{"gene":"JOSD1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2013,"finding":"JosD1 is a membrane-associated deubiquitinating enzyme (MJD family cysteine protease) whose DUB activity is activated only after it is monoubiquitinated; unmodified JosD1 cannot cleave ubiquitin chains in vitro, but monoubiquitinated JosD1 can.","method":"In vitro ubiquitin chain cleavage assays; comparison of unmodified vs. monoubiquitinated forms","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrate, single lab but multiple orthogonal approaches (biochemical activity assay + cell-based localization + time-lapse imaging)","pmids":["23625928"],"is_preprint":false},{"year":2013,"finding":"Monoubiquitinated JosD1 preferentially localizes to the plasma membrane, whereas unubiquitinated JosD1 is more cytoplasmic; membrane localization is dependent on ubiquitination status.","method":"Cell-based imaging and subcellular fractionation comparing ubiquitinated and non-ubiquitinated JosD1 in diverse mouse tissues and cultured cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (membrane dynamics), single lab, multiple cell-based methods","pmids":["23625928"],"is_preprint":false},{"year":2013,"finding":"JosD1 enhances membrane dynamics and cell motility, and increases macropinocytosis uptake while decreasing clathrin- and caveolae-mediated endocytosis in cultured cells.","method":"Time-lapse imaging of membrane dynamics; endocytic marker uptake assays in cultured cells with JosD1 gain-of-function","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with multiple endocytosis readouts, single lab","pmids":["23625928"],"is_preprint":false},{"year":2017,"finding":"JOSD1 physically interacts with SOCS1 and deubiquitinates K48-linked polyubiquitin chains on SOCS1, thereby stabilizing SOCS1 protein and enabling suppression of the type-I interferon signaling pathway and antiviral response.","method":"Co-immunoprecipitation (physical interaction); ubiquitination assay showing removal of K48-linked chains; SOCS1 stability assay; functional IFN-I signaling readouts","journal":"Viral immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay, single lab, two orthogonal methods","pmids":["28355105"],"is_preprint":false},{"year":2019,"finding":"JOSD1 deubiquitinates MCL1, preventing its proteasomal degradation, thereby stabilizing MCL1 protein levels and suppressing mitochondrial apoptotic signaling, which drives acquired chemoresistance in gynaecological cancer cells.","method":"In vivo/in vitro ubiquitination assays; JOSD1 depletion leading to MCL1 degradation and apoptosis; chemoresistant xenograft model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo xenograft validation, single lab but multiple orthogonal methods with clear mechanistic readout","pmids":["31043700"],"is_preprint":false},{"year":2021,"finding":"JOSD1 interacts with and stabilizes JAK2-V617F (mutant JAK2) by preventing its ubiquitination and proteasomal degradation; inactivation of JOSD1 increases JAK2-V617F ubiquitination, shortens its protein half-life, and leads to degradation of the mutant kinase while sparing wild-type JAK2.","method":"Chemical genetics screen; Co-IP for JOSD1-JAK2-V617F interaction; ubiquitination assay; protein half-life (cycloheximide chase); genetic JOSD1 inactivation with primary AML cell viability readout","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, cycloheximide chase, primary cell functional readout; single lab but multiple orthogonal methods","pmids":["34326465"],"is_preprint":false},{"year":2022,"finding":"JOSD1 stabilizes Snail protein via deubiquitination, promoting epithelial-to-mesenchymal transition (EMT) and tumor invasion in lung adenocarcinoma; JOSD1's pro-invasive effect is dependent on Snail.","method":"Co-immunoprecipitation; ubiquitination assay; Snail protein stability assay; rescue experiments in JOSD1 knockdown/overexpression cells","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with rescue, single lab","pmids":["35693075"],"is_preprint":false},{"year":2022,"finding":"JOSD1 stabilizes SOCS1 by binding its SH2 domain and mediating deubiquitination of SOCS1 during duck Tembusu virus infection, which in turn enables SOCS1 to act as E3 ubiquitin ligase for IRF7 and promote K48-linked ubiquitination and proteasomal degradation of IRF7, inhibiting type I IFN production.","method":"Co-IP (JOSD1-SOCS1 SH2 domain interaction); ubiquitination assay (SOCS1 deubiquitination by JOSD1; K48-linked polyubiquitination of IRF7 by SOCS1); protein stability assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and ubiquitination assays, single lab, mechanistic chain validated","pmids":["36069544"],"is_preprint":false},{"year":2024,"finding":"JOSD1 mitigates hepatic proteotoxicity through monoubiquitination-dependent plasma membrane accumulation; the enzymatically inactive C36A mutant is instead polyubiquitinated, fails to localize to the membrane, and cannot reverse proteotoxicity. JOSD1 physically interacts with SOCS1 and deubiquitinates it under proteotoxic stress, and SOCS1 stabilization is necessary and sufficient for JOSD1's hepatoprotective function.","method":"siRNA screen of 96 DUBs; gain/loss-of-function in primary mouse hepatocytes; JOSD1 C36A catalytic mutant; membrane fractionation; Co-IP; ubiquitination assay; adenovirus-mediated in vivo JOSD1 expression/depletion with Bortezomib challenge","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active site mutagenesis (C36A), in vivo mouse model, Co-IP, ubiquitination assay, and primary hepatocytes; multiple orthogonal methods with in vivo validation","pmids":["39284830"],"is_preprint":false},{"year":2024,"finding":"JOSD1 deubiquitinates YAP, preventing K48-linked polyubiquitination, thereby stabilizing YAP and enhancing Hippo/YAP transcriptional activity in colon cancer; a positive feedback loop exists in which YAP binds JOSD1's promoter and promotes its transcription.","method":"shRNA-mediated JOSD1 knockdown with tumorigenesis readout; ubiquitination assay (K48-linked polyubiquitination on YAP); ChIP assay (YAP binding to JOSD1 promoter); correlation analysis of DUBs expression with Hippo target gene signatures","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus ChIP, single lab, two orthogonal methods","pmids":["39143074"],"is_preprint":false},{"year":2026,"finding":"JOSD1, together with AARS1, regulates ubiquitination-lactylation crosstalk at lysine K251 of PGAM1; JOSD1 deubiquitinates PGAM1 at this residue, enabling its lactylation, which stabilizes PGAM1, enhances its enzymatic activity, promotes lactate accumulation, and drives immune suppression (impaired CD8+ T cell infiltration) in hepatocellular carcinoma.","method":"Multi-omics analyses; Co-IP; ubiquitination assay; site-specific mutagenesis (K251); metabolic flux assays; immune cell functional assays; animal models; liver-targeted JOSD1 inhibition combined with anti-PD-1 therapy","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific mutagenesis, reconstituted PTM crosstalk, Co-IP, in vivo models, and multi-omics; single lab but highly rigorous with multiple orthogonal methods","pmids":["42049490"],"is_preprint":false},{"year":2026,"finding":"JOSD1 directly binds and deubiquitinates Twist1 in glioblastoma, preventing its proteasomal degradation and extending its protein half-life; depletion of JOSD1 accelerates Twist1 turnover, and re-expression of Twist1 rescues impaired invasiveness in JOSD1-deficient cells.","method":"Co-IP (JOSD1-Twist1 interaction); deubiquitination assay; cycloheximide chase assay; rescue experiments with Twist1 re-expression; gain/loss-of-function studies","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, cycloheximide chase, rescue; single lab, multiple orthogonal methods","pmids":["41952254"],"is_preprint":false},{"year":2026,"finding":"JOSD1 directly interacts with SULF1 and stabilizes it by inhibiting its ubiquitination and proteasomal degradation; stabilized SULF1 then binds FZD1 and facilitates Wnt7B-FZD1 complex formation, activating canonical Wnt/β-catenin signaling in gastric cancer.","method":"Co-immunoprecipitation; ubiquitination assay; rescue experiments; subcutaneous xenograft model; Western blotting; immunofluorescence","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue, single lab, multiple methods","pmids":["42140034"],"is_preprint":false},{"year":2026,"finding":"JOSD1 directly interacts with SUFU and stabilizes it by inhibiting its ubiquitination and proteasomal degradation; SUFU drives pancreatic cancer cell proliferation through a non-canonical, Hh-independent mechanism, and JOSD1 depletion suppresses tumor growth in vivo, which is rescued by SUFU re-expression.","method":"Co-IP (JOSD1-SUFU interaction); ubiquitination assay; JOSD1/SUFU knockdown with proliferation/apoptosis readouts; in vivo xenograft with SUFU rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo rescue; single lab, multiple orthogonal methods","pmids":["42248831"],"is_preprint":false}],"current_model":"JOSD1 is a membrane-associated MJD-family cysteine deubiquitinase whose catalytic activity is allosterically activated by its own monoubiquitination, enabling it to cleave ubiquitin chains and localize to the plasma membrane; in this active state it stabilizes multiple substrates—including MCL1, SOCS1, JAK2-V617F, Snail, YAP, Twist1, SULF1, SUFU, and PGAM1—by removing K48-linked polyubiquitin chains and preventing their proteasomal degradation, thereby regulating apoptosis, interferon signaling, oncogenic kinase stability, EMT, Hippo/Wnt/Hedgehog pathway activity, and hepatic proteotoxicity across diverse cellular contexts."},"narrative":{"mechanistic_narrative":"JOSD1 is an MJD-family cysteine deubiquitinase that serves as a broad stabilizer of substrate proteins by removing K48-linked polyubiquitin chains and protecting its targets from proteasomal degradation [PMID:23625928, PMID:31043700]. Its catalytic activity is conditionally switched on: unmodified JOSD1 is inert in vitro, but monoubiquitination of the enzyme licenses ubiquitin-chain cleavage and drives its accumulation at the plasma membrane, where it remodels membrane dynamics and endocytic trafficking [PMID:23625928]. The catalytic cysteine is required for both function and proper localization, as the C36A active-site mutant is instead polyubiquitinated, fails to reach the membrane, and is non-functional [PMID:39284830]. Through this deubiquitinase activity JOSD1 stabilizes a diverse set of substrates to govern distinct cellular programs: it stabilizes MCL1 to suppress mitochondrial apoptosis and drive chemoresistance [PMID:31043700], stabilizes SOCS1 to restrain type-I interferon signaling and the antiviral response [PMID:28355105, PMID:36069544], and stabilizes the oncogenic mutant kinase JAK2-V617F while sparing wild-type JAK2 [PMID:34326465]. In cancer contexts it additionally stabilizes EMT and invasion drivers Snail and Twist1 [PMID:35693075, PMID:41952254] and reinforces Hippo/YAP, Wnt/β-catenin, and Hedgehog-pathway components YAP, SULF1, and SUFU [PMID:39143074, PMID:42140034, PMID:42248831]. Beyond degradation control, JOSD1 deubiquitinates PGAM1 at K251 to enable its lactylation, enhancing glycolytic enzyme activity and immune suppression [PMID:42049490], and counteracts hepatic proteotoxicity in a monoubiquitination- and SOCS1-dependent manner [PMID:39284830].","teleology":[{"year":2013,"claim":"Established that JOSD1 is a deubiquitinase with an unusual activation requirement, answering how this enzyme is regulated: it is catalytically silent until monoubiquitinated.","evidence":"In vitro ubiquitin-chain cleavage assays comparing unmodified versus monoubiquitinated JosD1, plus cell-based localization and time-lapse imaging","pmids":["23625928"],"confidence":"High","gaps":["Identity of the E3 ligase that monoubiquitinates JOSD1 not defined","Structural basis of allosteric activation by monoubiquitination not resolved","Physiological linkage chains cleaved in cells not fully enumerated"]},{"year":2013,"claim":"Linked JOSD1's activation state to its subcellular address and cellular phenotype, showing monoubiquitination drives membrane localization and alters membrane dynamics and endocytosis.","evidence":"Subcellular fractionation and imaging in mouse tissues and cultured cells, with macropinocytosis and clathrin/caveolae uptake assays under JosD1 gain-of-function","pmids":["23625928"],"confidence":"Medium","gaps":["Membrane substrates underlying altered trafficking not identified","Mechanism coupling membrane localization to endocytic remodeling unknown"]},{"year":2017,"claim":"First defined a specific substrate and pathway, showing JOSD1 stabilizes SOCS1 by removing K48 chains to suppress type-I interferon signaling.","evidence":"Reciprocal Co-IP, K48-linked deubiquitination assay, SOCS1 stability assay, and IFN-I functional readouts","pmids":["28355105"],"confidence":"Medium","gaps":["Whether JOSD1 monoubiquitination is required for SOCS1 deubiquitination not tested here","Single-lab observation"]},{"year":2019,"claim":"Connected JOSD1 to apoptosis control and therapy resistance by identifying MCL1 as a stabilized substrate.","evidence":"In vivo/in vitro ubiquitination assays, JOSD1 depletion driving MCL1 loss and apoptosis, and a chemoresistant xenograft model","pmids":["31043700"],"confidence":"High","gaps":["Direct binding interface with MCL1 not mapped","Generality across non-gynaecological tumors not established"]},{"year":2021,"claim":"Demonstrated mutant-selective substrate control, showing JOSD1 stabilizes oncogenic JAK2-V617F while sparing the wild-type kinase, defining a therapeutic vulnerability.","evidence":"Chemical genetics screen, Co-IP, ubiquitination assay, cycloheximide chase, and genetic inactivation with primary AML cell viability readout","pmids":["34326465"],"confidence":"High","gaps":["Structural basis for selective recognition of the V617F mutant unknown","No defined small-molecule inhibitor characterized"]},{"year":2022,"claim":"Extended JOSD1's role to EMT and viral immune evasion, stabilizing Snail to promote invasion and stabilizing SOCS1 via its SH2 domain to drive IRF7 degradation.","evidence":"Co-IP (including SOCS1 SH2-domain mapping), ubiquitination assays, stability and rescue experiments in tumor cells and during duck Tembusu virus infection","pmids":["35693075","36069544"],"confidence":"Medium","gaps":["Direct linkage between JOSD1 membrane localization and these cytoplasmic substrates unaddressed","Single-lab findings per substrate"]},{"year":2024,"claim":"Tied catalytic activity, monoubiquitination, and membrane localization together in vivo and identified a protective physiological role, showing JOSD1 mitigates hepatic proteotoxicity through SOCS1 stabilization.","evidence":"siRNA DUB screen, C36A catalytic mutant, membrane fractionation, Co-IP, ubiquitination assay, and adenoviral in vivo expression/depletion with Bortezomib challenge in mouse hepatocytes","pmids":["39284830"],"confidence":"High","gaps":["How proteotoxic stress triggers JOSD1 monoubiquitination not defined","Downstream effectors of SOCS1 in hepatoprotection not fully mapped"]},{"year":2024,"claim":"Revealed a feed-forward circuit by which JOSD1 stabilizes YAP while YAP transcriptionally induces JOSD1, amplifying Hippo/YAP output in colon cancer.","evidence":"shRNA knockdown with tumorigenesis readout, K48-linked ubiquitination assay on YAP, and ChIP showing YAP occupancy at the JOSD1 promoter","pmids":["39143074"],"confidence":"Medium","gaps":["Whether the feedback loop operates in non-colon tissues unknown","Quantitative contribution of the loop to YAP activity not defined"]},{"year":2026,"claim":"Broadened JOSD1's mechanistic repertoire beyond degradation control to PTM crosstalk, showing site-specific deubiquitination of PGAM1 K251 enables its lactylation and metabolic/immunosuppressive reprogramming.","evidence":"Multi-omics, Co-IP, ubiquitination assay, K251 site-specific mutagenesis, metabolic flux and immune assays, and animal models with liver-targeted JOSD1 inhibition plus anti-PD-1","pmids":["42049490"],"confidence":"High","gaps":["Mechanism by which deubiquitination permits lactylation at the same residue not fully resolved","Role of AARS1 partnership in directing JOSD1 not detailed"]},{"year":2026,"claim":"Generalized JOSD1 as a pan-cancer stabilizer of invasion and developmental-pathway regulators, identifying Twist1, SULF1, and SUFU as additional substrates linking it to EMT, Wnt/β-catenin, and Hedgehog-pathway components.","evidence":"Co-IP, deubiquitination assays, cycloheximide chase, and in vivo xenografts with substrate re-expression rescue in glioblastoma, gastric, and pancreatic cancer models","pmids":["41952254","42140034","42248831"],"confidence":"Medium","gaps":["Determinants of JOSD1 substrate selectivity across these diverse targets unknown","Whether monoubiquitination/membrane localization gates these interactions untested","Single-lab studies per substrate"]},{"year":null,"claim":"It remains unknown what determines JOSD1's broad substrate selectivity and how its monoubiquitination-dependent activation and membrane localization are coordinated with recognition of its many cytoplasmic and nuclear substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate engagement","E3 ligase and signals controlling JOSD1 monoubiquitination not identified","Relationship between membrane localization and substrate stabilization not mechanistically unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,5,8,10]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4]}],"complexes":[],"partners":["SOCS1","MCL1","JAK2","SNAIL","YAP","SUFU","SULF1","TWIST1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15040","full_name":"Josephin-1","aliases":["Josephin domain-containing protein 1"],"length_aa":202,"mass_kda":23.2,"function":"Deubiquitinates monoubiquitinated probes (in vitro). When ubiquitinated, cleaves 'Lys-63'-linked and 'Lys-48'-linked poly-ubiquitin chains (in vitro), hence may act as a deubiquitinating enzyme. May increase macropinocytosis and suppress clathrin- and caveolae-mediated endocytosis. May enhance membrane dynamics and cell motility independently of its catalytic activity","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JOSD1","classification":"Not Classified","n_dependent_lines":37,"n_total_lines":1208,"dependency_fraction":0.030629139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JOSD1","total_profiled":1310},"omim":[{"mim_id":"615324","title":"JOSEPHIN DOMAIN-CONTAINING PROTEIN 2; JOSD2","url":"https://www.omim.org/entry/615324"},{"mim_id":"615323","title":"JOSEPHIN DOMAIN-CONTAINING PROTEIN 1; JOSD1","url":"https://www.omim.org/entry/615323"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JOSD1"},"hgnc":{"alias_symbol":["KIAA0063"],"prev_symbol":[]},"alphafold":{"accession":"Q15040","domains":[{"cath_id":"3.90.70.40","chopping":"35-194","consensus_level":"medium","plddt":89.2192,"start":35,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15040","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15040-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JOSD1","jax_strain_url":"https://www.jax.org/strain/search?query=JOSD1"},"sequence":{"accession":"Q15040","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15040"}},"corpus_meta":[{"pmid":"23625928","id":"PMC_23625928","title":"JosD1, a membrane-targeted deubiquitinating enzyme, is activated by ubiquitination and regulates membrane dynamics, cell motility, and endocytosis.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23625928","citation_count":68,"is_preprint":false},{"pmid":"31043700","id":"PMC_31043700","title":"JOSD1 inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing MCL1.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/31043700","citation_count":60,"is_preprint":false},{"pmid":"34326465","id":"PMC_34326465","title":"Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2.","date":"2021","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/34326465","citation_count":27,"is_preprint":false},{"pmid":"28355105","id":"PMC_28355105","title":"JOSD1 Negatively Regulates Type-I Interferon Antiviral Activity by Deubiquitinating and Stabilizing SOCS1.","date":"2017","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28355105","citation_count":21,"is_preprint":false},{"pmid":"34261480","id":"PMC_34261480","title":"JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34261480","citation_count":17,"is_preprint":false},{"pmid":"36069544","id":"PMC_36069544","title":"Duck Tembusu Virus Inhibits Type I Interferon Production through the JOSD1-SOCS1-IRF7 Negative-Feedback Regulation Pathway.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/36069544","citation_count":12,"is_preprint":false},{"pmid":"39143074","id":"PMC_39143074","title":"Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39143074","citation_count":12,"is_preprint":false},{"pmid":"35693075","id":"PMC_35693075","title":"Deubiquitinase JOSD1 promotes tumor progression via stabilizing Snail in lung adenocarcinoma.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35693075","citation_count":10,"is_preprint":false},{"pmid":"39284830","id":"PMC_39284830","title":"Deubiquitinase JOSD1 tempers hepatic proteotoxicity.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39284830","citation_count":1,"is_preprint":false},{"pmid":"42049490","id":"PMC_42049490","title":"JOSD1 drives hepatocellular carcinoma malignancy by modulating the ubiquitination-lactylation switch on PGAM1.","date":"2026","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/42049490","citation_count":0,"is_preprint":false},{"pmid":"41952254","id":"PMC_41952254","title":"JOSD1 Deubiquitinates Twist1 and Facilitates Epithelial-Mesenchymal Transition in Glioblastoma.","date":"2026","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/41952254","citation_count":0,"is_preprint":false},{"pmid":"42140034","id":"PMC_42140034","title":"JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer.","date":"2026","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42140034","citation_count":0,"is_preprint":false},{"pmid":"42248831","id":"PMC_42248831","title":"JOSD1-mediated stabilization of SUFU controls pancreatic cancer progression.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42248831","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.03.621734","title":"A Perturbation Cell Atlas of Human Induced Pluripotent Stem Cells","date":"2024-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.03.621734","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10103,"output_tokens":3618,"usd":0.04229,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11238,"output_tokens":3830,"usd":0.07597,"stage2_stop_reason":"end_turn"},"total_usd":0.11826,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"JosD1 is a membrane-associated deubiquitinating enzyme (MJD family cysteine protease) whose DUB activity is activated only after it is monoubiquitinated; unmodified JosD1 cannot cleave ubiquitin chains in vitro, but monoubiquitinated JosD1 can.\",\n      \"method\": \"In vitro ubiquitin chain cleavage assays; comparison of unmodified vs. monoubiquitinated forms\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrate, single lab but multiple orthogonal approaches (biochemical activity assay + cell-based localization + time-lapse imaging)\",\n      \"pmids\": [\"23625928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Monoubiquitinated JosD1 preferentially localizes to the plasma membrane, whereas unubiquitinated JosD1 is more cytoplasmic; membrane localization is dependent on ubiquitination status.\",\n      \"method\": \"Cell-based imaging and subcellular fractionation comparing ubiquitinated and non-ubiquitinated JosD1 in diverse mouse tissues and cultured cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (membrane dynamics), single lab, multiple cell-based methods\",\n      \"pmids\": [\"23625928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JosD1 enhances membrane dynamics and cell motility, and increases macropinocytosis uptake while decreasing clathrin- and caveolae-mediated endocytosis in cultured cells.\",\n      \"method\": \"Time-lapse imaging of membrane dynamics; endocytic marker uptake assays in cultured cells with JosD1 gain-of-function\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with multiple endocytosis readouts, single lab\",\n      \"pmids\": [\"23625928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JOSD1 physically interacts with SOCS1 and deubiquitinates K48-linked polyubiquitin chains on SOCS1, thereby stabilizing SOCS1 protein and enabling suppression of the type-I interferon signaling pathway and antiviral response.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction); ubiquitination assay showing removal of K48-linked chains; SOCS1 stability assay; functional IFN-I signaling readouts\",\n      \"journal\": \"Viral immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"28355105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JOSD1 deubiquitinates MCL1, preventing its proteasomal degradation, thereby stabilizing MCL1 protein levels and suppressing mitochondrial apoptotic signaling, which drives acquired chemoresistance in gynaecological cancer cells.\",\n      \"method\": \"In vivo/in vitro ubiquitination assays; JOSD1 depletion leading to MCL1 degradation and apoptosis; chemoresistant xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo xenograft validation, single lab but multiple orthogonal methods with clear mechanistic readout\",\n      \"pmids\": [\"31043700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JOSD1 interacts with and stabilizes JAK2-V617F (mutant JAK2) by preventing its ubiquitination and proteasomal degradation; inactivation of JOSD1 increases JAK2-V617F ubiquitination, shortens its protein half-life, and leads to degradation of the mutant kinase while sparing wild-type JAK2.\",\n      \"method\": \"Chemical genetics screen; Co-IP for JOSD1-JAK2-V617F interaction; ubiquitination assay; protein half-life (cycloheximide chase); genetic JOSD1 inactivation with primary AML cell viability readout\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, cycloheximide chase, primary cell functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34326465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JOSD1 stabilizes Snail protein via deubiquitination, promoting epithelial-to-mesenchymal transition (EMT) and tumor invasion in lung adenocarcinoma; JOSD1's pro-invasive effect is dependent on Snail.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; Snail protein stability assay; rescue experiments in JOSD1 knockdown/overexpression cells\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with rescue, single lab\",\n      \"pmids\": [\"35693075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JOSD1 stabilizes SOCS1 by binding its SH2 domain and mediating deubiquitination of SOCS1 during duck Tembusu virus infection, which in turn enables SOCS1 to act as E3 ubiquitin ligase for IRF7 and promote K48-linked ubiquitination and proteasomal degradation of IRF7, inhibiting type I IFN production.\",\n      \"method\": \"Co-IP (JOSD1-SOCS1 SH2 domain interaction); ubiquitination assay (SOCS1 deubiquitination by JOSD1; K48-linked polyubiquitination of IRF7 by SOCS1); protein stability assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and ubiquitination assays, single lab, mechanistic chain validated\",\n      \"pmids\": [\"36069544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JOSD1 mitigates hepatic proteotoxicity through monoubiquitination-dependent plasma membrane accumulation; the enzymatically inactive C36A mutant is instead polyubiquitinated, fails to localize to the membrane, and cannot reverse proteotoxicity. JOSD1 physically interacts with SOCS1 and deubiquitinates it under proteotoxic stress, and SOCS1 stabilization is necessary and sufficient for JOSD1's hepatoprotective function.\",\n      \"method\": \"siRNA screen of 96 DUBs; gain/loss-of-function in primary mouse hepatocytes; JOSD1 C36A catalytic mutant; membrane fractionation; Co-IP; ubiquitination assay; adenovirus-mediated in vivo JOSD1 expression/depletion with Bortezomib challenge\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active site mutagenesis (C36A), in vivo mouse model, Co-IP, ubiquitination assay, and primary hepatocytes; multiple orthogonal methods with in vivo validation\",\n      \"pmids\": [\"39284830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JOSD1 deubiquitinates YAP, preventing K48-linked polyubiquitination, thereby stabilizing YAP and enhancing Hippo/YAP transcriptional activity in colon cancer; a positive feedback loop exists in which YAP binds JOSD1's promoter and promotes its transcription.\",\n      \"method\": \"shRNA-mediated JOSD1 knockdown with tumorigenesis readout; ubiquitination assay (K48-linked polyubiquitination on YAP); ChIP assay (YAP binding to JOSD1 promoter); correlation analysis of DUBs expression with Hippo target gene signatures\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus ChIP, single lab, two orthogonal methods\",\n      \"pmids\": [\"39143074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JOSD1, together with AARS1, regulates ubiquitination-lactylation crosstalk at lysine K251 of PGAM1; JOSD1 deubiquitinates PGAM1 at this residue, enabling its lactylation, which stabilizes PGAM1, enhances its enzymatic activity, promotes lactate accumulation, and drives immune suppression (impaired CD8+ T cell infiltration) in hepatocellular carcinoma.\",\n      \"method\": \"Multi-omics analyses; Co-IP; ubiquitination assay; site-specific mutagenesis (K251); metabolic flux assays; immune cell functional assays; animal models; liver-targeted JOSD1 inhibition combined with anti-PD-1 therapy\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific mutagenesis, reconstituted PTM crosstalk, Co-IP, in vivo models, and multi-omics; single lab but highly rigorous with multiple orthogonal methods\",\n      \"pmids\": [\"42049490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JOSD1 directly binds and deubiquitinates Twist1 in glioblastoma, preventing its proteasomal degradation and extending its protein half-life; depletion of JOSD1 accelerates Twist1 turnover, and re-expression of Twist1 rescues impaired invasiveness in JOSD1-deficient cells.\",\n      \"method\": \"Co-IP (JOSD1-Twist1 interaction); deubiquitination assay; cycloheximide chase assay; rescue experiments with Twist1 re-expression; gain/loss-of-function studies\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, cycloheximide chase, rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41952254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JOSD1 directly interacts with SULF1 and stabilizes it by inhibiting its ubiquitination and proteasomal degradation; stabilized SULF1 then binds FZD1 and facilitates Wnt7B-FZD1 complex formation, activating canonical Wnt/β-catenin signaling in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; rescue experiments; subcutaneous xenograft model; Western blotting; immunofluorescence\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue, single lab, multiple methods\",\n      \"pmids\": [\"42140034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"JOSD1 directly interacts with SUFU and stabilizes it by inhibiting its ubiquitination and proteasomal degradation; SUFU drives pancreatic cancer cell proliferation through a non-canonical, Hh-independent mechanism, and JOSD1 depletion suppresses tumor growth in vivo, which is rescued by SUFU re-expression.\",\n      \"method\": \"Co-IP (JOSD1-SUFU interaction); ubiquitination assay; JOSD1/SUFU knockdown with proliferation/apoptosis readouts; in vivo xenograft with SUFU rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42248831\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JOSD1 is a membrane-associated MJD-family cysteine deubiquitinase whose catalytic activity is allosterically activated by its own monoubiquitination, enabling it to cleave ubiquitin chains and localize to the plasma membrane; in this active state it stabilizes multiple substrates—including MCL1, SOCS1, JAK2-V617F, Snail, YAP, Twist1, SULF1, SUFU, and PGAM1—by removing K48-linked polyubiquitin chains and preventing their proteasomal degradation, thereby regulating apoptosis, interferon signaling, oncogenic kinase stability, EMT, Hippo/Wnt/Hedgehog pathway activity, and hepatic proteotoxicity across diverse cellular contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JOSD1 is an MJD-family cysteine deubiquitinase that serves as a broad stabilizer of substrate proteins by removing K48-linked polyubiquitin chains and protecting its targets from proteasomal degradation [#0, #4]. Its catalytic activity is conditionally switched on: unmodified JOSD1 is inert in vitro, but monoubiquitination of the enzyme licenses ubiquitin-chain cleavage and drives its accumulation at the plasma membrane, where it remodels membrane dynamics and endocytic trafficking [#0, #1, #2]. The catalytic cysteine is required for both function and proper localization, as the C36A active-site mutant is instead polyubiquitinated, fails to reach the membrane, and is non-functional [#8]. Through this deubiquitinase activity JOSD1 stabilizes a diverse set of substrates to govern distinct cellular programs: it stabilizes MCL1 to suppress mitochondrial apoptosis and drive chemoresistance [#4], stabilizes SOCS1 to restrain type-I interferon signaling and the antiviral response [#3, #7], and stabilizes the oncogenic mutant kinase JAK2-V617F while sparing wild-type JAK2 [#5]. In cancer contexts it additionally stabilizes EMT and invasion drivers Snail and Twist1 [#6, #11] and reinforces Hippo/YAP, Wnt/\\u03b2-catenin, and Hedgehog-pathway components YAP, SULF1, and SUFU [#9, #12, #13]. Beyond degradation control, JOSD1 deubiquitinates PGAM1 at K251 to enable its lactylation, enhancing glycolytic enzyme activity and immune suppression [#10], and counteracts hepatic proteotoxicity in a monoubiquitination- and SOCS1-dependent manner [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that JOSD1 is a deubiquitinase with an unusual activation requirement, answering how this enzyme is regulated: it is catalytically silent until monoubiquitinated.\",\n      \"evidence\": \"In vitro ubiquitin-chain cleavage assays comparing unmodified versus monoubiquitinated JosD1, plus cell-based localization and time-lapse imaging\",\n      \"pmids\": [\"23625928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase that monoubiquitinates JOSD1 not defined\", \"Structural basis of allosteric activation by monoubiquitination not resolved\", \"Physiological linkage chains cleaved in cells not fully enumerated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked JOSD1's activation state to its subcellular address and cellular phenotype, showing monoubiquitination drives membrane localization and alters membrane dynamics and endocytosis.\",\n      \"evidence\": \"Subcellular fractionation and imaging in mouse tissues and cultured cells, with macropinocytosis and clathrin/caveolae uptake assays under JosD1 gain-of-function\",\n      \"pmids\": [\"23625928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Membrane substrates underlying altered trafficking not identified\", \"Mechanism coupling membrane localization to endocytic remodeling unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"First defined a specific substrate and pathway, showing JOSD1 stabilizes SOCS1 by removing K48 chains to suppress type-I interferon signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linked deubiquitination assay, SOCS1 stability assay, and IFN-I functional readouts\",\n      \"pmids\": [\"28355105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JOSD1 monoubiquitination is required for SOCS1 deubiquitination not tested here\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected JOSD1 to apoptosis control and therapy resistance by identifying MCL1 as a stabilized substrate.\",\n      \"evidence\": \"In vivo/in vitro ubiquitination assays, JOSD1 depletion driving MCL1 loss and apoptosis, and a chemoresistant xenograft model\",\n      \"pmids\": [\"31043700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with MCL1 not mapped\", \"Generality across non-gynaecological tumors not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated mutant-selective substrate control, showing JOSD1 stabilizes oncogenic JAK2-V617F while sparing the wild-type kinase, defining a therapeutic vulnerability.\",\n      \"evidence\": \"Chemical genetics screen, Co-IP, ubiquitination assay, cycloheximide chase, and genetic inactivation with primary AML cell viability readout\",\n      \"pmids\": [\"34326465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selective recognition of the V617F mutant unknown\", \"No defined small-molecule inhibitor characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended JOSD1's role to EMT and viral immune evasion, stabilizing Snail to promote invasion and stabilizing SOCS1 via its SH2 domain to drive IRF7 degradation.\",\n      \"evidence\": \"Co-IP (including SOCS1 SH2-domain mapping), ubiquitination assays, stability and rescue experiments in tumor cells and during duck Tembusu virus infection\",\n      \"pmids\": [\"35693075\", \"36069544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct linkage between JOSD1 membrane localization and these cytoplasmic substrates unaddressed\", \"Single-lab findings per substrate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tied catalytic activity, monoubiquitination, and membrane localization together in vivo and identified a protective physiological role, showing JOSD1 mitigates hepatic proteotoxicity through SOCS1 stabilization.\",\n      \"evidence\": \"siRNA DUB screen, C36A catalytic mutant, membrane fractionation, Co-IP, ubiquitination assay, and adenoviral in vivo expression/depletion with Bortezomib challenge in mouse hepatocytes\",\n      \"pmids\": [\"39284830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How proteotoxic stress triggers JOSD1 monoubiquitination not defined\", \"Downstream effectors of SOCS1 in hepatoprotection not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a feed-forward circuit by which JOSD1 stabilizes YAP while YAP transcriptionally induces JOSD1, amplifying Hippo/YAP output in colon cancer.\",\n      \"evidence\": \"shRNA knockdown with tumorigenesis readout, K48-linked ubiquitination assay on YAP, and ChIP showing YAP occupancy at the JOSD1 promoter\",\n      \"pmids\": [\"39143074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the feedback loop operates in non-colon tissues unknown\", \"Quantitative contribution of the loop to YAP activity not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Broadened JOSD1's mechanistic repertoire beyond degradation control to PTM crosstalk, showing site-specific deubiquitination of PGAM1 K251 enables its lactylation and metabolic/immunosuppressive reprogramming.\",\n      \"evidence\": \"Multi-omics, Co-IP, ubiquitination assay, K251 site-specific mutagenesis, metabolic flux and immune assays, and animal models with liver-targeted JOSD1 inhibition plus anti-PD-1\",\n      \"pmids\": [\"42049490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which deubiquitination permits lactylation at the same residue not fully resolved\", \"Role of AARS1 partnership in directing JOSD1 not detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized JOSD1 as a pan-cancer stabilizer of invasion and developmental-pathway regulators, identifying Twist1, SULF1, and SUFU as additional substrates linking it to EMT, Wnt/\\u03b2-catenin, and Hedgehog-pathway components.\",\n      \"evidence\": \"Co-IP, deubiquitination assays, cycloheximide chase, and in vivo xenografts with substrate re-expression rescue in glioblastoma, gastric, and pancreatic cancer models\",\n      \"pmids\": [\"41952254\", \"42140034\", \"42248831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of JOSD1 substrate selectivity across these diverse targets unknown\", \"Whether monoubiquitination/membrane localization gates these interactions untested\", \"Single-lab studies per substrate\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what determines JOSD1's broad substrate selectivity and how its monoubiquitination-dependent activation and membrane localization are coordinated with recognition of its many cytoplasmic and nuclear substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate engagement\", \"E3 ligase and signals controlling JOSD1 monoubiquitination not identified\", \"Relationship between membrane localization and substrate stabilization not mechanistically unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 5, 8, 10]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SOCS1\", \"MCL1\", \"JAK2\", \"Snail\", \"YAP\", \"SUFU\", \"SULF1\", \"Twist1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}