n      \"method\": \"LC-MS/MS protein interaction identification, co-immunoprecipitation, in vivo deubiquitination assay, knockdown/overexpression, in vitro and in vivo tumor assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS identification, Co-IP, DUB assay, functional tumor assays, single lab\",\n      \"pmids\": [\"31521612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP11 deubiquitinates ARID1A and stabilizes it; the E3 ligase TRIM32 opposes USP11 by targeting ARID1A for degradation. USP11 depletion promotes ARID1A degradation and SCC development, while TRIM32 depletion inhibits SCC by stabilizing ARID1A. Syndecan-2 (SDC2) is identified as a downstream target of both ARID1A and USP11.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, tumor proliferation/metastasis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, functional cancer readouts, single lab\",\n      \"pmids\": [\"31914402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP11 interacts with NF90 and deubiquitinates it, stabilizing NF90 protein levels in HCC cells; USP11-promoted HCC proliferation and metastasis is dependent on NF90.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, cell proliferation/metastasis assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS identification, Co-IP, DUB assay, functional rescue experiment, single lab\",\n      \"pmids\": [\"32509388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRL4-DCAF8 E3 ligase and USP11 oppositely regulate the stability of myeloid leukemia factors MLF1 and MLF2: DCAF8 promotes their degradation through ubiquitin-proteasome pathway while USP11 associates with MLF2 (and MLF1) and increases their stability.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP interaction shown but in vitro DUB activity not directly demonstrated, single lab, limited methods\",\n      \"pmids\": [\"32703400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates and stabilizes Beclin 1, promoting autophagy activation which in turn enhances ferroptosis after spinal cord ischemia-reperfusion injury. USP11 knockout reduces neuronal ferroptosis and improves functional recovery; autophagy inhibition weakens USP11-mediated ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, USP11 KO mouse model, autophagy/ferroptosis functional assays, in vitro knockdown/overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, in vivo KO model, functional epistasis, but single lab\",\n      \"pmids\": [\"34839355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates and stabilizes NRF2; USP11 depletion suppresses cell proliferation and induces ferroptotic cell death due to ROS-mediated stress, effects that are largely abrogated by NRF2 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, overexpression rescue, cell death/proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, functional rescue, single lab, single study\",\n      \"pmids\": [\"33531626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates SPRTN metalloprotease by cleaving monoubiquitinated SPRTN in cells and in vitro. USP11 depletion impairs SPRTN deubiquitination, promotes SPRTN auto-proteolysis, causes accumulation of unrepaired DNA-protein cross-links, and hypersensitivity to DPC-inducing agents.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, DPC repair assay, formaldehyde sensitivity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro DUB assay with monoubiquitinated SPRTN substrate, Co-IP, knockdown with functional DPC repair readouts, multiple methods\",\n      \"pmids\": [\"33567341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates and stabilizes senataxin (SETX), preventing K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels, reduces R-loop dissolution, and causes accumulation of R-loops and DNA double-strand breaks. Compensatory transcriptional downregulation of the E3 ubiquitin ligase KEAP1 partially restores SETX levels in USP11 KO cells.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination analysis, USP11 KO cells, R-loop immunofluorescence, DSB assay, KEAP1 overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, KO cells with epistasis to KEAP1, functional R-loop and DSB readouts, comprehensive mechanistic study\",\n      \"pmids\": [\"34526504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 interacts with E2F1 and maintains E2F1 protein stability by removing its ubiquitin. E2F1 regulates USP11 expression at the transcriptional level, forming a positive feedback loop. This E2F1/USP11 axis promotes HCC proliferation, migration, and inhibits autophagy via ERK/mTOR pathway.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, ChIP/promoter analysis, siRNA knockdown, functional cell assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, transcriptional regulation confirmed, functional readouts, single lab\",\n      \"pmids\": [\"34044068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates KLF4 by removing K63-dependent polyubiquitination from it, thereby destabilizing KLF4 expression. USP11 depletion inhibits HCC cell growth and chemoresistance by enhancing KLF4 stability.\",\n      \"method\": \"Proteomic approach (IP/MS), co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, cell growth assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS identification, Co-IP, DUB assay with K63 linkage specificity, functional readouts, single lab\",\n      \"pmids\": [\"34114341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 restricts autophagy: USP11 KO in mammalian cells results in elevated autophagic flux. USP11 coprecipitates with autophagy-specific class III PI3K complex I and limits its interaction with NRBF2, decreasing lipid kinase activity and recruitment of WIPI proteins. USP11 also interacts with and stabilizes mTOR kinase. USP11 homolog depletion in C. elegans triggers hyperactivation of autophagy and protects against amyloid-β aggregation-induced paralysis.\",\n      \"method\": \"Co-immunoprecipitation, KO cell analysis, autophagic flux assay, PI3K activity assay, C. elegans genetic model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple substrates/interactions identified, KO phenotype, PI3K activity assay, cross-species validation, multiple orthogonal methods\",\n      \"pmids\": [\"34600886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 deubiquitinates RAE1, and USP11 is associated with the mitotic spindle. USP11 knockdown leads to multipolar spindle formation and drastically reduces cell proliferation; USP11 controls RAE1 ubiquitination at the mitotic spindle, modulating its interaction with NuMA.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, lentiviral knockdown, immunofluorescence (spindle localization), flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, spindle localization confirmed, functional multipolar spindle phenotype, single lab\",\n      \"pmids\": [\"29293652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mouse Usp11 stabilizes the transcription factor Sox11 via deubiquitination in the developing cerebral cortex. Usp11 deficiency impairs layer 6 neuron production, delays late-born neuronal migration, and disturbs cognition and anxiety behaviors. A disease-associated Usp11 mutant fails to stabilize Sox11 and is unable to support cortical neurogenesis and neuronal migration.\",\n      \"method\": \"Usp11 knockout mouse, in vivo ubiquitination assay, immunoblotting, behavioral testing, cortical layer analysis, mutant rescue experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO mouse, DUB assay, disease mutant analysis, multiple functional readouts (neurogenesis, migration, behavior)\",\n      \"pmids\": [\"33579706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP11 stabilizes p53 by deubiquitination and p53 transcriptionally represses KLF2, thereby activating the NF-κB pathway and promoting neuroinflammation after intracerebral hemorrhage. USP11 silencing blocks pro-inflammatory cytokine release by downregulating p53, protecting against neurological impairment.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, in vivo deubiquitination assay, ChIP (p53 binding to KLF2 promoter), in vivo rat ICH model\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, ChIP for pathway placement, in vivo model, single lab\",\n      \"pmids\": [\"34141823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP11 interacts with and deubiquitinates Sirt3, stabilizing it and thereby reducing oxidative stress-induced ferroptosis. USP11 knockout exacerbates intervertebral disc degeneration and is reversed by Sirt3 overexpression.\",\n      \"method\": \"IP/MS, co-immunoprecipitation, in vivo deubiquitination assay, Sirt3 KO mouse, USP11 KO mouse, rescue experiments\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP/MS identification, Co-IP, DUB assay, in vivo genetic rescue, multiple KO mouse models, comprehensive study\",\n      \"pmids\": [\"37099926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERK1/2 phosphorylates USP11 at Ser905, which promotes cytoplasmic localization of USP11. In the cytoplasm, USP11 colocalizes and interacts with p21, catalyzing removal of polyubiquitin chains from cytoplasmic p21 and stabilizing it. USP11-mediated stabilization of cytoplasmic p21 induces breast cancer cell proliferation.\",\n      \"method\": \"Phosphorylation mapping, co-immunoprecipitation, subcellular fractionation, in vitro/in vivo deubiquitination assay, knockdown/overexpression, cell proliferation assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phosphorylation site identified, Co-IP, DUB assay, localization experiment with functional consequence, single lab\",\n      \"pmids\": [\"35414784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Non-mitochondrial HK2 directly interacts with CD133 and promotes binding of USP11 to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. USP11-mediated deubiquitination of CD133 enhances cancer stem cell stemness and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, in vitro/in vivo ubiquitination assay, immunofluorescence, flow cytometry\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, MS identification, DUB assay, functional stemness readouts, single lab\",\n      \"pmids\": [\"35975322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP11 interacts with LSH chromatin-remodeling protein and stabilizes it via deubiquitination; erastin treatment disrupts USP11-LSH interaction, increasing LSH ubiquitination and degradation. LSH binds the CYP24A1 promoter to promote its transcription, which inhibits ferroptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, ChIP analysis, siRNA knockdown, ferroptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, ChIP for pathway placement, single lab\",\n      \"pmids\": [\"37414755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP11 interacts with eEF1A1 and deubiquitinates it on Lys439, preventing ubiquitin-mediated degradation. Elevated eEF1A1 binds SP1, driving SP1-dependent HGF gene transcription and PI3K/AKT activation, promoting EMT and metastasis in HCC.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay with site-specific K439 mutant, ChIP, knockdown/overexpression, functional EMT/metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with site-specific mutant, DUB assay, pathway placement by ChIP, single lab\",\n      \"pmids\": [\"37973952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP11 stabilizes SMYD5 (a lysine methyltransferase) post-transcriptionally in the context of HIV-1 transcription; the Tat cofactor function of USP11 is required for SMYD5 protein level increases in cells expressing Tat. SMYD5 methylates Tat in vitro.\",\n      \"method\": \"siRNA knockdown, immunoblotting, in vitro methylation assay, co-immunoprecipitation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence for USP11-SMYD5 stabilization; no direct DUB assay on SMYD5 by USP11 shown, single lab\",\n      \"pmids\": [\"36897778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 deubiquitinates both AR (androgen receptor) and c-Myc to increase their protein stability, and also deubiquitinates H2A-K119Ub (a repressive histone mark) on promoters of AR and c-Myc genes to increase their transcription. ChIP-seq with catalytic-inactive USP11 mutant confirmed both mechanisms.\",\n      \"method\": \"RNA-seq, ChIP-seq, catalytic-inactive mutant, co-immunoprecipitation, in vivo deubiquitination assay, knockdown/rescue, cell growth assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP-seq, catalytic mutant analysis, two distinct substrates and two distinct mechanisms (protein stabilization and histone mark), multiple orthogonal methods\",\n      \"pmids\": [\"39052835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 deubiquitinates and stabilizes DNMT3A, opposing degradation by CUL4-DCAF8 E3 ligase. USP11 also enhances DNMT3A SUMOylation by promoting DNMT3A interaction with SUMO E3 ligases, and enhances DNMT3A binding to the polycomb complex and maintains its DNA methyltransferase activity.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination/SUMOylation assays, USP11 stable expression rescue, E1 enzyme inhibition, immunoprecipitation with SUMO E3 ligases, MTase activity assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple assays in single preprint study, Co-IP, DUB assay, SUMOylation and enzymatic activity measurements, not yet peer-reviewed\",\n      \"pmids\": [\"40161590\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 deubiquitinates E-cadherin at K738, stabilizing it. USP11 binds E-cadherin through its C-terminal region. This deubiquitinase activity of USP11 maintains luminal differentiation of mammary epithelial cells and suppresses luminal breast cancer; deubiquitinase-inactive USP11 mutant fails to support these functions.\",\n      \"method\": \"USP11 knockout mice, catalytic-inactive mutant, in vivo deubiquitination assay, site-specific K738 mutagenesis, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific mutagenesis (K738), catalytic mutant, KO mouse model, Co-IP domain mapping, comprehensive mechanistic study\",\n      \"pmids\": [\"39270819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 depletion leads to increased MDM2 polyubiquitination and reduced MDM2 half-life, elevating p53 protein levels and p21 mRNA in a p53-dependent manner. USP11 acts as a deubiquitinase for MDM2, thereby regulating the MDM2-p53-p21 axis and cell cycle progression. USP11 depletion also promotes cellular senescence in a deubiquitinase-activity-dependent manner.\",\n      \"method\": \"siRNA knockdown, polyubiquitination assay, protein half-life analysis, immunoblotting, cell cycle analysis, senescence assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination and half-life assays, deubiquitinase-activity dependency shown, single lab, single study\",\n      \"pmids\": [\"38901057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 deubiquitinates TPIT transcription factor and stabilizes it in functioning ACTH pituitary tumors, thereby enhancing POMC transcription and ACTH secretion. USP11 knockdown reduces both POMC transcription and ACTH secretion in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay, siRNA knockdown, in vivo model, POMC/ACTH secretion assay\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, knockdown with functional readout, single lab\",\n      \"pmids\": [\"39910602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 promotes angiogenesis by binding PRDX2 and removing its K63-linked polyubiquitination, facilitating PRDX2 nuclear translocation. Nuclear PRDX2 promotes concurrent nuclear translocation of c-MYC, which enhances transcription of KDR (VEGFR2) and activates VEGFR2 signaling. USP11 KO markedly inhibits angiogenesis in vivo and in vitro.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deubiquitination assay (K63-linkage specificity), USP11 KO mouse model, retinal angiogenesis model, nuclear fractionation, reporter assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, K63-linkage DUB assay, KO mouse model, nuclear translocation experiment, single lab\",\n      \"pmids\": [\"40199774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The UBL2 domain of USP11 directs its selectivity toward K48-linked polyubiquitin chains; removal of UBL2-IDR reduces ability to cleave K48 chains most significantly. This K48 chain selectivity function of UBL2 is not shared by paralogs USP4 and USP15. FDA-approved drugs Fenoldopam and Olanzapine were identified as selective USP11 inhibitors that act through a unique scaffold.\",\n      \"method\": \"In vitro Ub-tetramer cleavage assay, cell-based K48-ubiquitin analysis, UBL2 domain deletion/mutation, paralog comparison, AI-based virtual screening, in vitro and cell-based inhibitor assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined Ub chains, domain truncation and mutagenesis, paralog comparison, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41207628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRM1 interacts with USP11 in the cytoplasm; ionizing radiation-induced recruitment of RRM1 to LaminB1 facilitates USP11 binding to the nuclear pore complex and nuclear translocation of USP11. In the nucleus, USP11 binds E2F1 and prevents ubiquitin-mediated E2F1 degradation, enhancing transcription of RAD51AP1 to promote homologous recombination.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, NPC binding assay, in vivo ubiquitination assay, ChIP, dominant-negative RRM1 mutant, HR repair assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, nuclear translocation experiment, DUB assay, HR functional readout, single lab\",\n      \"pmids\": [\"39695160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPRYD3-MYCBP2 E3 ligase complex promotes ubiquitination of USP11 specifically at cysteine 318 (non-canonical ubiquitination), which promotes bipolar spindle formation and mitotic slippage in the presence of microtubule targeting drugs.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping (C318), site-directed mutagenesis, mitotic spindle assay, mitotic slippage assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — site-specific mutagenesis, functional spindle assay, novel non-canonical ubiquitination site identified, single lab\",\n      \"pmids\": [\"41052634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 deubiquitinates and stabilizes HINT3, and HINT3 interacts with BCL2. USP11 overexpression increases BCL2 levels, and HINT3 knockdown depletes BCL2, suggesting USP11 promotes endothelial apoptosis resistance in pulmonary arterial hypertension through HINT3-BCL2.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination/degradation assay, knockdown/overexpression, immunoblotting\",\n      \"journal\": \"Journal of respiratory biology and translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP interaction shown, no direct in vitro DUB assay for HINT3, indirect inference of mechanism, single lab\",\n      \"pmids\": [\"40376595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 interacts with and deubiquitinates GSK3β, modulating its Ser9 phosphorylation level and enzymatic activity, thereby impairing synaptic integrity in the prefrontal cortex under chronic stress. USP11 deficiency protects against stress-induced synaptic injury and depression-like behaviors via GSK3β/mTOR signaling.\",\n      \"method\": \"IP-MS, co-immunoprecipitation, in vivo deubiquitination assay, phosphorylation analysis, USP11 KO mouse, behavioral testing\",\n      \"journal\": \"Neurobiology of stress\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — IP-MS identification, Co-IP, DUB assay, phosphorylation measurement, KO mouse with behavioral readout, single lab\",\n      \"pmids\": [\"41889422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 interacts with and deubiquitinates PGAM5, stabilizing it in neurotoxic astrocytes after intracerebral hemorrhage. PGAM5 promotes mPTP opening and Drp1-mediated mitochondrial fission, amplifying mtDNA leakage and cGAS-STING pathway activation. Astrocyte-specific Usp11 KO suppresses neurotoxic astrocyte reactivity and improves neurological recovery.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, astrocyte-specific KO mouse, mitochondrial function assay, mtDNA quantification, cGAS-STING pathway analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, DUB assay, cell-type-specific KO, pathway placement, single lab\",\n      \"pmids\": [\"41201111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Usp11 maintains survival of marginal zone B cells by regulating ubiquitination of Notch ligands DLL1 and JAG2; Usp11-/- mice show higher MZ B cell survival rates after total body irradiation.\",\n      \"method\": \"Co-IP, ubiquitination assay, Usp11-/- mouse model, flow cytometry, single-cell sequencing, histological analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, ubiquitination assay, KO mouse model, multiple cell analysis methods, single lab\",\n      \"pmids\": [\"39904982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 deubiquitinates OTUD5, and this mechanism implicates the OTUD5-STING signaling pathway in the inflammatory response of endothelial cells after radiation. USP11 KO mice show decreased radiation-induced pneumonitis with reduced proinflammatory cytokines.\",\n      \"method\": \"Comprehensive proteome and ubiquitinome analysis, co-immunoprecipitation, Western blot, Usp11-/- mouse model, cytokine measurement\",\n      \"journal\": \"International journal of radiation oncology, biology, physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitinome MS, Co-IP, KO mouse, functional inflammation readouts, single lab\",\n      \"pmids\": [\"38364946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 stabilizes SFTPC (surfactant protein C) by interacting with, deubiquitinating it, and extending its half-life; USP11 stabilizes mutant SFTPC-I73T significantly more than wild-type. USP11 depletion in hiPSC-derived alveolar organoids mitigates SFTPC-I73T-induced fibrosis.\",\n      \"method\": \"CRISPR/Cas9 screen, immunoprecipitation, TUBEs assay for ubiquitination, hiPSC-derived alveolar organoids, bleomycin mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genome-wide CRISPR screen, Co-IP, TUBEs ubiquitination assay, organoid and in vivo model, single lab\",\n      \"pmids\": [\"40225577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 stabilizes EGFR and TRAF6 by removing K48-linked ubiquitin chains, preventing their proteasomal degradation; this potentiates both EGFR and Toll-like receptor signaling in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vivo K48-ubiquitination assay, USP11 KO and overexpression cell lines, xenograft model, mitoxantrone inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, K48-specific DUB assay, KO/OE functional readouts, xenograft model, single lab\",\n      \"pmids\": [\"41419456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP11 deubiquitinates CK2α, stabilizing its protein level and promoting mitochondrial dysfunction. USP11 KO in mouse prefrontal cortex protects against stress-induced synaptic injury and depressive-like behaviors, effects reversed by CK2α stabilization.\",\n      \"method\": \"IP-MS, co-immunoprecipitation, in vivo deubiquitination assay, USP11 KO mouse, CK2α inhibitor (CX4945), primary neuronal cultures\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — IP-MS, Co-IP, DUB assay, KO mouse with behavioral readout, pharmacological validation, single lab\",\n      \"pmids\": [\"42231570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP11 is an X-linked deubiquitinase (cysteine protease, USP family) that localizes primarily to the nucleus and is phosphorylated by ERK1/2 at Ser905 to redistribute to the cytoplasm; its non-catalytic UBL2 domain confers selectivity for K48-linked polyubiquitin chains and provides a unique peptide-binding interface absent in paralogs USP4/USP15. USP11 stabilizes a broad array of substrates by deubiquitination—including BRCA2, p21, p53, MDM2, IκBα, ALK5/TβRII, PML, XIAP, cIAP2, NRF2, RAE1, Sox11, E-cadherin, senataxin, SPRTN, eIF4B, AR, c-Myc, H2AK119ub, γH2AX, Beclin-1, PTEN, VGLL4, and many others—and thereby regulates multiple cellular processes including DNA double-strand break repair by homologous recombination, NER, DNA-protein cross-link repair, R-loop homeostasis, autophagy, ferroptosis, NF-κB and TGFβ signaling, cell cycle progression, mitotic spindle integrity, cortical neurogenesis, and cancer cell survival and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP11 is an X-linked ubiquitin-specific protease (cysteine-protease deubiquitinase) that controls the stability and activity of a broad set of nuclear and cytoplasmic regulatory proteins, thereby governing DNA damage repair, cell-cycle progression, chromatin organization, and growth-factor signaling [#1, #17]. Its substrate selectivity is structurally encoded: a noncatalytic UBL2 domain bearing a peptide-binding interface absent from paralogs USP4/USP15 directs USP11 toward K48-linked polyubiquitin chains and modulates its DNA-repair function [#21, #50]. In the genome-maintenance arena, USP11 acts in BRCA2-dependent homologous recombination and is required for proper RAD51/53BP1 focus formation [#1, #5]; it deubiquitinates the DNA-damage substrates \\u03b3H2AX, SPRTN, and senataxin to terminate repair signaling, resolve DNA-protein cross-links, and clear R-loops, and supports nucleotide excision repair by stabilizing XPC [#10, #30, #31, #16]. As a histone deubiquitinase acting on H2AK119ub/H2BK120ub in concert with the NuRD complex, USP11 couples chromatin reorganization to repair termination and also regulates transcription of target loci such as AR and c-Myc [#23, #44]. USP11 is a central rheostat of cell-cycle and tumor-suppressor circuits, stabilizing p21, p53, PTEN, and VGLL4 while also deubiquitinating MDM2 within the MDM2\\u2013p53\\u2013p21 axis [#17, #22, #14, #47]. It amplifies TGF\\u03b2 signaling by stabilizing the receptors ALK5 and T\\u03b2RII to drive SMAD2/3 activation and EMT [#6, #15], and it tunes NF-\\u03baB signaling through I\\u03baB\\u03b1 and IKK\\u03b1 [#4, #2]. USP11 further restrains autophagy by limiting class III PI3K complex activity and stabilizing mTOR, while stabilizing Beclin-1, NRF2, and Sirt3 to modulate autophagic flux and ferroptosis [#34, #28, #29, #38]. ERK1/2 phosphorylation at Ser905 redistributes USP11 to the cytoplasm to stabilize cytoplasmic p21, linking signaling input to subcellular substrate choice [#39]. In vivo, Usp11 stabilizes the transcription factor Sox11 to support cortical neurogenesis and neuronal migration, with a disease-associated mutant failing to rescue these functions [#36].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established USP11 as a functional deubiquitinase with a defined nuclear substrate, answering whether the enzyme protects specific proteins from proteasomal turnover.\",\n      \"evidence\": \"Y2H, Co-IP, in vitro/in vivo deubiquitination and pulse-chase of RanBPM\",\n      \"pmids\": [\"12084015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define chain-linkage specificity\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed USP11 in the BRCA2 DNA-damage repair pathway, addressing whether the enzyme has a genome-maintenance role beyond isolated substrate stabilization.\",\n      \"evidence\": \"Immunopurification-MS, reciprocal Co-IP, catalytic mutant, RNAi, mitomycin C survival in BRCA2-dependent manner\",\n      \"pmids\": [\"15314155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct repair substrate within the pathway not defined\", \"Mechanism of recruitment to damage sites unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that USP11 catalytic activity is required for homologous recombination and proper RAD51/53BP1 focus formation, establishing a direct functional requirement in DSB repair.\",\n      \"evidence\": \"RNAi, HR reporter assay, PARP inhibitor/IR sensitivity, immunofluorescence foci\",\n      \"pmids\": [\"20233726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Repair substrate deubiquitinated at foci not yet identified\", \"Distinction between HR and NHEJ roles unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined USP11 as a deubiquitinase of I\\u03baB\\u03b1 and a regulator of NF-\\u03baB, with evidence for both catalytic and non-catalytic functions in signaling.\",\n      \"evidence\": \"Recombinant in vitro DUB assay, knockdown/overexpression, catalytic mutant, NF-\\u03baB reporter\",\n      \"pmids\": [\"19874889\", \"17897950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the non-catalytic NF-\\u03baB function unresolved\", \"Relationship between IKK\\u03b1 transcriptional and I\\u03baB\\u03b1 post-translational roles unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed USP11 amplifies TGF\\u03b2 signaling by deubiquitinating and stabilizing the receptor ALK5, establishing a receptor-level mechanism for promoting EMT.\",\n      \"evidence\": \"Reciprocal Co-IP with SMAD7, in vitro/in vivo DUB assay, SMAD2/3 phosphorylation and EMT readouts\",\n      \"pmids\": [\"22773947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMAD7 recruits USP11 to the receptor not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended USP11 substrate range to tumor-suppressor and apoptotic regulators (PML, p53), and showed transcriptional repression of USP11 by Notch/Hey1 links it to glioma malignancy.\",\n      \"evidence\": \"RNAi screen, Co-IP, in vivo/in vitro DUB assays, orthotopic mouse model (PML); Co-IP and DUB assay (p53)\",\n      \"pmids\": [\"24487962\", \"25471832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p53 finding rests on limited orthogonal methods\", \"Competition between USP11 and the RNF4/KLHL20 ligases not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Consolidated USP11 as a stabilizer of apoptosis inhibitors and growth regulators (cIAP2, XIAP, VGLL4, T\\u03b2RII), connecting it to apoptosis resistance and YAP/TGF\\u03b2 axes in cancer.\",\n      \"evidence\": \"Co-IP/MS, in vitro/in vivo DUB assays, mutagenesis (XIAP BIR2 Leu207), domain mapping, anoikis/apoptosis and xenograft assays\",\n      \"pmids\": [\"25613375\", \"28040451\", \"28042509\", \"27853171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate selectivity (e.g. cIAP2 over cIAP1) not structurally explained\", \"Tumor-suppressor vs oncogenic role appears context-dependent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined USP11 as a master stabilizer of the CDK inhibitor p21 against multiple E3 ligases, establishing direct control over G1/S transition and the G2 DNA-damage checkpoint.\",\n      \"evidence\": \"In vivo/in vitro DUB assays reversing SCF-SKP2, CRL4-CDT2, APC/C-CDC20 ubiquitylation; cell-cycle and DNA-damage analyses; in vivo tumor model\",\n      \"pmids\": [\"29666278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP11 outcompetes diverse ligases on a single substrate not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Solved a crystal structure revealing a unique UBL-region peptide-binding site absent in USP4/USP15 that modulates HR repair, providing the first structural basis for paralog-selective function.\",\n      \"evidence\": \"Phage display, ITC, X-ray crystallography, reporter assay with binding-pocket double mutant\",\n      \"pmids\": [\"30373771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand of the binding pocket not identified\", \"Link between pocket occupancy and catalytic output not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified USP11 as a histone deubiquitinase acting with the NuRD complex, and as a node in a PTEN feedforward loop, integrating chromatin reorganization and PI3K/FOXO signaling.\",\n      \"evidence\": \"In vitro/in vivo histone DUB assays (H2AK119ub/H2BK120ub), Co-IP with NuRD, DNA-repair readouts; Co-IP, DUB assay and Usp11 KO mouse tumor model for PTEN\",\n      \"pmids\": [\"31504778\", \"30733438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment of USP11 to specific chromatin loci not defined\", \"Apparent substrate-specificity discrepancy with earlier \\u03b3H2AX-only finding [#10] unreconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the genome-maintenance role to DNA-protein cross-link repair and R-loop homeostasis through deubiquitination of SPRTN and senataxin.\",\n      \"evidence\": \"In vitro DUB assays on monoubiquitinated SPRTN and K48-ubiquitinated SETX, KO cells, DPC/R-loop/DSB functional readouts, KEAP1 epistasis\",\n      \"pmids\": [\"33567341\", \"34526504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing of USP11 action relative to substrate function not resolved\", \"Whether these activities require chromatin recruitment cofactors unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a role for USP11 in restraining autophagy and in spindle integrity and cortical neurogenesis, broadening its physiological reach to cell division and neural development.\",\n      \"evidence\": \"KO cells with autophagic-flux and PI3K activity assays, C. elegans model (autophagy); spindle localization and multipolar-spindle phenotype (RAE1); Usp11 KO mouse with Sox11 DUB assay, neurogenesis, migration and behavior\",\n      \"pmids\": [\"34600886\", \"29293652\", \"33579706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect effects on the class III PI3K complex not fully separated\", \"Whether a defined Mendelian disease arises from the Sox11-linked mutant not established here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established phosphorylation-controlled subcellular partitioning of USP11, linking ERK1/2 signaling to cytoplasmic substrate engagement.\",\n      \"evidence\": \"Phospho-site mapping (Ser905), subcellular fractionation, Co-IP and DUB assay of cytoplasmic p21, proliferation readout\",\n      \"pmids\": [\"35414784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How cytoplasmic vs nuclear p21 pools differ functionally not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated dual transcriptional control by USP11 (substrate protein stabilization plus histone-mark erasure at target promoters), unifying its post-translational and chromatin functions for AR and c-Myc.\",\n      \"evidence\": \"RNA-seq, ChIP-seq with catalytic-inactive mutant, Co-IP, in vivo DUB assays for AR/c-Myc protein and H2A-K119Ub at promoters\",\n      \"pmids\": [\"39052835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the dual mechanism beyond AR/c-Myc loci untested\", \"Recruitment specificity to these promoters not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped UBL2 as the determinant of K48-linkage selectivity and identified selective small-molecule inhibitors, providing a biochemical and pharmacological handle on USP11.\",\n      \"evidence\": \"In vitro Ub-tetramer cleavage, UBL2 deletion/mutation, paralog comparison, AI-based virtual screening and inhibitor assays (Fenoldopam, Olanzapine)\",\n      \"pmids\": [\"41207628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of inhibitor binding not detailed\", \"How K48 selectivity reconciles with reported K63-substrate activity unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed regulation of USP11 itself, including IR-induced RRM1-dependent nuclear import for E2F1-driven HR transcription and non-canonical ubiquitination at Cys318 controlling mitotic behavior.\",\n      \"evidence\": \"Co-IP, nuclear fractionation/NPC binding, ChIP, HR assay (RRM1/E2F1); ubiquitination-site mapping and spindle/slippage assays (SPRYD3-MYCBP2 at C318)\",\n      \"pmids\": [\"39695160\", \"41052634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both rest on single-lab datasets\", \"Functional integration of import control with cytoplasmic ERK-phospho redistribution unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP11 achieves substrate and linkage selectivity across its very large substrate set in vivo, and how its many context-dependent oncogenic versus tumor-suppressive roles are determined, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model reconciling K48 selectivity with reported K63 substrates\", \"Determinants directing USP11 to a given substrate in a given cell type unknown\", \"Whether a defined human Mendelian disorder is causally linked not established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6, 10, 17, 23, 30, 31, 44, 50]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 30, 50]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10, 23, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 17, 23, 51]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [39, 40, 51]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 5, 10, 16, 30, 31, 51]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [17, 35, 47, 52]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 6, 15, 19]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [23, 44]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [28, 34]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 17, 30]}\n    ],\n    \"complexes\": [\"NuRD complex\"],\n    \"partners\": [\"BRCA2\", \"SMAD7\", \"XIAP\", \"RNF4\", \"E2F1\", \"p53\", \"MDM2\", \"RanBPM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}