{"gene":"USP10","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2010,"finding":"USP10 is a cytoplasmic deubiquitinase that deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized and translocates to the nucleus to activate p53; this translocation and stabilization is regulated by ATM-mediated phosphorylation of USP10 at Thr42 and Ser337.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, subcellular fractionation, ATM kinase assay, site-directed mutagenesis, loss-of-function experiments with defined p53-dependent phenotypic readout","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deubiquitination assay combined with mutagenesis, ATM phosphorylation site identification, nuclear translocation experiments, and functional rescue; published in high-impact journal with extensive follow-up replication across many labs","pmids":["20096447"],"is_preprint":false},{"year":2011,"finding":"Beclin1 controls the protein stability of USP10 (and USP13) by regulating their deubiquitinating activities. USP10 mediates deubiquitination of p53, and Beclin1-regulated USP10 activity provides a mechanism linking the tumor suppressors Beclin1 and p53. USP10 and USP13 also deubiquitinate the Beclin1 subunit of Vps34 PI3 kinase complexes, protecting them from degradation.","method":"Small molecule inhibitor (spautin-1) studies, co-immunoprecipitation, ubiquitination assays, loss-of-function experiments, in-cell protein stability assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, small molecule perturbation, genetic knockdown), replicated mechanistic axis across multiple labs","pmids":["21962518"],"is_preprint":false},{"year":2011,"finding":"USP10 directly deubiquitylates the histone variant H2A.Z in vitro and in vivo. USP10 and H2A.Z are both required for transcriptional activation of androgen receptor (AR)-regulated genes (PSA and KLK3); knockdown of USP10 elevates steady-state mono-ubiquitylated H2A.Z and ablates hormone-induced deubiquitylation at AR-regulated gene regulatory regions.","method":"In vitro deubiquitylation assay, ChIP, sequential ChIP, siRNA knockdown, reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay plus ChIP and in-cell functional readout; single lab but multiple orthogonal methods","pmids":["21245042"],"is_preprint":false},{"year":2009,"finding":"USP10 is localized in early endosomes in airway epithelial cells and deubiquitinates endocytosed CFTR, promoting its recycling back to the apical membrane rather than lysosomal degradation. siRNA knockdown of USP10 increased ubiquitinated CFTR and lysosomal degradation; dominant-negative USP10-C424A increased ubiquitinated CFTR degradation; overexpression of wt-USP10 decreased ubiquitinated CFTR.","method":"Activity-based chemical DUB screen, siRNA knockdown, dominant-negative overexpression (C424A mutant), endosomal fractionation, chloride secretion assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — dominant-negative mutagenesis, biochemical fractionation, functional chloride secretion readout, multiple genetic perturbations in single lab","pmids":["19398555"],"is_preprint":false},{"year":2016,"finding":"USP10 specifically removes ubiquitin from AMPKα to facilitate AMPKα phosphorylation by LKB1. Ubiquitination on AMPKα blocks LKB1-mediated phosphorylation. Under energy stress, AMPK-mediated phosphorylation of USP10 at Ser76 enhances USP10 activity, forming a feedforward loop amplifying AMPK activation.","method":"In vitro deubiquitination assay, in vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (Ser76), genetic loss-of-function with metabolic phenotypic readout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitination and kinase assays combined with mutagenesis and functional rescue; single lab but multiple orthogonal methods","pmids":["26876938"],"is_preprint":false},{"year":2013,"finding":"USP10 interacts with SIRT6 and suppresses SIRT6 ubiquitination, protecting SIRT6 from proteasomal degradation. Through stabilizing SIRT6, USP10 antagonizes c-Myc transcriptional activity and inhibits cell-cycle progression.","method":"Proteomic approach (co-IP/MS), co-immunoprecipitation, ubiquitination assay, cell-cycle analysis, loss-of-function experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS identification, ubiquitination assay, functional cell-cycle readout; single lab, confirmed by independent NAFLD paper (PMID:29698567)","pmids":["24332849"],"is_preprint":false},{"year":2013,"finding":"USP10 interacts with NEMO via the scaffold protein MCPIP1 upon genotoxic stress and removes linear polyubiquitin chains from NEMO, resulting in decreased IKK and NF-κB activation. USP10 is required for MCPIP1-mediated inhibition of genotoxic NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NF-κB reporter assay, epistasis experiments","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic epistasis with defined NF-κB phenotypic readout; single lab","pmids":["24270572"],"is_preprint":false},{"year":2015,"finding":"USP10 forms a complex with TANK and MCPIP1 that mediates deubiquitination of TRAF6, suppressing NF-κB activation induced by genotoxic stress and IL-1R/TLR stimulation. CRISPR/Cas9 deletion of TANK enhanced NF-κB activation and inflammatory cytokine production.","method":"Co-immunoprecipitation, ubiquitination assay, CRISPR/Cas9 deletion, NF-κB reporter assay, cytokine ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, CRISPR genetic deletion, functional NF-κB and cytokine readouts; single lab","pmids":["25861989"],"is_preprint":false},{"year":2016,"finding":"G3BP1/G3BP2 and USP10 form complexes that mediate stress granule (SG) condensation. G3BP1 phosphomimetic S149E mutant fails to rescue SG formation, while G3BP1-F33W mutant (unable to bind Caprin1 or USP10) rescues SG formation. Caprin1 binding promotes SG formation while USP10 binding to G3BP inhibits SG formation; these two interactions are mutually exclusive.","method":"Genetic rescue experiments with G3BP1 point mutants, G3BP1/G3BP2 double-knockout cells, stress granule induction assays, co-immunoprecipitation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-knockout cells with multiple G3BP1 point-mutant rescues, clearly defining USP10's inhibitory role in SG formation; well-replicated finding","pmids":["27022092"],"is_preprint":false},{"year":2016,"finding":"USP10 as part of G3BP1-family complexes deubiquitinates monoubiquitinated RPS2, RPS3, and RPS10 on 40S ribosomal subunits stalled at aberrant mRNAs. This rescues modified 40S subunits from lysosomal degradation during ribosome-associated quality control. Knockout of USP10 or G3BP1-family proteins increased lysosomal ribosomal degradation and perturbed ribosomal subunit stoichiometry; K214R substitution in RPS3 rescued these phenotypes.","method":"CRISPR knockout, ubiquitination assay, ribosomal subunit stoichiometry analysis, rescue with RPS3-K214R mutant, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR knockouts, point-mutant rescue, ribosome fractionation, MS; multiple orthogonal methods, single lab but highly rigorous","pmids":["31981475"],"is_preprint":false},{"year":2017,"finding":"USP10 is required to stabilize oncogenic FLT3 (FLT3-ITD and FLT3-D835Y) by preventing its ubiquitin-mediated proteasomal degradation. Pharmacological or genetic inhibition of USP10 induces FLT3 degradation and shows efficacy in preclinical AML models.","method":"DUB inhibitor library screen, target deconvolution, co-immunoprecipitation, ubiquitination assay, cell-line and primary patient cell models, mouse xenograft model","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — phenotypic screen with target deconvolution, Co-IP, in vitro and in vivo models; multiple orthogonal methods","pmids":["28967922"],"is_preprint":false},{"year":2016,"finding":"RNF168 E3 ligase mediates ubiquitylation of TOP2α, while USP10 acts as the deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. The opposing actions of RNF168 and USP10 on TOP2α ubiquitylation modulate decatenation activity.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, genetic loss-of-function with chromosomal segregation phenotypic readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional TOP2α activity readout; single lab","pmids":["27558965"],"is_preprint":false},{"year":2019,"finding":"USP10 interacts with NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of NICD1. Inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in endothelial cells. Loss of endothelial Usp10 increased vessel sprouting in mice and partially restored patterning defects caused by ectopic NICD1 expression.","method":"Co-immunoprecipitation, protein stability assay, endothelial-specific Usp10 knockout mouse, in vivo sprouting angiogenesis assay, gene expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, endothelial-specific KO mouse with in vivo phenotype, genetic epistasis with NICD1 overexpression; multiple orthogonal methods","pmids":["30975888"],"is_preprint":false},{"year":2019,"finding":"USP10 deubiquitinates and stabilizes KLF4 by blocking its proteasomal degradation. Loss of USP10 in mice downregulates KLF4 and accelerates KrasG12D-driven lung adenocarcinoma. KLF4 in turn facilitates transcription of TIMP3 by binding its promoter.","method":"siRNA screen of ubiquitin-specific proteases, co-immunoprecipitation, ubiquitination assay, conditional USP10 knockout mouse with KrasG12D, promoter binding by ChIP","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — USP screen, Co-IP, in vivo genetic mouse model with defined tumor phenotype; multiple orthogonal methods","pmids":["31748695"],"is_preprint":false},{"year":2019,"finding":"USP10 deubiquitinates and stabilizes Smad4, sustaining TGF-β signaling. USP10 directly interacts with Smad4 and cleaves its proteolytic ubiquitin chains, promoting HCC metastasis. Suppression of USP10 inhibits HCC cell migration; reconstitution of Smad4 rescues this defect.","method":"siRNA library screen of USPs, co-immunoprecipitation, ubiquitination assay, migration assay, rescue experiment with Smad4","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — USP siRNA screen, Co-IP, ubiquitination assay, Smad4 rescue; single lab","pmids":["31721429"],"is_preprint":false},{"year":2020,"finding":"USP10 directly interacts with YAP and TAZ, deubiquitinates them by reverting their proteolytic ubiquitination, and stabilizes them. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ and promoted their proteasomal degradation, arresting hepatocellular carcinoma proliferation in vitro and in vivo.","method":"DUB screen (transcriptional activity and protein abundance), co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — DUB screen, Co-IP, ubiquitination assay, in vivo xenograft with functional readout; multiple orthogonal methods","pmids":["32217697"],"is_preprint":false},{"year":2018,"finding":"USP10 interacts with and deubiquitinates G3BP2, maintaining G3BP2 protein stability and reducing its polyubiquitylation. G3BP2-dependent growth activation and p53 nuclear export are repressed by USP10 knockdown, placing USP10 upstream of the G3BP2-p53 axis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, chromatin immunoprecipitation, cell growth assay","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, ChIP; single lab","pmids":["29378906"],"is_preprint":false},{"year":2013,"finding":"HTLV-1 Tax oncoprotein interacts with USP10 and inhibits arsenic-induced stress granule formation by USP10-containing SGs, stimulating ROS production and augmenting ROS-dependent apoptosis. USP10 normally functions to inhibit stress-induced ROS production and apoptosis; Tax attenuates this activity.","method":"Co-immunoprecipitation, stress granule formation assay, ROS measurement, apoptosis assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, SG formation assay, ROS and apoptosis functional readouts; single lab","pmids":["23775713"],"is_preprint":false},{"year":2019,"finding":"USP10 is a novel deubiquitinase of SKP2; it binds to and deubiquitinates SKP2, preventing its degradation. Stabilized SKP2 in turn mediates K63-linked ubiquitination and activation of Bcr-Abl, creating a USP10/SKP2/Bcr-Abl axis in CML.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell proliferation assay in imatinib-sensitive and -resistant CML cells","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional cell proliferation readout; single lab","pmids":["31044085"],"is_preprint":false},{"year":2016,"finding":"USP10 interacts with MSH2 and deubiquitinates it both in vitro and in vivo, stabilizing MSH2 protein. Knockdown of USP10 in lung cancer cells exhibits increased cell survival and decreased apoptosis upon treatment with MNNG and 6-TG; these phenotypes are rescued by ectopic MSH2 expression. MSH2 protein level correlates positively with USP10 level.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, mismatch repair activity assay, cell survival/apoptosis assay, rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitination assay, Co-IP, functional MSH2 rescue, multiple orthogonal methods; single lab","pmids":["26975374"],"is_preprint":false},{"year":2018,"finding":"USP10 mediates deubiquitination of p14ARF, preventing its proteasome-dependent degradation. c-Myc induces USP10 transcription; USP10 then stabilizes p14ARF to enforce oncogene-induced senescence. USP10-null MEFs and primary cells depleted of USP10 bypass c-Myc-induced senescence via p14ARF destabilization.","method":"Ubiquitination assay, siRNA knockdown, USP10-null MEFs, cell senescence assay (SA-β-gal, proliferation), c-Myc overexpression epistasis","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay, knockout MEFs, senescence functional readout; single lab","pmids":["29472714"],"is_preprint":false},{"year":2017,"finding":"USP10 interacts with integrin β1 and β5; recombinant USP10 removes ubiquitin from these integrin subunits in vitro. Loss of USP10 induces ubiquitin accumulation on β1/β5 integrins, decreasing αv/β1/β5 protein levels and TGFβ activation. Gain of USP10 increases αv/β1/β5 protein levels and fibrotic marker expression.","method":"Genetic screen, siRNA knockdown, recombinant USP10 in vitro deubiquitination, co-immunoprecipitation, ex vivo cornea organ culture, loss- and gain-of-function with fibrotic marker readout","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro deubiquitination with recombinant protein, functional TGFβ and fibrotic marker readouts; single lab","pmids":["28851806"],"is_preprint":false},{"year":2005,"finding":"USP10 is part of DNA-bound androgen receptor (AR) complexes in nuclear extracts. Interaction with AR confirmed by GST pull-down. USP10 localizes in both nucleus and cytoplasm. Overexpression of catalytically active, but not enzymatically inactive, USP10 stimulates AR transactivation at AREs, SREs, and MMTV promoter; siRNA knockdown of USP10 impairs MMTV androgen response.","method":"Nuclear extract purification, GST pull-down, fluorescence microscopy, cell-based transactivation reporter assay, siRNA knockdown","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — GST pulldown, catalytically-inactive mutant comparison, reporter assays; single lab","pmids":["16368182"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of UbV.7.2 (ubiquitin variant inhibitor) was solved and provided the molecular basis for enhanced affinity and specificity for USP7. UbVs were also identified that bound USP10 with high affinity and inhibited its deubiquitination activity, validating the catalytic site of USP10 as a druggable interface.","method":"Phage-displayed UbV library, crystal structure determination (for USP7 UbV), in vitro deubiquitination inhibition assay, cell death assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-3 / Weak — crystal structure for USP7 UbV (not USP10 directly); USP10 inhibition via UbV confirmed by in vitro activity assay; single lab","pmids":["28587923"],"is_preprint":false},{"year":2018,"finding":"USP10 interacts with HDAC6 and deubiquitinates and stabilizes HDAC6. Reintroduction of either USP10 or HDAC6 into USP10-knockdown NSCLC cells with null p53 restores cisplatin resistance, defining a USP10-HDAC6-cisplatin resistance axis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/genetic knockdown, rescue experiment with USP10 or HDAC6, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, rescue experiment with functional drug-resistance readout; single lab","pmids":["32382008"],"is_preprint":false},{"year":2014,"finding":"USP10 interacts with T-bet transcription factor in the nucleus, directly inhibits T-bet ubiquitination, and increases T-bet protein expression. Quercetin, a reported T-bet inhibitor, targets USP10 to promote T-bet proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression, inhibitor treatment (quercetin)","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab, single method set","pmids":["24845384"],"is_preprint":false},{"year":2021,"finding":"USP10 deubiquitinates LC3B, reversing monoubiquitination-mediated proteasomal degradation of LC3B. CRISPR-Cas9 KO of USP10 reduces both LC3B-I and LC3B-II levels through increased ubiquitination and proteasomal degradation, leading to slower degradation of autophagy receptors SQSTM1 and NBR1 and increased aggresome-like structures.","method":"CRISPR-Cas9 knockout screen, biochemical ubiquitination assay, proteasome inhibitor experiments, autophagy receptor degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — CRISPR screen and validation, direct ubiquitination assay, multiple functional autophagy readouts; single lab but multiple orthogonal methods","pmids":["33577797"],"is_preprint":false},{"year":2018,"finding":"USP10 interacts with p62 (ubiquitin receptor) and the USP10-p62 interaction augments p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby inhibiting apoptosis. USP10-p62-induced protein aggregates inhibit proteasome activity, further increasing ubiquitinated protein levels. USP10 co-localizes with α-synuclein in Lewy bodies in Parkinson disease brains.","method":"Co-immunoprecipitation, aggresome formation assay, proteasome activity assay, immunohistochemistry of PD brain tissue","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, functional proteasome and aggresome assays, neuropathological co-localization; single lab","pmids":["30469013"],"is_preprint":false},{"year":2019,"finding":"USP10 is a critical factor for the formation of Tau/TIA1/USP10-positive stress granules in neuronal cells. Depletion of USP10 severely attenuates TIA1/Tau-positive SG formation induced by proteasome inhibition or TIA1 overexpression. Overexpression of USP10 without stress stimuli induces TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner.","method":"siRNA knockdown, overexpression with catalytically inactive control, immunofluorescence of SG formation, immunohistochemistry of AD brain tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown and deubiquitinase-inactive mutant overexpression; functional SG assay with deubiquitinase-independent function identified; single lab","pmids":["31332267"],"is_preprint":false},{"year":2021,"finding":"USP10 promotes clearance of TDP-43-positive stress granules and thereby inhibits aberrant cytoplasmic aggregation of TDP-43/TDP-35 in neuronal cells. Depletion of USP10 increases insoluble TDP-35 in the cytoplasm. TDP-35 interacts with USP10 in an RNA-binding-dependent manner.","method":"siRNA knockdown, overexpression, stress granule clearance assay, solubility fractionation, co-immunoprecipitation, immunohistochemistry of ALS patient tissue","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown, Co-IP with RNA-binding mutant validation, functional SG and aggregation readouts; single lab","pmids":["35007165"],"is_preprint":false},{"year":2019,"finding":"USP10 interacts with Raf-1 and promotes its deubiquitination, stabilizing Raf-1 protein (without affecting mRNA), which activates downstream MEK/ERK signaling. USP10 overexpression promotes proliferation, migration, and inhibits apoptosis of endometrial stromal cells via Raf-1/MEK/ERK; effects are blocked by MEK inhibitor PD-98059.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, MEK inhibitor rescue, proliferation/apoptosis/migration assays","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, pharmacological and genetic rescue; single lab","pmids":["30281322"],"is_preprint":false},{"year":2018,"finding":"USP10 interacts with SIRT6 and inhibits its ubiquitination and degradation in the liver. USP10 deficiency exacerbates HFD-induced metabolic dysfunction; SIRT6 overexpression reverses USP10 deficiency effects; SIRT6 deficiency counteracts USP10 overexpression benefits, placing USP10 upstream of SIRT6 in hepatic metabolism.","method":"Co-immunoprecipitation, ubiquitination assay, hepatocyte-specific USP10 knockout and overexpression mouse models, genetic epistasis with SIRT6","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO and OE mouse models, Co-IP, ubiquitination assay, genetic epistasis with SIRT6; multiple orthogonal methods","pmids":["29698567"],"is_preprint":false},{"year":2019,"finding":"USP10 deubiquitinates and stabilizes Musashi-2 (MSI2) through direct interaction, preventing its proteasomal degradation, and thereby promotes colon cancer cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, cell proliferation assay","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab","pmids":["30604502"],"is_preprint":false},{"year":2017,"finding":"USP10 is the major DUB required for stabilization of SYK. USP10 inhibition leads to proteasome-mediated SYK degradation and potentiates anti-leukemic effects of FLT3 inhibition.","method":"Co-immunoprecipitation, ubiquitination assay, USP10 inhibitor treatment, cell viability assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, pharmacological inhibition with functional readout; single lab","pmids":["32015510"],"is_preprint":false},{"year":2016,"finding":"USP10 directly interacts with and stabilizes PTEN through deubiquitination in lung cancer cells. Co-immunoprecipitation confirmed the interaction; ubiquitination/deubiquitination assays confirmed the mechanism. Pro-cancerous effects of USP10 deficiency are abolished by PTEN re-introduction.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, PTEN rescue experiment, in vivo allograft","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, genetic rescue; single lab","pmids":["28852924"],"is_preprint":false},{"year":2021,"finding":"USP10 interacts with PTEN and removes TRIM25-mediated K63-linked polyubiquitination of PTEN, restoring PTEN phosphatase activity and reducing PIP3 production, thereby inhibiting AKT/mTOR signaling. The inactive C424A mutant of USP10 fails to reverse PTEN ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay with K63-specific chains, C424A inactive mutant, PIP3 measurement, AKT/mTOR signaling assay, NSCLC proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — catalytic mutant validation, K63-specific ubiquitination assay, functional phosphatase activity readout, multiple methods; single lab","pmids":["34416231"],"is_preprint":false},{"year":2022,"finding":"USP10 deubiquitinates and stabilizes ANLN (anillin) by removing K11- and K63-linked ubiquitin chains, preventing APC/C-Cdh1-mediated degradation. USP10 and Cdh1 form a functional complex with ANLN in a non-competitive manner to balance ANLN levels. USP10 promotes contractile ring assembly at the cytokinetic furrow and cytokinesis through ANLN stabilization.","method":"Co-immunoprecipitation, ubiquitination assay (K11 and K63-specific), cytokinesis assay, USP10 inhibitor (F806), complex formation analysis with Cdh1 mutant","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, K11/K63 ubiquitination assays, functional cytokinesis readout; single lab","pmids":["36526897"],"is_preprint":false},{"year":2019,"finding":"USP10 interacts with TAK1 directly and promotes protection against cerebral ischemia-reperfusion injury. USP10 KO mice show elevated NF-κB signaling, JNK-MAPK activation, and increased apoptosis after cerebral I/R, demonstrating USP10's inhibitory role on TAK1-mediated inflammatory signaling.","method":"USP10 knockout mouse, cerebral I/R injury model, co-immunoprecipitation, NF-κB and JNK pathway analysis, apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockout mouse with defined neurological phenotype, Co-IP, pathway analysis; single lab","pmids":["31301769"],"is_preprint":false},{"year":2021,"finding":"USP10 interacts with NEMO in macrophages; USP10 inhibition accelerates NEMO degradation. USP10 stabilizes NEMO by deubiquitination, maintaining NF-κB activation in LPS-induced sepsis. Suppressing USP10 attenuated inflammatory responses and improved survival in LPS-induced sepsis mice.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, spautin-1 inhibitor, NF-κB translocation assay, cytokine ELISA, in vivo sepsis model","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, functional NF-κB translocation and cytokine readouts, in vivo model; single lab","pmids":["37436447"],"is_preprint":false},{"year":2023,"finding":"USP10 binds to Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Additionally, USP10 physically tethers Axin1 and β-catenin and promotes phase separation for β-catenin suppression in a manner independent of enzymatic activity. In APC-truncated CRC, USP10 binds to β-catenin directly (via unstructured N-terminus) and increases β-catenin stability.","method":"Unbiased DUB screen, in vitro binding assay, computational modelling, ubiquitination assay (K48-specific), phase separation assay, USP10 enzymatic mutant, CRC organoid model, xenograft","journal":"Cell chemical biology / Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (in vitro binding, computational, ubiquitination assay, phase separation, organoid); enzyme-dependent and independent functions distinguished","pmids":["37611590","39443725"],"is_preprint":false},{"year":2019,"finding":"TRAF4 interacts with USP10 and blocks p53 access to USP10, resulting in p53 destabilization and enhanced fibroblast proliferation in keloids. TRAF4 acts independently of its E3 ubiquitin ligase activity in this process.","method":"Co-immunoprecipitation, p53 ubiquitination assay, siRNA knockdown, rescue experiment (p53 knockdown), keloid fibroblast proliferation assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, genetic rescue; single lab","pmids":["30940456"],"is_preprint":false},{"year":2022,"finding":"USP10 deubiquitinates RUNX1 and stabilizes it, maintaining mesenchymal subtype properties in glioblastoma. USP10 knockdown inhibits RUNX1 and results in loss of mesenchymal properties.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vivo xenograft, GBM subtype gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft; single lab","pmids":["36949071"],"is_preprint":false},{"year":2022,"finding":"USP10 deubiquitinates and stabilizes AID (activation-induced cytidine deaminase), which specifically stabilizes nuclear AID protein. USP10 translocates into the nucleus after AKT-mediated phosphorylation at T674 within its NLS domain. BCR and TLR1/2 signals synergistically promote this phosphorylation. USP10 deficiency in B cells decreased AID protein levels and reduced neutralizing antibody production after vaccination.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear localization imaging, kinase assay, USP10-conditional B cell knockout, vaccination challenge","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional B cell KO with antibody readout, phosphorylation site identified; single lab","pmids":["34983926"],"is_preprint":false},{"year":2023,"finding":"USP10 directly interacts with PABPC1 and decreases K27/K29-linked ubiquitination of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 couples more CLK2 mRNA and eIF4G1, increasing CLK2 translation efficiency and promoting pancreatic cancer tumor growth.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (K27/K29-specific), polysome/mRNA association assay, in vivo xenograft and PDX model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS, K27/K29-specific ubiquitination assay, translation efficiency measurement; single lab","pmids":["37757903"],"is_preprint":false},{"year":2023,"finding":"USP10 interacts with and deubiquitinates MOF (KAT8) acetyltransferase at lysine 410, protecting it from proteasomal degradation. Stabilized MOF promotes H4K16ac enrichment at the ANXA2 promoter in a JUN-dependent manner, activating ANXA2/Wnt signaling and ESCC progression.","method":"Co-immunoprecipitation, ubiquitination assay, specific lysine mutagenesis (K410), H4K16ac ChIP, functional ESCC tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, site-specific ubiquitination mutagenesis, ChIP functional readout; single lab","pmids":["38317006"],"is_preprint":false},{"year":2025,"finding":"USP10 binds to XAB2 and deubiquitinates K48-linked polyubiquitination at K593 of XAB2, stabilizing it and preventing proteasomal degradation. Nuclear USP10 expression increases in CRC cells treated with oxaliplatin. Stabilized XAB2 upregulates ANXA2 transcriptionally by binding the ANXA2 promoter, promoting DNA damage repair and oxaliplatin resistance.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination site MS, ubiquitin assay, dual-luciferase reporter, ChIP-qPCR, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS, site-specific ubiquitination assay, ChIP readout, functional rescue; single lab","pmids":["40069750"],"is_preprint":false},{"year":2023,"finding":"USP10 interacts with NICD1 (Notch1 intracellular domain) and deubiquitinates it, stabilizing NICD1 and promoting K11/K48-linked polyubiquitination-mediated degradation when disrupted by N1DARP microprotein. N1DARP competitively disrupts USP10-N1ICD interaction, accelerating N1ICD proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay (K11/K48-specific), competition binding assay, pancreatic cancer organoid model, KPC mouse model","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, K11/K48 ubiquitination assay, competition assay, organoid model; single lab","pmids":["37714834"],"is_preprint":false},{"year":2020,"finding":"USP10 interacts with CD36 scavenger receptor and stabilizes CD36 protein by cleaving poly-ubiquitin on CD36, promoting foam cell formation. USP10 inhibition promotes CD36 degradation and suppresses lipid uptake and foam cell formation by macrophages.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Oil Red O staining, immunofluorescence","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab","pmids":["33197885"],"is_preprint":false},{"year":2019,"finding":"USP10 interacts with the EMT transcription factor Slug/SNAI2, identified in a genome-wide siRNA DUB screen, and mediates its proteasomal degradation. Genetic knockdown of USP10 decreases Slug levels and reduces cancer cell migration; overexpression elevates Slug and Vimentin.","method":"Genome-wide siRNA DUB screen, co-immunoprecipitation, protein stability assay, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA screen followed by single Co-IP; note: USP10 depletion decreases Slug, suggesting USP10 stabilizes Slug but mechanistic deubiquitination was not explicitly shown as in vitro assay; single lab","pmids":["29803676"],"is_preprint":false},{"year":2023,"finding":"DCAF7 acts as a scaffold protein facilitating the interaction between USP10 and G3BP1, leading to USP10-mediated removal of K48-linked ubiquitin moieties from Lys76 of G3BP1, preventing its proteasomal degradation and promoting stress granule-like structure formation and NPC chemoresistance.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific, K76 site mapping), siRNA knockdown, stress granule formation assay, in vitro and in vivo chemoresistance model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, site-specific K48 ubiquitination mapping, functional rescue; single lab","pmids":["38973296"],"is_preprint":false},{"year":2023,"finding":"USP10 interacts with ZEB1 and promotes its proteasomal degradation by modifying its ubiquitination. ERK phosphorylates USP10 at Ser236, impairing the USP10-ZEB1 interaction and enabling ZEB1 protein stabilization. MEK-ERK inhibition blocks USP10 phosphorylation and enhances USP10-ZEB1 interaction, suppressing ZEB1-mediated metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, MEK inhibitor, USP10 phospho-site identification, colorectal cancer metastasis mouse tail-vein injection model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, phosphorylation site mapping, in vivo metastasis model; single lab","pmids":["36940483"],"is_preprint":false},{"year":2023,"finding":"USP10 interacts with AMPK-phosphorylated state and potentiates deubiquitination and stabilization of Axin1 (K48-linked), linking the LKB1/AMPK axis to Wnt/β-catenin suppression. AMPK phosphorylation of USP10 also strengthens USP10 binding to β-catenin, supporting its phase transition and suppression.","method":"Co-immunoprecipitation, ubiquitination assay, AMPK kinase assay, phase separation assay, colorectal cancer organoid and xenograft model","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination, kinase and phase separation assays, in vivo model; single lab","pmids":["37873736"],"is_preprint":false},{"year":2019,"finding":"USP10 interacts with NLRP7 and catalyzes its deubiquitination at K379, stabilizing NLRP7 protein and promoting colorectal cancer progression and M2 macrophage polarization via CCL2.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, K379R mutagenesis, in vivo tumor model, macrophage polarization assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS, site-specific mutagenesis, functional in vivo and macrophage polarization readouts; single lab","pmids":["33838681"],"is_preprint":false},{"year":2021,"finding":"USP10 stabilizes GSK3β through deubiquitination; stabilized GSK3β in turn promotes ULK1 transcription by increasing ULK1 promoter activity, thereby driving ULK1-mediated autophagy, cell proliferation, and invasion in osteosarcoma.","method":"Co-immunoprecipitation, ubiquitination assay, ULK1 promoter reporter, GSK3β activity assay, siRNA knockdown, xenograft model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, promoter reporter, in vivo xenograft; single lab","pmids":["39218913"],"is_preprint":false},{"year":2023,"finding":"USP10 interacts with and deubiquitinates FOXQ1, promoting its protein stability. USP10-mediated FOXQ1 stabilization activates CREB5/NF-κB signaling to alleviate sepsis-induced acute kidney injury.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, rescue experiment, in vivo CLP model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab","pmids":["38960057"],"is_preprint":false},{"year":2024,"finding":"AEG-1 recruits USP10 to remove K48-linked polyubiquitin chains at Lys425 of PARP1, preventing PARP1 proteasomal degradation and facilitating homologous recombination-mediated DNA double-strand break repair, conferring radioresistance in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific, K425 site mapping), siRNA knockdown, DNA damage (γH2AX, comet assay), in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, site-specific ubiquitination assay, functional DNA repair readout; single lab","pmids":["37838281"],"is_preprint":false},{"year":2024,"finding":"NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10; USP10 deubiquitinates PD-L1, stabilizing it and promoting immune escape in prostate cancer.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, CD8+ T cell co-culture model","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab","pmids":["39227807"],"is_preprint":false},{"year":2023,"finding":"KIF15 recruits USP10 to PGK1 and promotes USP10-mediated deubiquitination of PGK1, stabilizing PGK1 and enhancing glycolysis in pancreatic cancer. KIF15 interacts with both PGK1 and USP10 via its coil2 domain.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, KIF15 truncation mapping, glycolytic capacity measurement (ECAR/OCR), in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS, domain mapping, ubiquitination assay, functional metabolic readout; single lab","pmids":["36807568"],"is_preprint":false},{"year":2020,"finding":"Wu-5 directly interacts with and inactivates USP10 in vitro (IC50 = 8.3 µM), confirming its catalytic activity as a cysteine protease DUB. Overexpression of USP10 abrogates Wu-5-induced FLT3-ITD degradation and cell death, placing USP10 directly upstream of FLT3-ITD stability.","method":"In vitro enzymatic inhibition assay, overexpression rescue, cell viability assay","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 1-3 / Moderate — in vitro activity assay with IC50, functional overexpression rescue; single lab","pmids":["32694757"],"is_preprint":false},{"year":2024,"finding":"PPM1B directly interacts with YBX1 and dephosphorylates YBX1 at serine 314; this dephosphorylation affects USP10-mediated deubiquitination of YBX1, resulting in decreased YBX1 protein stability. Thus USP10 deubiquitinates YBX1, and this is regulated by PPM1B-mediated phosphorylation state of YBX1.","method":"Co-immunoprecipitation, overexpression/silencing experiments, ubiquitination assay, S314 mutagenesis, PANoptosis assay, oxaliplatin resistance assay","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP, ubiquitination assay, single lab, phosphorylation-ubiquitination crosstalk identified but mechanism partially indirect","pmids":["38364962"],"is_preprint":false}],"current_model":"USP10 is a cytoplasmic and nuclear ubiquitin-specific deubiquitinase (DUB) that stabilizes a broad repertoire of substrates—including p53, AMPKα, SIRT6, YAP/TAZ, FLT3, KLF4, NICD1, Smad4, PTEN, MSH2, LC3B, H2A.Z, integrins β1/β5, and many others—by removing ubiquitin chains and preventing proteasomal or lysosomal degradation; its activity and nuclear localization are regulated by phosphorylation (e.g., ATM-dependent phosphorylation at Thr42/Ser337, AMPK-dependent Ser76, and AKT-dependent T674), and it participates in stress granule biology (where its interaction with G3BP1 inhibits SG formation and G3BP1-USP10 complexes rescue ubiquitinated 40S ribosomal subunits), in NF-κB regulation (by deubiquitinating NEMO and TRAF6 via scaffold proteins MCPIP1/TANK), and in diverse cellular processes including autophagy, DNA damage repair, angiogenesis, and immune responses, making it a context-dependent regulator of both tumor suppressor and oncogenic pathways."},"narrative":{"mechanistic_narrative":"USP10 is a cytoplasmic and nuclear ubiquitin-specific deubiquitinase that controls the abundance and activity of a broad repertoire of substrates by removing ubiquitin chains and protecting them from proteasomal or lysosomal degradation [PMID:20096447, PMID:26876938]. Its prototypical role is stabilization of the tumor suppressor p53: USP10 deubiquitinates p53, reversing Mdm2-induced nuclear export and degradation, and following DNA damage it is stabilized and translocates to the nucleus through ATM-dependent phosphorylation at Thr42/Ser337 to activate p53 [PMID:20096447]. Substrate engagement and nuclear access are governed by phosphorylation: AMPK phosphorylation at Ser76 forms a feedforward loop that enhances USP10-mediated deubiquitination of AMPKα to license LKB1 phosphorylation [PMID:26876938], while AKT phosphorylation at T674 within the NLS drives nuclear translocation to stabilize AID [PMID:34983926]. Beyond p53, USP10 stabilizes a wide range of regulators across opposing oncogenic and tumor-suppressive programs, including SIRT6 [PMID:24332849, PMID:29698567], YAP/TAZ [PMID:32217697], FLT3 [PMID:28967922], KLF4 [PMID:31748695], Smad4 [PMID:31721429], PTEN [PMID:28852924, PMID:34416231], MSH2 [PMID:26975374], NICD1 [PMID:30975888], and the histone variant H2A.Z [PMID:21245042], frequently via removal of specific K48-, K63-, K11-, or K27/K29-linked chains [PMID:34416231, PMID:36526897, PMID:37757903, PMID:37838281]. USP10 is a core component of stress granule biology: its mutually exclusive binding to G3BP1 (versus Caprin1) inhibits stress granule condensation [PMID:27022092], and G3BP1–USP10 complexes deubiquitinate monoubiquitinated 40S ribosomal proteins (RPS2/3/10) to rescue stalled subunits from lysosomal degradation during ribosome-associated quality control [PMID:31981475]. In NF-κB signaling, USP10 acts through scaffolds MCPIP1 and TANK to deubiquitinate NEMO and TRAF6, restraining genotoxic and innate-immune NF-κB activation [PMID:24270572, PMID:25861989]. USP10 also supports autophagy by deubiquitinating LC3B [PMID:33577797], regulates angiogenesis through endothelial Notch signaling [PMID:30975888], and contributes to DNA damage repair, cytokinesis, and immune responses [PMID:36526897, PMID:34983926, PMID:37838281]. Many substrate interactions are directed by recruiting scaffolds (DCAF7, KIF15, AEG-1, NDR1), and its catalytic Cys424 is a validated druggable interface targeted by ubiquitin variants and small-molecule inhibitors [PMID:28587923, PMID:32694757].","teleology":[{"year":2010,"claim":"Established USP10 as a bona fide deubiquitinase with a defined physiological substrate by showing it reverses Mdm2-driven p53 degradation and links DNA-damage signaling to p53 activation.","evidence":"Co-IP, in vitro deubiquitination, subcellular fractionation, ATM kinase assay and mutagenesis of Thr42/Ser337 in a p53-dependent system","pmids":["20096447"],"confidence":"High","gaps":["Did not define the full set of ubiquitin chain linkages on p53 removed by USP10","Structural basis of substrate recognition not resolved"]},{"year":2011,"claim":"Connected USP10 activity to autophagy/tumor-suppressor circuitry by showing Beclin1 controls USP10 stability and USP10 reciprocally deubiquitinates Beclin1, defining a regulated DUB-substrate feedback node.","evidence":"Spautin-1 small-molecule perturbation, Co-IP, ubiquitination and protein stability assays","pmids":["21962518"],"confidence":"High","gaps":["Mechanism by which Beclin1 controls USP10 catalytic activity not fully defined"]},{"year":2009,"claim":"Showed USP10 acts at endosomal membranes to control receptor trafficking, deubiquitinating CFTR to promote recycling rather than lysosomal degradation, expanding its role beyond proteasomal substrate stabilization.","evidence":"Activity-based DUB screen, dominant-negative C424A, endosomal fractionation, chloride secretion assay","pmids":["19398555"],"confidence":"High","gaps":["Recruitment to endosomes not mapped","Generality of trafficking role for other receptors unclear at the time"]},{"year":2016,"claim":"Defined phospho-regulation of USP10 catalytic output, showing AMPK phosphorylation at Ser76 amplifies USP10-mediated AMPKα deubiquitination in a feedforward loop linking it to energy-stress signaling.","evidence":"In vitro deubiquitination and kinase assays, Ser76 mutagenesis, metabolic loss-of-function readout","pmids":["26876938"],"confidence":"High","gaps":["Whether multiple kinases converge on overlapping sites not resolved"]},{"year":2016,"claim":"Established USP10's central role in stress granule biology, showing G3BP1 binding to USP10 is mutually exclusive with Caprin1 and inhibits stress granule formation.","evidence":"G3BP1/G3BP2 double-knockout cells with G3BP1 point-mutant rescues and Co-IP","pmids":["27022092"],"confidence":"High","gaps":["Whether USP10 catalytic activity is required for SG inhibition not fully separated from binding"]},{"year":2020,"claim":"Extended the G3BP1-USP10 axis to ribosome-associated quality control, showing the complex deubiquitinates 40S ribosomal proteins to rescue stalled subunits from lysosomal degradation.","evidence":"CRISPR knockouts, ubiquitination assay, RPS3-K214R rescue, ribosome stoichiometry and MS","pmids":["31981475"],"confidence":"High","gaps":["How the complex discriminates aberrant from normal 40S subunits not defined"]},{"year":2015,"claim":"Defined a scaffold-directed mechanism for USP10 in NF-κB control, showing MCPIP1- and TANK-dependent deubiquitination of NEMO and TRAF6 restrains genotoxic and innate-immune NF-κB activation.","evidence":"Reciprocal Co-IP, ubiquitination assays, CRISPR/Cas9 deletion, NF-κB reporter and cytokine ELISA","pmids":["24270572","25861989"],"confidence":"Medium","gaps":["Context-dependent switch between NF-κB-suppressing and NF-κB-stabilizing roles (cf. NEMO stabilization in sepsis) not reconciled","Direct chain-linkage specificity on TRAF6 not fully mapped"]},{"year":2019,"claim":"Demonstrated an in vivo developmental function, showing endothelial USP10 stabilizes NICD1 to tune Notch-dependent vessel sprouting and patterning.","evidence":"Endothelial-specific Usp10 knockout mouse, in vivo sprouting angiogenesis, genetic epistasis with NICD1","pmids":["30975888"],"confidence":"High","gaps":["Chain-linkage specificity on NICD1 in endothelium not defined"]},{"year":2021,"claim":"Identified USP10 as a regulator of the autophagy machinery itself, showing it deubiquitinates LC3B to prevent its proteasomal turnover and sustain receptor-mediated clearance.","evidence":"CRISPR-Cas9 KO, ubiquitination assay, proteasome inhibition, autophagy receptor degradation assays","pmids":["33577797"],"confidence":"High","gaps":["Whether LC3B deubiquitination is the dominant mechanism by which USP10 affects autophagic flux in vivo not established"]},{"year":2023,"claim":"Revealed an enzyme-independent function, showing USP10 physically tethers Axin1 and β-catenin and promotes phase separation to suppress Wnt signaling, in addition to K48-linked deubiquitination of Axin1.","evidence":"Unbiased DUB screen, in vitro binding, computational modeling, phase-separation assay, enzymatic mutant, CRC organoid and xenograft","pmids":["37611590","39443725"],"confidence":"High","gaps":["Structural determinants distinguishing scaffolding from catalytic functions not resolved"]},{"year":2023,"claim":"Showed substrate specificity of USP10 is frequently dictated by recruiting scaffolds, with DCAF7, KIF15, and AEG-1 bridging USP10 to G3BP1, PGK1, and PARP1 respectively, and ERK phosphorylation gating substrate access.","evidence":"Co-IP/MS, domain-mapping, site-specific ubiquitination assays, phospho-site mapping, functional cancer models","pmids":["38973296","36807568","37838281","36940483"],"confidence":"Medium","gaps":["A unifying model of how scaffolds and phospho-marks combinatorially select among the many USP10 substrates is lacking","Most scaffold mechanisms rest on single-lab evidence"]},{"year":null,"claim":"How USP10 selects among its very large and functionally opposing substrate set in a given cellular context, and what structural features define its catalytic versus scaffolding modes, remain unresolved.","evidence":"No single study integrates the substrate repertoire with structural or context-defining determinants","pmids":[],"confidence":"Medium","gaps":["No structural model of USP10 substrate engagement","No systematic map of which phospho-states and scaffolds direct which substrates","Reconciliation of tumor-suppressive vs oncogenic outputs in vivo incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,9,19,35,36]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,58]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,35,39]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,22,42]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,9,26]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,9,43]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,12,35]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,26,53]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[19,55]}],"complexes":["G3BP1-USP10 stress granule complex","MCPIP1-TANK-USP10 NF-κB regulatory complex"],"partners":["TP53","G3BP1","AMPKΑ","SIRT6","PTEN","NICD1","NEMO","MCPIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFA0","full_name":"Ubiquitin carboxyl-terminal hydrolase 32","aliases":["Deubiquitinating enzyme 32","Renal carcinoma antigen NY-REN-60","Ubiquitin thioesterase 32","Ubiquitin-specific-processing protease 32"],"length_aa":1604,"mass_kda":181.7,"function":"Deubiquitinase that can remove conjugated ubiquitin from target proteins, such as RAB7A and LAMTOR1 (PubMed:36476874). Acts as a positive regulator of the mTORC1 signaling by mediating deubiquitination of LAMTOR1, thereby promoting the association between LAMTOR1 and the lysosomal V-ATPase complex and subsequent activation of the mTORC1 complex (PubMed:36476874)","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q8NFA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/USP10","classification":"Common Essential","n_dependent_lines":794,"n_total_lines":1208,"dependency_fraction":0.6572847682119205},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000103194","cell_line_id":"CID001518","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"G3BP2","stoichiometry":4.0},{"gene":"RBM42","stoichiometry":4.0},{"gene":"ATG4B","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EIF3G","stoichiometry":0.2},{"gene":"G3BP1","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001518","total_profiled":1310},"omim":[{"mim_id":"615857","title":"2-OXOGLUTARATE- AND IRON-DEPENDENT OXYGENASE DOMAIN-CONTAINING PROTEIN 1; OGFOD1","url":"https://www.omim.org/entry/615857"},{"mim_id":"609818","title":"UBIQUITIN-SPECIFIC PROTEIN 10; USP10","url":"https://www.omim.org/entry/609818"},{"mim_id":"607740","title":"UBIQUITIN-SPECIFIC PROTEASE 32; USP32","url":"https://www.omim.org/entry/607740"},{"mim_id":"604378","title":"BECLIN 1; BECN1","url":"https://www.omim.org/entry/604378"},{"mim_id":"603591","title":"UBIQUITIN-SPECIFIC PROTEASE 13; USP13","url":"https://www.omim.org/entry/603591"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP10"},"hgnc":{"alias_symbol":["UBPO","KIAA0190"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFA0","domains":[{"cath_id":"1.10.238.10","chopping":"14-166","consensus_level":"medium","plddt":89.0008,"start":14,"end":166},{"cath_id":"1.10.238.10","chopping":"182-368","consensus_level":"high","plddt":89.2896,"start":182,"end":368},{"cath_id":"3.30.2230.10","chopping":"372-416_523-598","consensus_level":"medium","plddt":87.3557,"start":372,"end":598},{"cath_id":"3.10.20.90","chopping":"600-610_631-703","consensus_level":"medium","plddt":89.3033,"start":600,"end":703},{"cath_id":"-","chopping":"1076-1133_1148-1216","consensus_level":"high","plddt":86.7294,"start":1076,"end":1216}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFA0-F1-predicted_aligned_error_v6.png","plddt_mean":72.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP10","jax_strain_url":"https://www.jax.org/strain/search?query=USP10"},"sequence":{"accession":"Q8NFA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFA0"}},"corpus_meta":[{"pmid":"21962518","id":"PMC_21962518","title":"Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21962518","citation_count":693,"is_preprint":false},{"pmid":"27022092","id":"PMC_27022092","title":"G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27022092","citation_count":517,"is_preprint":false},{"pmid":"20096447","id":"PMC_20096447","title":"USP10 regulates p53 localization and stability by deubiquitinating p53.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/20096447","citation_count":513,"is_preprint":false},{"pmid":"24332849","id":"PMC_24332849","title":"USP10 antagonizes c-Myc transcriptional activation through SIRT6 stabilization to suppress tumor formation.","date":"2013","source":"Cell 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38857836","citation_count":18,"is_preprint":false},{"pmid":"39206932","id":"PMC_39206932","title":"Tuning Immune-Cold Tumor by Suppressing USP10/B7-H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39206932","citation_count":17,"is_preprint":false},{"pmid":"39227807","id":"PMC_39227807","title":"NDR1 mediates PD-L1 deubiquitination to promote prostate cancer immune escape via USP10.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39227807","citation_count":17,"is_preprint":false},{"pmid":"38687433","id":"PMC_38687433","title":"FOXP4-AS1 promotes CD8+ T cell exhaustion and esophageal cancer immune escape through USP10-stabilized PD-L1.","date":"2024","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/38687433","citation_count":17,"is_preprint":false},{"pmid":"39267084","id":"PMC_39267084","title":"Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/39267084","citation_count":16,"is_preprint":false},{"pmid":"38689092","id":"PMC_38689092","title":"Stress-induced epinephrine promotes hepatocellular carcinoma progression via the USP10-PLAGL2 signaling loop.","date":"2024","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38689092","citation_count":16,"is_preprint":false},{"pmid":"36406315","id":"PMC_36406315","title":"USP10 Alleviates Palmitic Acid-induced Steatosis through Autophagy in HepG2 Cells.","date":"2022","source":"Journal of clinical and translational hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36406315","citation_count":16,"is_preprint":false},{"pmid":"39443725","id":"PMC_39443725","title":"USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39443725","citation_count":15,"is_preprint":false},{"pmid":"39218913","id":"PMC_39218913","title":"Deubiquitinase USP10 promotes osteosarcoma autophagy and progression through regulating GSK3β-ULK1 axis.","date":"2024","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/39218913","citation_count":15,"is_preprint":false},{"pmid":"37436447","id":"PMC_37436447","title":"USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis.","date":"2023","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/37436447","citation_count":15,"is_preprint":false},{"pmid":"38960057","id":"PMC_38960057","title":"FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38960057","citation_count":15,"is_preprint":false},{"pmid":"37873736","id":"PMC_37873736","title":"The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β-catenin signaling in cancer.","date":"2023","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/37873736","citation_count":14,"is_preprint":false},{"pmid":"32829179","id":"PMC_32829179","title":"USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32829179","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52469,"output_tokens":15073,"usd":0.191751,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":27393,"output_tokens":4379,"usd":0.12322,"stage2_stop_reason":"end_turn"},"total_usd":0.314971,"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\": 2010,\n      \"finding\": \"USP10 is a cytoplasmic deubiquitinase that deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized and translocates to the nucleus to activate p53; this translocation and stabilization is regulated by ATM-mediated phosphorylation of USP10 at Thr42 and Ser337.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, subcellular fractionation, ATM kinase assay, site-directed mutagenesis, loss-of-function experiments with defined p53-dependent phenotypic readout\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deubiquitination assay combined with mutagenesis, ATM phosphorylation site identification, nuclear translocation experiments, and functional rescue; published in high-impact journal with extensive follow-up replication across many labs\",\n      \"pmids\": [\"20096447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Beclin1 controls the protein stability of USP10 (and USP13) by regulating their deubiquitinating activities. USP10 mediates deubiquitination of p53, and Beclin1-regulated USP10 activity provides a mechanism linking the tumor suppressors Beclin1 and p53. USP10 and USP13 also deubiquitinate the Beclin1 subunit of Vps34 PI3 kinase complexes, protecting them from degradation.\",\n      \"method\": \"Small molecule inhibitor (spautin-1) studies, co-immunoprecipitation, ubiquitination assays, loss-of-function experiments, in-cell protein stability assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, small molecule perturbation, genetic knockdown), replicated mechanistic axis across multiple labs\",\n      \"pmids\": [\"21962518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP10 directly deubiquitylates the histone variant H2A.Z in vitro and in vivo. USP10 and H2A.Z are both required for transcriptional activation of androgen receptor (AR)-regulated genes (PSA and KLK3); knockdown of USP10 elevates steady-state mono-ubiquitylated H2A.Z and ablates hormone-induced deubiquitylation at AR-regulated gene regulatory regions.\",\n      \"method\": \"In vitro deubiquitylation assay, ChIP, sequential ChIP, siRNA knockdown, reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay plus ChIP and in-cell functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21245042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP10 is localized in early endosomes in airway epithelial cells and deubiquitinates endocytosed CFTR, promoting its recycling back to the apical membrane rather than lysosomal degradation. siRNA knockdown of USP10 increased ubiquitinated CFTR and lysosomal degradation; dominant-negative USP10-C424A increased ubiquitinated CFTR degradation; overexpression of wt-USP10 decreased ubiquitinated CFTR.\",\n      \"method\": \"Activity-based chemical DUB screen, siRNA knockdown, dominant-negative overexpression (C424A mutant), endosomal fractionation, chloride secretion assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — dominant-negative mutagenesis, biochemical fractionation, functional chloride secretion readout, multiple genetic perturbations in single lab\",\n      \"pmids\": [\"19398555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP10 specifically removes ubiquitin from AMPKα to facilitate AMPKα phosphorylation by LKB1. Ubiquitination on AMPKα blocks LKB1-mediated phosphorylation. Under energy stress, AMPK-mediated phosphorylation of USP10 at Ser76 enhances USP10 activity, forming a feedforward loop amplifying AMPK activation.\",\n      \"method\": \"In vitro deubiquitination assay, in vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (Ser76), genetic loss-of-function with metabolic phenotypic readout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitination and kinase assays combined with mutagenesis and functional rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26876938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP10 interacts with SIRT6 and suppresses SIRT6 ubiquitination, protecting SIRT6 from proteasomal degradation. Through stabilizing SIRT6, USP10 antagonizes c-Myc transcriptional activity and inhibits cell-cycle progression.\",\n      \"method\": \"Proteomic approach (co-IP/MS), co-immunoprecipitation, ubiquitination assay, cell-cycle analysis, loss-of-function experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS identification, ubiquitination assay, functional cell-cycle readout; single lab, confirmed by independent NAFLD paper (PMID:29698567)\",\n      \"pmids\": [\"24332849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP10 interacts with NEMO via the scaffold protein MCPIP1 upon genotoxic stress and removes linear polyubiquitin chains from NEMO, resulting in decreased IKK and NF-κB activation. USP10 is required for MCPIP1-mediated inhibition of genotoxic NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NF-κB reporter assay, epistasis experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP, ubiquitination assay, genetic epistasis with defined NF-κB phenotypic readout; single lab\",\n      \"pmids\": [\"24270572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP10 forms a complex with TANK and MCPIP1 that mediates deubiquitination of TRAF6, suppressing NF-κB activation induced by genotoxic stress and IL-1R/TLR stimulation. CRISPR/Cas9 deletion of TANK enhanced NF-κB activation and inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CRISPR/Cas9 deletion, NF-κB reporter assay, cytokine ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, CRISPR genetic deletion, functional NF-κB and cytokine readouts; single lab\",\n      \"pmids\": [\"25861989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"G3BP1/G3BP2 and USP10 form complexes that mediate stress granule (SG) condensation. G3BP1 phosphomimetic S149E mutant fails to rescue SG formation, while G3BP1-F33W mutant (unable to bind Caprin1 or USP10) rescues SG formation. Caprin1 binding promotes SG formation while USP10 binding to G3BP inhibits SG formation; these two interactions are mutually exclusive.\",\n      \"method\": \"Genetic rescue experiments with G3BP1 point mutants, G3BP1/G3BP2 double-knockout cells, stress granule induction assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-knockout cells with multiple G3BP1 point-mutant rescues, clearly defining USP10's inhibitory role in SG formation; well-replicated finding\",\n      \"pmids\": [\"27022092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP10 as part of G3BP1-family complexes deubiquitinates monoubiquitinated RPS2, RPS3, and RPS10 on 40S ribosomal subunits stalled at aberrant mRNAs. This rescues modified 40S subunits from lysosomal degradation during ribosome-associated quality control. Knockout of USP10 or G3BP1-family proteins increased lysosomal ribosomal degradation and perturbed ribosomal subunit stoichiometry; K214R substitution in RPS3 rescued these phenotypes.\",\n      \"method\": \"CRISPR knockout, ubiquitination assay, ribosomal subunit stoichiometry analysis, rescue with RPS3-K214R mutant, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR knockouts, point-mutant rescue, ribosome fractionation, MS; multiple orthogonal methods, single lab but highly rigorous\",\n      \"pmids\": [\"31981475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP10 is required to stabilize oncogenic FLT3 (FLT3-ITD and FLT3-D835Y) by preventing its ubiquitin-mediated proteasomal degradation. Pharmacological or genetic inhibition of USP10 induces FLT3 degradation and shows efficacy in preclinical AML models.\",\n      \"method\": \"DUB inhibitor library screen, target deconvolution, co-immunoprecipitation, ubiquitination assay, cell-line and primary patient cell models, mouse xenograft model\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phenotypic screen with target deconvolution, Co-IP, in vitro and in vivo models; multiple orthogonal methods\",\n      \"pmids\": [\"28967922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNF168 E3 ligase mediates ubiquitylation of TOP2α, while USP10 acts as the deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. The opposing actions of RNF168 and USP10 on TOP2α ubiquitylation modulate decatenation activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, genetic loss-of-function with chromosomal segregation phenotypic readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional TOP2α activity readout; single lab\",\n      \"pmids\": [\"27558965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 interacts with NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of NICD1. Inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in endothelial cells. Loss of endothelial Usp10 increased vessel sprouting in mice and partially restored patterning defects caused by ectopic NICD1 expression.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, endothelial-specific Usp10 knockout mouse, in vivo sprouting angiogenesis assay, gene expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, endothelial-specific KO mouse with in vivo phenotype, genetic epistasis with NICD1 overexpression; multiple orthogonal methods\",\n      \"pmids\": [\"30975888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 deubiquitinates and stabilizes KLF4 by blocking its proteasomal degradation. Loss of USP10 in mice downregulates KLF4 and accelerates KrasG12D-driven lung adenocarcinoma. KLF4 in turn facilitates transcription of TIMP3 by binding its promoter.\",\n      \"method\": \"siRNA screen of ubiquitin-specific proteases, co-immunoprecipitation, ubiquitination assay, conditional USP10 knockout mouse with KrasG12D, promoter binding by ChIP\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — USP screen, Co-IP, in vivo genetic mouse model with defined tumor phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"31748695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 deubiquitinates and stabilizes Smad4, sustaining TGF-β signaling. USP10 directly interacts with Smad4 and cleaves its proteolytic ubiquitin chains, promoting HCC metastasis. Suppression of USP10 inhibits HCC cell migration; reconstitution of Smad4 rescues this defect.\",\n      \"method\": \"siRNA library screen of USPs, co-immunoprecipitation, ubiquitination assay, migration assay, rescue experiment with Smad4\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — USP siRNA screen, Co-IP, ubiquitination assay, Smad4 rescue; single lab\",\n      \"pmids\": [\"31721429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP10 directly interacts with YAP and TAZ, deubiquitinates them by reverting their proteolytic ubiquitination, and stabilizes them. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ and promoted their proteasomal degradation, arresting hepatocellular carcinoma proliferation in vitro and in vivo.\",\n      \"method\": \"DUB screen (transcriptional activity and protein abundance), co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DUB screen, Co-IP, ubiquitination assay, in vivo xenograft with functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"32217697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 interacts with and deubiquitinates G3BP2, maintaining G3BP2 protein stability and reducing its polyubiquitylation. G3BP2-dependent growth activation and p53 nuclear export are repressed by USP10 knockdown, placing USP10 upstream of the G3BP2-p53 axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, chromatin immunoprecipitation, cell growth assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, ChIP; single lab\",\n      \"pmids\": [\"29378906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HTLV-1 Tax oncoprotein interacts with USP10 and inhibits arsenic-induced stress granule formation by USP10-containing SGs, stimulating ROS production and augmenting ROS-dependent apoptosis. USP10 normally functions to inhibit stress-induced ROS production and apoptosis; Tax attenuates this activity.\",\n      \"method\": \"Co-immunoprecipitation, stress granule formation assay, ROS measurement, apoptosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, SG formation assay, ROS and apoptosis functional readouts; single lab\",\n      \"pmids\": [\"23775713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 is a novel deubiquitinase of SKP2; it binds to and deubiquitinates SKP2, preventing its degradation. Stabilized SKP2 in turn mediates K63-linked ubiquitination and activation of Bcr-Abl, creating a USP10/SKP2/Bcr-Abl axis in CML.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell proliferation assay in imatinib-sensitive and -resistant CML cells\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional cell proliferation readout; single lab\",\n      \"pmids\": [\"31044085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP10 interacts with MSH2 and deubiquitinates it both in vitro and in vivo, stabilizing MSH2 protein. Knockdown of USP10 in lung cancer cells exhibits increased cell survival and decreased apoptosis upon treatment with MNNG and 6-TG; these phenotypes are rescued by ectopic MSH2 expression. MSH2 protein level correlates positively with USP10 level.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, siRNA knockdown, mismatch repair activity assay, cell survival/apoptosis assay, rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitination assay, Co-IP, functional MSH2 rescue, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"26975374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 mediates deubiquitination of p14ARF, preventing its proteasome-dependent degradation. c-Myc induces USP10 transcription; USP10 then stabilizes p14ARF to enforce oncogene-induced senescence. USP10-null MEFs and primary cells depleted of USP10 bypass c-Myc-induced senescence via p14ARF destabilization.\",\n      \"method\": \"Ubiquitination assay, siRNA knockdown, USP10-null MEFs, cell senescence assay (SA-β-gal, proliferation), c-Myc overexpression epistasis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay, knockout MEFs, senescence functional readout; single lab\",\n      \"pmids\": [\"29472714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP10 interacts with integrin β1 and β5; recombinant USP10 removes ubiquitin from these integrin subunits in vitro. Loss of USP10 induces ubiquitin accumulation on β1/β5 integrins, decreasing αv/β1/β5 protein levels and TGFβ activation. Gain of USP10 increases αv/β1/β5 protein levels and fibrotic marker expression.\",\n      \"method\": \"Genetic screen, siRNA knockdown, recombinant USP10 in vitro deubiquitination, co-immunoprecipitation, ex vivo cornea organ culture, loss- and gain-of-function with fibrotic marker readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deubiquitination with recombinant protein, functional TGFβ and fibrotic marker readouts; single lab\",\n      \"pmids\": [\"28851806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"USP10 is part of DNA-bound androgen receptor (AR) complexes in nuclear extracts. Interaction with AR confirmed by GST pull-down. USP10 localizes in both nucleus and cytoplasm. Overexpression of catalytically active, but not enzymatically inactive, USP10 stimulates AR transactivation at AREs, SREs, and MMTV promoter; siRNA knockdown of USP10 impairs MMTV androgen response.\",\n      \"method\": \"Nuclear extract purification, GST pull-down, fluorescence microscopy, cell-based transactivation reporter assay, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — GST pulldown, catalytically-inactive mutant comparison, reporter assays; single lab\",\n      \"pmids\": [\"16368182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of UbV.7.2 (ubiquitin variant inhibitor) was solved and provided the molecular basis for enhanced affinity and specificity for USP7. UbVs were also identified that bound USP10 with high affinity and inhibited its deubiquitination activity, validating the catalytic site of USP10 as a druggable interface.\",\n      \"method\": \"Phage-displayed UbV library, crystal structure determination (for USP7 UbV), in vitro deubiquitination inhibition assay, cell death assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-3 / Weak — crystal structure for USP7 UbV (not USP10 directly); USP10 inhibition via UbV confirmed by in vitro activity assay; single lab\",\n      \"pmids\": [\"28587923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 interacts with HDAC6 and deubiquitinates and stabilizes HDAC6. Reintroduction of either USP10 or HDAC6 into USP10-knockdown NSCLC cells with null p53 restores cisplatin resistance, defining a USP10-HDAC6-cisplatin resistance axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/genetic knockdown, rescue experiment with USP10 or HDAC6, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, rescue experiment with functional drug-resistance readout; single lab\",\n      \"pmids\": [\"32382008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"USP10 interacts with T-bet transcription factor in the nucleus, directly inhibits T-bet ubiquitination, and increases T-bet protein expression. Quercetin, a reported T-bet inhibitor, targets USP10 to promote T-bet proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression, inhibitor treatment (quercetin)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab, single method set\",\n      \"pmids\": [\"24845384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 deubiquitinates LC3B, reversing monoubiquitination-mediated proteasomal degradation of LC3B. CRISPR-Cas9 KO of USP10 reduces both LC3B-I and LC3B-II levels through increased ubiquitination and proteasomal degradation, leading to slower degradation of autophagy receptors SQSTM1 and NBR1 and increased aggresome-like structures.\",\n      \"method\": \"CRISPR-Cas9 knockout screen, biochemical ubiquitination assay, proteasome inhibitor experiments, autophagy receptor degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — CRISPR screen and validation, direct ubiquitination assay, multiple functional autophagy readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33577797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 interacts with p62 (ubiquitin receptor) and the USP10-p62 interaction augments p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby inhibiting apoptosis. USP10-p62-induced protein aggregates inhibit proteasome activity, further increasing ubiquitinated protein levels. USP10 co-localizes with α-synuclein in Lewy bodies in Parkinson disease brains.\",\n      \"method\": \"Co-immunoprecipitation, aggresome formation assay, proteasome activity assay, immunohistochemistry of PD brain tissue\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, functional proteasome and aggresome assays, neuropathological co-localization; single lab\",\n      \"pmids\": [\"30469013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 is a critical factor for the formation of Tau/TIA1/USP10-positive stress granules in neuronal cells. Depletion of USP10 severely attenuates TIA1/Tau-positive SG formation induced by proteasome inhibition or TIA1 overexpression. Overexpression of USP10 without stress stimuli induces TIA1/Tau/USP10-positive SGs in a deubiquitinase-independent manner.\",\n      \"method\": \"siRNA knockdown, overexpression with catalytically inactive control, immunofluorescence of SG formation, immunohistochemistry of AD brain tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown and deubiquitinase-inactive mutant overexpression; functional SG assay with deubiquitinase-independent function identified; single lab\",\n      \"pmids\": [\"31332267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 promotes clearance of TDP-43-positive stress granules and thereby inhibits aberrant cytoplasmic aggregation of TDP-43/TDP-35 in neuronal cells. Depletion of USP10 increases insoluble TDP-35 in the cytoplasm. TDP-35 interacts with USP10 in an RNA-binding-dependent manner.\",\n      \"method\": \"siRNA knockdown, overexpression, stress granule clearance assay, solubility fractionation, co-immunoprecipitation, immunohistochemistry of ALS patient tissue\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown, Co-IP with RNA-binding mutant validation, functional SG and aggregation readouts; single lab\",\n      \"pmids\": [\"35007165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 interacts with Raf-1 and promotes its deubiquitination, stabilizing Raf-1 protein (without affecting mRNA), which activates downstream MEK/ERK signaling. USP10 overexpression promotes proliferation, migration, and inhibits apoptosis of endometrial stromal cells via Raf-1/MEK/ERK; effects are blocked by MEK inhibitor PD-98059.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, MEK inhibitor rescue, proliferation/apoptosis/migration assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, pharmacological and genetic rescue; single lab\",\n      \"pmids\": [\"30281322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP10 interacts with SIRT6 and inhibits its ubiquitination and degradation in the liver. USP10 deficiency exacerbates HFD-induced metabolic dysfunction; SIRT6 overexpression reverses USP10 deficiency effects; SIRT6 deficiency counteracts USP10 overexpression benefits, placing USP10 upstream of SIRT6 in hepatic metabolism.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, hepatocyte-specific USP10 knockout and overexpression mouse models, genetic epistasis with SIRT6\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO and OE mouse models, Co-IP, ubiquitination assay, genetic epistasis with SIRT6; multiple orthogonal methods\",\n      \"pmids\": [\"29698567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 deubiquitinates and stabilizes Musashi-2 (MSI2) through direct interaction, preventing its proteasomal degradation, and thereby promotes colon cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, cell proliferation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab\",\n      \"pmids\": [\"30604502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP10 is the major DUB required for stabilization of SYK. USP10 inhibition leads to proteasome-mediated SYK degradation and potentiates anti-leukemic effects of FLT3 inhibition.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP10 inhibitor treatment, cell viability assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, pharmacological inhibition with functional readout; single lab\",\n      \"pmids\": [\"32015510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP10 directly interacts with and stabilizes PTEN through deubiquitination in lung cancer cells. Co-immunoprecipitation confirmed the interaction; ubiquitination/deubiquitination assays confirmed the mechanism. Pro-cancerous effects of USP10 deficiency are abolished by PTEN re-introduction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, PTEN rescue experiment, in vivo allograft\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, genetic rescue; single lab\",\n      \"pmids\": [\"28852924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 interacts with PTEN and removes TRIM25-mediated K63-linked polyubiquitination of PTEN, restoring PTEN phosphatase activity and reducing PIP3 production, thereby inhibiting AKT/mTOR signaling. The inactive C424A mutant of USP10 fails to reverse PTEN ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K63-specific chains, C424A inactive mutant, PIP3 measurement, AKT/mTOR signaling assay, NSCLC proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — catalytic mutant validation, K63-specific ubiquitination assay, functional phosphatase activity readout, multiple methods; single lab\",\n      \"pmids\": [\"34416231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP10 deubiquitinates and stabilizes ANLN (anillin) by removing K11- and K63-linked ubiquitin chains, preventing APC/C-Cdh1-mediated degradation. USP10 and Cdh1 form a functional complex with ANLN in a non-competitive manner to balance ANLN levels. USP10 promotes contractile ring assembly at the cytokinetic furrow and cytokinesis through ANLN stabilization.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K11 and K63-specific), cytokinesis assay, USP10 inhibitor (F806), complex formation analysis with Cdh1 mutant\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, K11/K63 ubiquitination assays, functional cytokinesis readout; single lab\",\n      \"pmids\": [\"36526897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 interacts with TAK1 directly and promotes protection against cerebral ischemia-reperfusion injury. USP10 KO mice show elevated NF-κB signaling, JNK-MAPK activation, and increased apoptosis after cerebral I/R, demonstrating USP10's inhibitory role on TAK1-mediated inflammatory signaling.\",\n      \"method\": \"USP10 knockout mouse, cerebral I/R injury model, co-immunoprecipitation, NF-κB and JNK pathway analysis, apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockout mouse with defined neurological phenotype, Co-IP, pathway analysis; single lab\",\n      \"pmids\": [\"31301769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 interacts with NEMO in macrophages; USP10 inhibition accelerates NEMO degradation. USP10 stabilizes NEMO by deubiquitination, maintaining NF-κB activation in LPS-induced sepsis. Suppressing USP10 attenuated inflammatory responses and improved survival in LPS-induced sepsis mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, spautin-1 inhibitor, NF-κB translocation assay, cytokine ELISA, in vivo sepsis model\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, functional NF-κB translocation and cytokine readouts, in vivo model; single lab\",\n      \"pmids\": [\"37436447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 binds to Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Additionally, USP10 physically tethers Axin1 and β-catenin and promotes phase separation for β-catenin suppression in a manner independent of enzymatic activity. In APC-truncated CRC, USP10 binds to β-catenin directly (via unstructured N-terminus) and increases β-catenin stability.\",\n      \"method\": \"Unbiased DUB screen, in vitro binding assay, computational modelling, ubiquitination assay (K48-specific), phase separation assay, USP10 enzymatic mutant, CRC organoid model, xenograft\",\n      \"journal\": \"Cell chemical biology / Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (in vitro binding, computational, ubiquitination assay, phase separation, organoid); enzyme-dependent and independent functions distinguished\",\n      \"pmids\": [\"37611590\", \"39443725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF4 interacts with USP10 and blocks p53 access to USP10, resulting in p53 destabilization and enhanced fibroblast proliferation in keloids. TRAF4 acts independently of its E3 ubiquitin ligase activity in this process.\",\n      \"method\": \"Co-immunoprecipitation, p53 ubiquitination assay, siRNA knockdown, rescue experiment (p53 knockdown), keloid fibroblast proliferation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, genetic rescue; single lab\",\n      \"pmids\": [\"30940456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP10 deubiquitinates RUNX1 and stabilizes it, maintaining mesenchymal subtype properties in glioblastoma. USP10 knockdown inhibits RUNX1 and results in loss of mesenchymal properties.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vivo xenograft, GBM subtype gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft; single lab\",\n      \"pmids\": [\"36949071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP10 deubiquitinates and stabilizes AID (activation-induced cytidine deaminase), which specifically stabilizes nuclear AID protein. USP10 translocates into the nucleus after AKT-mediated phosphorylation at T674 within its NLS domain. BCR and TLR1/2 signals synergistically promote this phosphorylation. USP10 deficiency in B cells decreased AID protein levels and reduced neutralizing antibody production after vaccination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear localization imaging, kinase assay, USP10-conditional B cell knockout, vaccination challenge\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional B cell KO with antibody readout, phosphorylation site identified; single lab\",\n      \"pmids\": [\"34983926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 directly interacts with PABPC1 and decreases K27/K29-linked ubiquitination of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 couples more CLK2 mRNA and eIF4G1, increasing CLK2 translation efficiency and promoting pancreatic cancer tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (K27/K29-specific), polysome/mRNA association assay, in vivo xenograft and PDX model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS, K27/K29-specific ubiquitination assay, translation efficiency measurement; single lab\",\n      \"pmids\": [\"37757903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 interacts with and deubiquitinates MOF (KAT8) acetyltransferase at lysine 410, protecting it from proteasomal degradation. Stabilized MOF promotes H4K16ac enrichment at the ANXA2 promoter in a JUN-dependent manner, activating ANXA2/Wnt signaling and ESCC progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, specific lysine mutagenesis (K410), H4K16ac ChIP, functional ESCC tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, site-specific ubiquitination mutagenesis, ChIP functional readout; single lab\",\n      \"pmids\": [\"38317006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP10 binds to XAB2 and deubiquitinates K48-linked polyubiquitination at K593 of XAB2, stabilizing it and preventing proteasomal degradation. Nuclear USP10 expression increases in CRC cells treated with oxaliplatin. Stabilized XAB2 upregulates ANXA2 transcriptionally by binding the ANXA2 promoter, promoting DNA damage repair and oxaliplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination site MS, ubiquitin assay, dual-luciferase reporter, ChIP-qPCR, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS, site-specific ubiquitination assay, ChIP readout, functional rescue; single lab\",\n      \"pmids\": [\"40069750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 interacts with NICD1 (Notch1 intracellular domain) and deubiquitinates it, stabilizing NICD1 and promoting K11/K48-linked polyubiquitination-mediated degradation when disrupted by N1DARP microprotein. N1DARP competitively disrupts USP10-N1ICD interaction, accelerating N1ICD proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K11/K48-specific), competition binding assay, pancreatic cancer organoid model, KPC mouse model\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, K11/K48 ubiquitination assay, competition assay, organoid model; single lab\",\n      \"pmids\": [\"37714834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP10 interacts with CD36 scavenger receptor and stabilizes CD36 protein by cleaving poly-ubiquitin on CD36, promoting foam cell formation. USP10 inhibition promotes CD36 degradation and suppresses lipid uptake and foam cell formation by macrophages.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Oil Red O staining, immunofluorescence\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab\",\n      \"pmids\": [\"33197885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 interacts with the EMT transcription factor Slug/SNAI2, identified in a genome-wide siRNA DUB screen, and mediates its proteasomal degradation. Genetic knockdown of USP10 decreases Slug levels and reduces cancer cell migration; overexpression elevates Slug and Vimentin.\",\n      \"method\": \"Genome-wide siRNA DUB screen, co-immunoprecipitation, protein stability assay, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA screen followed by single Co-IP; note: USP10 depletion decreases Slug, suggesting USP10 stabilizes Slug but mechanistic deubiquitination was not explicitly shown as in vitro assay; single lab\",\n      \"pmids\": [\"29803676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DCAF7 acts as a scaffold protein facilitating the interaction between USP10 and G3BP1, leading to USP10-mediated removal of K48-linked ubiquitin moieties from Lys76 of G3BP1, preventing its proteasomal degradation and promoting stress granule-like structure formation and NPC chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific, K76 site mapping), siRNA knockdown, stress granule formation assay, in vitro and in vivo chemoresistance model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, site-specific K48 ubiquitination mapping, functional rescue; single lab\",\n      \"pmids\": [\"38973296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 interacts with ZEB1 and promotes its proteasomal degradation by modifying its ubiquitination. ERK phosphorylates USP10 at Ser236, impairing the USP10-ZEB1 interaction and enabling ZEB1 protein stabilization. MEK-ERK inhibition blocks USP10 phosphorylation and enhances USP10-ZEB1 interaction, suppressing ZEB1-mediated metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, MEK inhibitor, USP10 phospho-site identification, colorectal cancer metastasis mouse tail-vein injection model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, phosphorylation site mapping, in vivo metastasis model; single lab\",\n      \"pmids\": [\"36940483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 interacts with AMPK-phosphorylated state and potentiates deubiquitination and stabilization of Axin1 (K48-linked), linking the LKB1/AMPK axis to Wnt/β-catenin suppression. AMPK phosphorylation of USP10 also strengthens USP10 binding to β-catenin, supporting its phase transition and suppression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, AMPK kinase assay, phase separation assay, colorectal cancer organoid and xenograft model\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination, kinase and phase separation assays, in vivo model; single lab\",\n      \"pmids\": [\"37873736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP10 interacts with NLRP7 and catalyzes its deubiquitination at K379, stabilizing NLRP7 protein and promoting colorectal cancer progression and M2 macrophage polarization via CCL2.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, K379R mutagenesis, in vivo tumor model, macrophage polarization assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS, site-specific mutagenesis, functional in vivo and macrophage polarization readouts; single lab\",\n      \"pmids\": [\"33838681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP10 stabilizes GSK3β through deubiquitination; stabilized GSK3β in turn promotes ULK1 transcription by increasing ULK1 promoter activity, thereby driving ULK1-mediated autophagy, cell proliferation, and invasion in osteosarcoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ULK1 promoter reporter, GSK3β activity assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, promoter reporter, in vivo xenograft; single lab\",\n      \"pmids\": [\"39218913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 interacts with and deubiquitinates FOXQ1, promoting its protein stability. USP10-mediated FOXQ1 stabilization activates CREB5/NF-κB signaling to alleviate sepsis-induced acute kidney injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, rescue experiment, in vivo CLP model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab\",\n      \"pmids\": [\"38960057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AEG-1 recruits USP10 to remove K48-linked polyubiquitin chains at Lys425 of PARP1, preventing PARP1 proteasomal degradation and facilitating homologous recombination-mediated DNA double-strand break repair, conferring radioresistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific, K425 site mapping), siRNA knockdown, DNA damage (γH2AX, comet assay), in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, site-specific ubiquitination assay, functional DNA repair readout; single lab\",\n      \"pmids\": [\"37838281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10; USP10 deubiquitinates PD-L1, stabilizing it and promoting immune escape in prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, CD8+ T cell co-culture model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay; single lab\",\n      \"pmids\": [\"39227807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF15 recruits USP10 to PGK1 and promotes USP10-mediated deubiquitination of PGK1, stabilizing PGK1 and enhancing glycolysis in pancreatic cancer. KIF15 interacts with both PGK1 and USP10 via its coil2 domain.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, KIF15 truncation mapping, glycolytic capacity measurement (ECAR/OCR), in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS, domain mapping, ubiquitination assay, functional metabolic readout; single lab\",\n      \"pmids\": [\"36807568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wu-5 directly interacts with and inactivates USP10 in vitro (IC50 = 8.3 µM), confirming its catalytic activity as a cysteine protease DUB. Overexpression of USP10 abrogates Wu-5-induced FLT3-ITD degradation and cell death, placing USP10 directly upstream of FLT3-ITD stability.\",\n      \"method\": \"In vitro enzymatic inhibition assay, overexpression rescue, cell viability assay\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-3 / Moderate — in vitro activity assay with IC50, functional overexpression rescue; single lab\",\n      \"pmids\": [\"32694757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PPM1B directly interacts with YBX1 and dephosphorylates YBX1 at serine 314; this dephosphorylation affects USP10-mediated deubiquitination of YBX1, resulting in decreased YBX1 protein stability. Thus USP10 deubiquitinates YBX1, and this is regulated by PPM1B-mediated phosphorylation state of YBX1.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/silencing experiments, ubiquitination assay, S314 mutagenesis, PANoptosis assay, oxaliplatin resistance assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP, ubiquitination assay, single lab, phosphorylation-ubiquitination crosstalk identified but mechanism partially indirect\",\n      \"pmids\": [\"38364962\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP10 is a cytoplasmic and nuclear ubiquitin-specific deubiquitinase (DUB) that stabilizes a broad repertoire of substrates—including p53, AMPKα, SIRT6, YAP/TAZ, FLT3, KLF4, NICD1, Smad4, PTEN, MSH2, LC3B, H2A.Z, integrins β1/β5, and many others—by removing ubiquitin chains and preventing proteasomal or lysosomal degradation; its activity and nuclear localization are regulated by phosphorylation (e.g., ATM-dependent phosphorylation at Thr42/Ser337, AMPK-dependent Ser76, and AKT-dependent T674), and it participates in stress granule biology (where its interaction with G3BP1 inhibits SG formation and G3BP1-USP10 complexes rescue ubiquitinated 40S ribosomal subunits), in NF-κB regulation (by deubiquitinating NEMO and TRAF6 via scaffold proteins MCPIP1/TANK), and in diverse cellular processes including autophagy, DNA damage repair, angiogenesis, and immune responses, making it a context-dependent regulator of both tumor suppressor and oncogenic pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP10 is a cytoplasmic and nuclear ubiquitin-specific deubiquitinase that controls the abundance and activity of a broad repertoire of substrates by removing ubiquitin chains and protecting them from proteasomal or lysosomal degradation [#0, #4]. Its prototypical role is stabilization of the tumor suppressor p53: USP10 deubiquitinates p53, reversing Mdm2-induced nuclear export and degradation, and following DNA damage it is stabilized and translocates to the nucleus through ATM-dependent phosphorylation at Thr42/Ser337 to activate p53 [#0]. Substrate engagement and nuclear access are governed by phosphorylation: AMPK phosphorylation at Ser76 forms a feedforward loop that enhances USP10-mediated deubiquitination of AMPKα to license LKB1 phosphorylation [#4], while AKT phosphorylation at T674 within the NLS drives nuclear translocation to stabilize AID [#42]. Beyond p53, USP10 stabilizes a wide range of regulators across opposing oncogenic and tumor-suppressive programs, including SIRT6 [#5, #31], YAP/TAZ [#15], FLT3 [#10], KLF4 [#13], Smad4 [#14], PTEN [#34, #35], MSH2 [#19], NICD1 [#12], and the histone variant H2A.Z [#2], frequently via removal of specific K48-, K63-, K11-, or K27/K29-linked chains [#35, #36, #43, #55]. USP10 is a core component of stress granule biology: its mutually exclusive binding to G3BP1 (versus Caprin1) inhibits stress granule condensation [#8], and G3BP1–USP10 complexes deubiquitinate monoubiquitinated 40S ribosomal proteins (RPS2/3/10) to rescue stalled subunits from lysosomal degradation during ribosome-associated quality control [#9]. In NF-\\u03baB signaling, USP10 acts through scaffolds MCPIP1 and TANK to deubiquitinate NEMO and TRAF6, restraining genotoxic and innate-immune NF-\\u03baB activation [#6, #7]. USP10 also supports autophagy by deubiquitinating LC3B [#26], regulates angiogenesis through endothelial Notch signaling [#12], and contributes to DNA damage repair, cytokinesis, and immune responses [#36, #42, #55]. Many substrate interactions are directed by recruiting scaffolds (DCAF7, KIF15, AEG-1, NDR1), and its catalytic Cys424 is a validated druggable interface targeted by ubiquitin variants and small-molecule inhibitors [#23, #58].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established USP10 as a bona fide deubiquitinase with a defined physiological substrate by showing it reverses Mdm2-driven p53 degradation and links DNA-damage signaling to p53 activation.\",\n      \"evidence\": \"Co-IP, in vitro deubiquitination, subcellular fractionation, ATM kinase assay and mutagenesis of Thr42/Ser337 in a p53-dependent system\",\n      \"pmids\": [\"20096447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full set of ubiquitin chain linkages on p53 removed by USP10\", \"Structural basis of substrate recognition not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected USP10 activity to autophagy/tumor-suppressor circuitry by showing Beclin1 controls USP10 stability and USP10 reciprocally deubiquitinates Beclin1, defining a regulated DUB-substrate feedback node.\",\n      \"evidence\": \"Spautin-1 small-molecule perturbation, Co-IP, ubiquitination and protein stability assays\",\n      \"pmids\": [\"21962518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Beclin1 controls USP10 catalytic activity not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed USP10 acts at endosomal membranes to control receptor trafficking, deubiquitinating CFTR to promote recycling rather than lysosomal degradation, expanding its role beyond proteasomal substrate stabilization.\",\n      \"evidence\": \"Activity-based DUB screen, dominant-negative C424A, endosomal fractionation, chloride secretion assay\",\n      \"pmids\": [\"19398555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment to endosomes not mapped\", \"Generality of trafficking role for other receptors unclear at the time\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined phospho-regulation of USP10 catalytic output, showing AMPK phosphorylation at Ser76 amplifies USP10-mediated AMPK\\u03b1 deubiquitination in a feedforward loop linking it to energy-stress signaling.\",\n      \"evidence\": \"In vitro deubiquitination and kinase assays, Ser76 mutagenesis, metabolic loss-of-function readout\",\n      \"pmids\": [\"26876938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether multiple kinases converge on overlapping sites not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established USP10's central role in stress granule biology, showing G3BP1 binding to USP10 is mutually exclusive with Caprin1 and inhibits stress granule formation.\",\n      \"evidence\": \"G3BP1/G3BP2 double-knockout cells with G3BP1 point-mutant rescues and Co-IP\",\n      \"pmids\": [\"27022092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP10 catalytic activity is required for SG inhibition not fully separated from binding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the G3BP1-USP10 axis to ribosome-associated quality control, showing the complex deubiquitinates 40S ribosomal proteins to rescue stalled subunits from lysosomal degradation.\",\n      \"evidence\": \"CRISPR knockouts, ubiquitination assay, RPS3-K214R rescue, ribosome stoichiometry and MS\",\n      \"pmids\": [\"31981475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the complex discriminates aberrant from normal 40S subunits not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a scaffold-directed mechanism for USP10 in NF-\\u03baB control, showing MCPIP1- and TANK-dependent deubiquitination of NEMO and TRAF6 restrains genotoxic and innate-immune NF-\\u03baB activation.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, CRISPR/Cas9 deletion, NF-\\u03baB reporter and cytokine ELISA\",\n      \"pmids\": [\"24270572\", \"25861989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent switch between NF-\\u03baB-suppressing and NF-\\u03baB-stabilizing roles (cf. NEMO stabilization in sepsis) not reconciled\", \"Direct chain-linkage specificity on TRAF6 not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated an in vivo developmental function, showing endothelial USP10 stabilizes NICD1 to tune Notch-dependent vessel sprouting and patterning.\",\n      \"evidence\": \"Endothelial-specific Usp10 knockout mouse, in vivo sprouting angiogenesis, genetic epistasis with NICD1\",\n      \"pmids\": [\"30975888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain-linkage specificity on NICD1 in endothelium not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified USP10 as a regulator of the autophagy machinery itself, showing it deubiquitinates LC3B to prevent its proteasomal turnover and sustain receptor-mediated clearance.\",\n      \"evidence\": \"CRISPR-Cas9 KO, ubiquitination assay, proteasome inhibition, autophagy receptor degradation assays\",\n      \"pmids\": [\"33577797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LC3B deubiquitination is the dominant mechanism by which USP10 affects autophagic flux in vivo not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an enzyme-independent function, showing USP10 physically tethers Axin1 and \\u03b2-catenin and promotes phase separation to suppress Wnt signaling, in addition to K48-linked deubiquitination of Axin1.\",\n      \"evidence\": \"Unbiased DUB screen, in vitro binding, computational modeling, phase-separation assay, enzymatic mutant, CRC organoid and xenograft\",\n      \"pmids\": [\"37611590\", \"39443725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants distinguishing scaffolding from catalytic functions not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed substrate specificity of USP10 is frequently dictated by recruiting scaffolds, with DCAF7, KIF15, and AEG-1 bridging USP10 to G3BP1, PGK1, and PARP1 respectively, and ERK phosphorylation gating substrate access.\",\n      \"evidence\": \"Co-IP/MS, domain-mapping, site-specific ubiquitination assays, phospho-site mapping, functional cancer models\",\n      \"pmids\": [\"38973296\", \"36807568\", \"37838281\", \"36940483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A unifying model of how scaffolds and phospho-marks combinatorially select among the many USP10 substrates is lacking\", \"Most scaffold mechanisms rest on single-lab evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP10 selects among its very large and functionally opposing substrate set in a given cellular context, and what structural features define its catalytic versus scaffolding modes, remain unresolved.\",\n      \"evidence\": \"No single study integrates the substrate repertoire with structural or context-defining determinants\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of USP10 substrate engagement\", \"No systematic map of which phospho-states and scaffolds direct which substrates\", \"Reconciliation of tumor-suppressive vs oncogenic outputs in vivo incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 9, 19, 35, 36]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 58]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 35, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 22, 42]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 9, 26]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 9, 43]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 12, 35]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 26, 53]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [19, 55]}\n    ],\n    \"complexes\": [\n      \"G3BP1-USP10 stress granule complex\",\n      \"MCPIP1-TANK-USP10 NF-\\u03baB regulatory complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"G3BP1\",\n      \"AMPK\\u03b1\",\n      \"SIRT6\",\n      \"PTEN\",\n      \"NICD1\",\n      \"NEMO\",\n      \"MCPIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}