{"gene":"USP27X","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2018,"finding":"USP27X deubiquitinates and stabilizes Snail1 protein: identified via siRNA screen, USP27X binds Snail1 and removes ubiquitin chains to prevent its proteasomal degradation, thereby promoting EMT, cell migration/invasion, and chemoresistance; USP27X expression is upregulated by TGFβ and is required for TGFβ-induced Snail1 expression and fibroblast activation.","method":"siRNA screen, co-immunoprecipitation, ubiquitination assays, knockdown/overexpression with phenotypic readouts (migration, invasion, EMT markers, cisplatin sensitivity), in vivo metastasis assay","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, multiple orthogonal functional readouts (migration, invasion, metastasis, chemosensitivity), replicated across multiple cell lines","pmids":["30341066"],"is_preprint":false},{"year":2016,"finding":"USP27X deubiquitinase binds the pro-apoptotic BH3-only protein Bim upon ERK-dependent phosphorylation of Bim, removes ubiquitin chains from phosphorylated Bim to stabilize it, counteracting ERK-driven Bim degradation and enhancing apoptosis; overexpression of USP27X reduces ERK-dependent Bim ubiquitination and sensitizes cells to ERK pathway inhibition, while loss of USP27X reduces apoptosis in EGFR-inhibitor-treated NSCLC cells.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown with apoptosis readouts (annexin V/PI staining), cell-line models (melanoma, NSCLC)","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, loss-of-function and gain-of-function with multiple orthogonal apoptosis readouts across cancer cell lines","pmids":["27013495"],"is_preprint":false},{"year":2019,"finding":"USP27X interacts with the cytosolic DNA sensor cGAS and cleaves K48-linked polyubiquitin chains from cGAS, preventing its proteasomal degradation and stabilizing it; knockout of Usp27x in mouse macrophages accelerates cGAS turnover, reduces cGAMP production, decreases TBK1 and IRF3 phosphorylation, impairs IFN-β production, and impairs innate antiviral responses against HSV-1.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), Usp27x knockout mouse macrophages, cGAMP ELISA, phospho-immunoblotting, HSV-1 infection assay","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model, reciprocal Co-IP, linkage-specific ubiquitination assay, multiple downstream signaling readouts, and in vivo infection model","pmids":["31534008"],"is_preprint":false},{"year":2020,"finding":"USP27X negatively regulates RIG-I-mediated antiviral signaling: identified via siRNA library screen, USP27X interacts with RIG-I and removes K63-linked polyubiquitin chains from RIG-I, thereby attenuating type I interferon signaling in response to RNA viruses.","method":"siRNA library screen, co-immunoprecipitation, K63-linkage specific ubiquitination assay, overexpression/knockdown with IFN-β luciferase reporter and immunoblotting","journal":"PLoS Pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA screen plus Co-IP and linkage-specific ubiquitination assay, multiple functional readouts, single lab","pmids":["32027733"],"is_preprint":false},{"year":2018,"finding":"USP27 (USP27X) interacts with Cyclin E, negatively regulates its ubiquitination, and promotes Cyclin E protein stability, thereby driving cell cycle progression; USP27 knockdown reduces Cyclin E levels and inhibits hepatocellular carcinoma cell growth, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays, immunohistochemistry of tumor tissues","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, loss-of-function phenotype, single lab","pmids":["29497124"],"is_preprint":false},{"year":2019,"finding":"Cathepsin K inhibition increases USP27X expression via mitochondrial ROS (through Raptor degradation), and elevated USP27X then stabilizes Bim by preventing its proteasomal degradation; knockdown of USP27X blocks Cathepsin K inhibition-induced Bim upregulation, linking the Cat K/Raptor/ROS/USP27X axis to Bim stabilization and enhanced apoptotic sensitivity.","method":"siRNA knockdown of USP27X, immunoblotting for Bim/Raptor/ROS, mitochondria-specific superoxide scavenger experiments, xenograft tumor model","journal":"Redox Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with specific phenotypic rescue, mitochondrial ROS intervention, in vivo xenograft validation, single lab","pmids":["31901727"],"is_preprint":false},{"year":2022,"finding":"USP27 (USP27X) specifically interacts with the histone methyltransferase SETD3, negatively regulates its ubiquitination, and enhances SETD3 protein stability; USP27 inhibition reduces SETD3 protein levels and blocks HCC cell proliferation and tumorigenesis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation and tumorigenesis readouts","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, loss-of-function phenotype, single lab","pmids":["35018513"],"is_preprint":false},{"year":2023,"finding":"GSK3β directly binds to and phosphorylates USP27X, and this phosphorylation enhances the interaction between USP27X and CBX2, leading to USP27X-mediated deubiquitination and stabilization of CBX2; USP27X deficiency causes CBX2 degradation and inhibits tumorigenesis, defining a GSK3β–USP27X–CBX2 regulatory axis.","method":"Mass spectrometry (identification of USP27X as CBX2 DUB), co-immunoprecipitation, overexpression/knockdown, phosphorylation assay, ubiquitination assay, tumorigenesis assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification, Co-IP, phosphorylation assay, ubiquitination assay, single lab","pmids":["38030604"],"is_preprint":false},{"year":2024,"finding":"PIM2 phosphorylates USP27X, enhancing its deubiquitylase activity toward MYC; USP27X then deubiquitylates and stabilizes MYC protein, promoting HK2-mediated aerobic glycolysis and breast cancer progression; the PIM2–USP27X–MYC axis was validated in PIM2-knockout mice.","method":"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, overexpression/knockdown with glycolysis readouts, PIM2-knockout mouse validation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase assay, ubiquitination assay, in vivo knockout mouse model, single lab","pmids":["38969771"],"is_preprint":false},{"year":2024,"finding":"USP27 (USP27X) stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating HCC tumor progression; CTCF transcription factor directly binds the USP27 promoter and upregulates its expression, establishing a CTCF/USP27/PFKFB3 axis.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP (CTCF binding to USP27 promoter), siRNA knockdown with glycolysis assays, in vivo xenograft","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP for upstream regulation, in vivo validation, single lab","pmids":["39746496"],"is_preprint":false},{"year":2024,"finding":"Disease-causing variants in USP27X associated with X-linked intellectual disability (XLID105) disrupt USP27X protein function via distinct mechanisms, including altered protein-protein interactions and reduced deubiquitylating activity; biochemical and cell biology analysis of 10 new patient variants showed these mechanisms underlie the neurodevelopmental disorder.","method":"Clinical genetics, bioinformatics, biochemical deubiquitylating activity assays, co-immunoprecipitation (protein-protein interaction analysis), cell biology assays","journal":"Life Science Alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro DUB activity assays and Co-IP for multiple patient variants, multiple families, single study","pmids":["38182161"],"is_preprint":false},{"year":2025,"finding":"A novel missense variant c.257C>T (p.Thr86Met) in USP27X is detrimental to USP27X protein expression and deubiquitination activity in vitro, functionally linking loss of DUB activity to X-linked intellectual disability.","method":"In vitro expression assay, deubiquitination activity assay with mutant USP27X construct","journal":"Journal of Human Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single in vitro functional study for one variant, no mechanistic pathway placement beyond DUB activity reduction","pmids":["40596734"],"is_preprint":false}],"current_model":"USP27X is a deubiquitylase that stabilizes multiple substrates—including Snail1, Bim, cGAS, RIG-I, Cyclin E, SETD3, CBX2, MYC, and PFKFB3—by removing K48- or K63-linked polyubiquitin chains to prevent proteasomal degradation; its activity is regulated by upstream kinases (GSK3β phosphorylates USP27X to enhance CBX2 interaction; PIM2 phosphorylates USP27X to enhance MYC deubiquitylation), it is transcriptionally induced by TGFβ to drive EMT via Snail1 stabilization, and loss-of-function variants disrupt these DUB and protein-interaction activities to cause X-linked intellectual disability (XLID105)."},"narrative":{"mechanistic_narrative":"USP27X is a deubiquitylase that controls the stability of diverse regulatory proteins by removing polyubiquitin chains to prevent their proteasomal degradation, thereby influencing epithelial-mesenchymal transition, apoptosis, cell cycle progression, innate antiviral signaling, and tumor metabolism [PMID:30341066, PMID:27013495, PMID:31534008]. In cancer it acts as a pro-tumorigenic stabilizer: it deubiquitylates and stabilizes Snail1 to drive TGFβ-induced EMT, migration, invasion and chemoresistance [PMID:30341066], and it likewise stabilizes Cyclin E, the histone methyltransferase SETD3, MYC, and the glycolytic enzymes PFKFB3 to promote proliferation and aerobic glycolysis [PMID:29497124, PMID:35018513, PMID:38969771, PMID:39746496]. In apoptotic signaling it removes ubiquitin from ERK-phosphorylated Bim, counteracting ERK-driven Bim degradation and sensitizing cells to pathway inhibition [PMID:27013495, PMID:31901727]. In innate immunity USP27X exerts opposing effects on two nucleic-acid sensors: it removes K48-linked chains from cGAS to stabilize it and support IFN-β production against DNA virus, yet removes K63-linked chains from RIG-I to attenuate type I interferon signaling against RNA virus [PMID:31534008, PMID:32027733]. Its activity is set by upstream kinases—GSK3β phosphorylates USP27X to enhance its interaction with and stabilization of CBX2, and PIM2 phosphorylates USP27X to boost MYC deubiquitylation—and its expression is transcriptionally controlled by TGFβ and by CTCF [PMID:38030604, PMID:38969771, PMID:39746496, PMID:30341066]. Loss-of-function and missense variants that reduce USP27X deubiquitylating activity and protein-interaction capacity cause X-linked intellectual disability (XLID105) [PMID:38182161, PMID:40596734].","teleology":[{"year":2016,"claim":"Established USP27X as a deubiquitylase that protects a specific substrate from degradation, by showing it binds and removes ubiquitin from ERK-phosphorylated Bim to enhance apoptosis.","evidence":"Co-IP, ubiquitination assays and gain/loss-of-function apoptosis readouts in melanoma and NSCLC cell lines","pmids":["27013495"],"confidence":"High","gaps":["Did not define the recognition determinant linking phospho-Bim to USP27X","No structural basis for substrate selection"]},{"year":2018,"claim":"Defined a pro-tumorigenic role by showing USP27X deubiquitylates and stabilizes Snail1, and is itself a TGFβ-induced gene required for TGFβ-driven EMT.","evidence":"siRNA screen, reciprocal Co-IP, ubiquitination assays, migration/invasion/metastasis and chemosensitivity readouts across cell lines","pmids":["30341066"],"confidence":"High","gaps":["Mechanism by which TGFβ induces USP27X transcription not resolved","Ubiquitin linkage type on Snail1 not specified"]},{"year":2018,"claim":"Extended the substrate range to cell cycle control by showing USP27X stabilizes Cyclin E to drive proliferation in hepatocellular carcinoma.","evidence":"Co-IP, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays and tumor IHC","pmids":["29497124"],"confidence":"Medium","gaps":["Single lab","Linkage specificity of Cyclin E deubiquitylation not defined"]},{"year":2019,"claim":"Showed USP27X positively regulates DNA-sensing innate immunity by cleaving K48-linked chains from cGAS to stabilize it and sustain IFN-β responses.","evidence":"Usp27x-knockout mouse macrophages, reciprocal Co-IP, K48-linkage-specific ubiquitination assay, cGAMP ELISA, phospho-immunoblot and HSV-1 infection","pmids":["31534008"],"confidence":"High","gaps":["Whether USP27X regulation of cGAS occurs in non-macrophage cells unknown","No structural model of the cGAS interaction"]},{"year":2019,"claim":"Placed USP27X downstream of a Cathepsin K/Raptor/mitochondrial ROS axis that induces its expression and thereby stabilizes Bim.","evidence":"siRNA knockdown, ROS scavenger experiments, immunoblotting and xenograft model","pmids":["31901727"],"confidence":"Medium","gaps":["Single lab","Direct mechanism coupling ROS to USP27X expression not defined"]},{"year":2020,"claim":"Revealed a context-dependent, opposing immune role by showing USP27X removes K63-linked chains from RIG-I to dampen RNA-virus-induced type I interferon signaling.","evidence":"siRNA library screen, Co-IP, K63-linkage-specific ubiquitination assay, IFN-β reporter and immunoblot","pmids":["32027733"],"confidence":"High","gaps":["How USP27X stabilizes cGAS yet destabilizes RIG-I signaling within the same cell is unresolved","No reconstitution of linkage selectivity"]},{"year":2022,"claim":"Identified SETD3 as a substrate, linking USP27X to epigenetic regulation and HCC tumorigenesis.","evidence":"Co-IP, ubiquitination assay, siRNA knockdown with proliferation/tumorigenesis readouts","pmids":["35018513"],"confidence":"Medium","gaps":["Single lab","Functional consequence of SETD3 stabilization on histone methylation not measured"]},{"year":2023,"claim":"Showed USP27X activity is kinase-regulated, with GSK3β phosphorylating USP27X to enhance its interaction with and stabilization of CBX2.","evidence":"Mass spectrometry, Co-IP, phosphorylation and ubiquitination assays, tumorigenesis assays","pmids":["38030604"],"confidence":"Medium","gaps":["Phosphosite on USP27X not mapped here","Single lab"]},{"year":2024,"claim":"Connected USP27X to tumor metabolism by showing PIM2 phosphorylation enhances its deubiquitylation of MYC to drive aerobic glycolysis.","evidence":"Co-IP, kinase assay, ubiquitination assay, glycolysis readouts and PIM2-knockout mouse validation","pmids":["38969771"],"confidence":"Medium","gaps":["Single lab","Phosphosite mediating MYC-directed activation not defined"]},{"year":2024,"claim":"Demonstrated CTCF-driven transcriptional control of USP27X and stabilization of the glycolytic enzyme PFKFB3, reinforcing a metabolic-tumorigenic axis.","evidence":"Co-IP, ubiquitination assay, ChIP for CTCF promoter binding, glycolysis assays and xenograft","pmids":["39746496"],"confidence":"Medium","gaps":["Single lab","Overlap with other USP27X transcriptional inputs (TGFβ) not integrated"]},{"year":2024,"claim":"Linked USP27X dysfunction to disease by showing patient variants causing X-linked intellectual disability disrupt DUB activity and protein interactions through distinct mechanisms.","evidence":"Clinical genetics across multiple families, in vitro DUB activity assays and Co-IP for 10 variants","pmids":["38182161"],"confidence":"Medium","gaps":["Which neuronal substrate(s) underlie the phenotype unknown","No in vivo neurodevelopmental model"]},{"year":2025,"claim":"Reinforced the loss-of-function disease mechanism with a single new missense variant impairing USP27X expression and DUB activity.","evidence":"In vitro expression and deubiquitination activity assay of mutant construct","pmids":["40596734"],"confidence":"Low","gaps":["Single lab, single variant in vitro only","No pathway placement beyond reduced DUB activity"]},{"year":null,"claim":"How USP27X selects among its many substrates and achieves opposing K48 versus K63 linkage specificity, and which substrate dysregulation drives the neurodevelopmental phenotype, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or linkage recognition","Neuronal substrate underlying XLID105 unidentified","Reconciliation of pro- versus anti-immune roles in vivo lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,4,6,7,8,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,3,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,6,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,4,6,8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11]}],"complexes":[],"partners":["SNAI1","BCL2L11","CGAS","DDX58","CCNE1","SETD3","CBX2","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A6NNY8","full_name":"Ubiquitin carboxyl-terminal hydrolase 27","aliases":["Deubiquitinating enzyme 27","Ubiquitin carboxyl-terminal hydrolase 22-like","Ubiquitin thioesterase 27","Ubiquitin-specific-processing protease 27","X-linked ubiquitin carboxyl-terminal hydrolase 27"],"length_aa":438,"mass_kda":49.6,"function":"Deubiquitinase involved in innate antiviral immunity by mediating deubiquitination of CGAS and RIGI (PubMed:31534008, PubMed:32027733). Negatively regulates RIGI by mediating 'Lys-63'-linked deubiquitination of RIGI, inhibiting type I interferon signaling (PubMed:32027733). Also regulates 'Lys-63'-linked ubiquitination level of MDA5/IFIH1 (PubMed:32027733). Acts as a positive regulator of the cGAS-STING pathway by catalyzing 'Lys-48'-linked deubiquitination of CGAS, thereby promoting its stabilization (PubMed:31534008). Can reduce the levels of BCL2L11/BIM ubiquitination and stabilize BCL2L11 in response to the RAF-MAPK-degradation signal (By similarity). By acting on BCL2L11 levels, may counteract the anti-apoptotic effects of MAPK activity (By similarity)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/A6NNY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP27X","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP27X","total_profiled":1310},"omim":[{"mim_id":"603599","title":"CASP8- AND FADD-LIKE APOPTOSIS REGULATOR; CFLAR","url":"https://www.omim.org/entry/603599"},{"mim_id":"300984","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 105; XLID105","url":"https://www.omim.org/entry/300984"},{"mim_id":"300975","title":"UBIQUITIN-SPECIFIC PROTEASE 27, X-LINKED; USP27X","url":"https://www.omim.org/entry/300975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":17.5}],"url":"https://www.proteinatlas.org/search/USP27X"},"hgnc":{"alias_symbol":["USP27"],"prev_symbol":[]},"alphafold":{"accession":"A6NNY8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NNY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-A6NNY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A6NNY8-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP27X","jax_strain_url":"https://www.jax.org/strain/search?query=USP27X"},"sequence":{"accession":"A6NNY8","fasta_url":"https://rest.uniprot.org/uniprotkb/A6NNY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A6NNY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A6NNY8"}},"corpus_meta":[{"pmid":"30341066","id":"PMC_30341066","title":"TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30341066","citation_count":93,"is_preprint":false},{"pmid":"31534008","id":"PMC_31534008","title":"Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31534008","citation_count":62,"is_preprint":false},{"pmid":"29497124","id":"PMC_29497124","title":"USP27-mediated Cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29497124","citation_count":49,"is_preprint":false},{"pmid":"27013495","id":"PMC_27013495","title":"The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27013495","citation_count":49,"is_preprint":false},{"pmid":"31901727","id":"PMC_31901727","title":"Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization.","date":"2019","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/31901727","citation_count":37,"is_preprint":false},{"pmid":"34571917","id":"PMC_34571917","title":"Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34571917","citation_count":30,"is_preprint":false},{"pmid":"32027733","id":"PMC_32027733","title":"USP27X negatively regulates antiviral signaling by deubiquitinating RIG-I.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/32027733","citation_count":23,"is_preprint":false},{"pmid":"35018513","id":"PMC_35018513","title":"Stabilization of SETD3 by deubiquitinase USP27 enhances cell proliferation and hepatocellular carcinoma progression.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35018513","citation_count":20,"is_preprint":false},{"pmid":"38279869","id":"PMC_38279869","title":"SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38279869","citation_count":12,"is_preprint":false},{"pmid":"38030604","id":"PMC_38030604","title":"Phosphorylation of USP27X by GSK3β maintains the stability and oncogenic functions of CBX2.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38030604","citation_count":7,"is_preprint":false},{"pmid":"38182161","id":"PMC_38182161","title":"USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38182161","citation_count":6,"is_preprint":false},{"pmid":"38969771","id":"PMC_38969771","title":"Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC.","date":"2024","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/38969771","citation_count":6,"is_preprint":false},{"pmid":"39746496","id":"PMC_39746496","title":"USP27 promotes glycolysis and hepatocellular carcinoma progression by stabilizing PFKFB3 through deubiquitination.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39746496","citation_count":4,"is_preprint":false},{"pmid":"39435421","id":"PMC_39435421","title":"MiR-214 promotes the antitumor effect of NK cells in colorectal cancer liver metastasis through USP27X/Bim.","date":"2024","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39435421","citation_count":1,"is_preprint":false},{"pmid":"40596734","id":"PMC_40596734","title":"A novel USP27X missense variant identified in an individual with intellectual disability.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40596734","citation_count":0,"is_preprint":false},{"pmid":"39007861","id":"PMC_39007861","title":"[Two new cases of X-linked intellectual developmental disorder-105 linked to a previously unreported pathogenic variant in the USP27X gene].","date":"2024","source":"Revista de neurologia","url":"https://pubmed.ncbi.nlm.nih.gov/39007861","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9125,"output_tokens":3217,"usd":0.037815,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10702,"output_tokens":3831,"usd":0.074643,"stage2_stop_reason":"end_turn"},"total_usd":0.112458,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"USP27X deubiquitinates and stabilizes Snail1 protein: identified via siRNA screen, USP27X binds Snail1 and removes ubiquitin chains to prevent its proteasomal degradation, thereby promoting EMT, cell migration/invasion, and chemoresistance; USP27X expression is upregulated by TGFβ and is required for TGFβ-induced Snail1 expression and fibroblast activation.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, ubiquitination assays, knockdown/overexpression with phenotypic readouts (migration, invasion, EMT markers, cisplatin sensitivity), in vivo metastasis assay\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, multiple orthogonal functional readouts (migration, invasion, metastasis, chemosensitivity), replicated across multiple cell lines\",\n      \"pmids\": [\"30341066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP27X deubiquitinase binds the pro-apoptotic BH3-only protein Bim upon ERK-dependent phosphorylation of Bim, removes ubiquitin chains from phosphorylated Bim to stabilize it, counteracting ERK-driven Bim degradation and enhancing apoptosis; overexpression of USP27X reduces ERK-dependent Bim ubiquitination and sensitizes cells to ERK pathway inhibition, while loss of USP27X reduces apoptosis in EGFR-inhibitor-treated NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown with apoptosis readouts (annexin V/PI staining), cell-line models (melanoma, NSCLC)\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, loss-of-function and gain-of-function with multiple orthogonal apoptosis readouts across cancer cell lines\",\n      \"pmids\": [\"27013495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP27X interacts with the cytosolic DNA sensor cGAS and cleaves K48-linked polyubiquitin chains from cGAS, preventing its proteasomal degradation and stabilizing it; knockout of Usp27x in mouse macrophages accelerates cGAS turnover, reduces cGAMP production, decreases TBK1 and IRF3 phosphorylation, impairs IFN-β production, and impairs innate antiviral responses against HSV-1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), Usp27x knockout mouse macrophages, cGAMP ELISA, phospho-immunoblotting, HSV-1 infection assay\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model, reciprocal Co-IP, linkage-specific ubiquitination assay, multiple downstream signaling readouts, and in vivo infection model\",\n      \"pmids\": [\"31534008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP27X negatively regulates RIG-I-mediated antiviral signaling: identified via siRNA library screen, USP27X interacts with RIG-I and removes K63-linked polyubiquitin chains from RIG-I, thereby attenuating type I interferon signaling in response to RNA viruses.\",\n      \"method\": \"siRNA library screen, co-immunoprecipitation, K63-linkage specific ubiquitination assay, overexpression/knockdown with IFN-β luciferase reporter and immunoblotting\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen plus Co-IP and linkage-specific ubiquitination assay, multiple functional readouts, single lab\",\n      \"pmids\": [\"32027733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP27 (USP27X) interacts with Cyclin E, negatively regulates its ubiquitination, and promotes Cyclin E protein stability, thereby driving cell cycle progression; USP27 knockdown reduces Cyclin E levels and inhibits hepatocellular carcinoma cell growth, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays, immunohistochemistry of tumor tissues\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, loss-of-function phenotype, single lab\",\n      \"pmids\": [\"29497124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cathepsin K inhibition increases USP27X expression via mitochondrial ROS (through Raptor degradation), and elevated USP27X then stabilizes Bim by preventing its proteasomal degradation; knockdown of USP27X blocks Cathepsin K inhibition-induced Bim upregulation, linking the Cat K/Raptor/ROS/USP27X axis to Bim stabilization and enhanced apoptotic sensitivity.\",\n      \"method\": \"siRNA knockdown of USP27X, immunoblotting for Bim/Raptor/ROS, mitochondria-specific superoxide scavenger experiments, xenograft tumor model\",\n      \"journal\": \"Redox Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with specific phenotypic rescue, mitochondrial ROS intervention, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"31901727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP27 (USP27X) specifically interacts with the histone methyltransferase SETD3, negatively regulates its ubiquitination, and enhances SETD3 protein stability; USP27 inhibition reduces SETD3 protein levels and blocks HCC cell proliferation and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with proliferation and tumorigenesis readouts\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, loss-of-function phenotype, single lab\",\n      \"pmids\": [\"35018513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GSK3β directly binds to and phosphorylates USP27X, and this phosphorylation enhances the interaction between USP27X and CBX2, leading to USP27X-mediated deubiquitination and stabilization of CBX2; USP27X deficiency causes CBX2 degradation and inhibits tumorigenesis, defining a GSK3β–USP27X–CBX2 regulatory axis.\",\n      \"method\": \"Mass spectrometry (identification of USP27X as CBX2 DUB), co-immunoprecipitation, overexpression/knockdown, phosphorylation assay, ubiquitination assay, tumorigenesis assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification, Co-IP, phosphorylation assay, ubiquitination assay, single lab\",\n      \"pmids\": [\"38030604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIM2 phosphorylates USP27X, enhancing its deubiquitylase activity toward MYC; USP27X then deubiquitylates and stabilizes MYC protein, promoting HK2-mediated aerobic glycolysis and breast cancer progression; the PIM2–USP27X–MYC axis was validated in PIM2-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, overexpression/knockdown with glycolysis readouts, PIM2-knockout mouse validation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase assay, ubiquitination assay, in vivo knockout mouse model, single lab\",\n      \"pmids\": [\"38969771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP27 (USP27X) stabilizes PFKFB3, a key glycolytic enzyme, through deubiquitination, thereby increasing glycolytic activity and facilitating HCC tumor progression; CTCF transcription factor directly binds the USP27 promoter and upregulates its expression, establishing a CTCF/USP27/PFKFB3 axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP (CTCF binding to USP27 promoter), siRNA knockdown with glycolysis assays, in vivo xenograft\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP for upstream regulation, in vivo validation, single lab\",\n      \"pmids\": [\"39746496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disease-causing variants in USP27X associated with X-linked intellectual disability (XLID105) disrupt USP27X protein function via distinct mechanisms, including altered protein-protein interactions and reduced deubiquitylating activity; biochemical and cell biology analysis of 10 new patient variants showed these mechanisms underlie the neurodevelopmental disorder.\",\n      \"method\": \"Clinical genetics, bioinformatics, biochemical deubiquitylating activity assays, co-immunoprecipitation (protein-protein interaction analysis), cell biology assays\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro DUB activity assays and Co-IP for multiple patient variants, multiple families, single study\",\n      \"pmids\": [\"38182161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel missense variant c.257C>T (p.Thr86Met) in USP27X is detrimental to USP27X protein expression and deubiquitination activity in vitro, functionally linking loss of DUB activity to X-linked intellectual disability.\",\n      \"method\": \"In vitro expression assay, deubiquitination activity assay with mutant USP27X construct\",\n      \"journal\": \"Journal of Human Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single in vitro functional study for one variant, no mechanistic pathway placement beyond DUB activity reduction\",\n      \"pmids\": [\"40596734\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP27X is a deubiquitylase that stabilizes multiple substrates—including Snail1, Bim, cGAS, RIG-I, Cyclin E, SETD3, CBX2, MYC, and PFKFB3—by removing K48- or K63-linked polyubiquitin chains to prevent proteasomal degradation; its activity is regulated by upstream kinases (GSK3β phosphorylates USP27X to enhance CBX2 interaction; PIM2 phosphorylates USP27X to enhance MYC deubiquitylation), it is transcriptionally induced by TGFβ to drive EMT via Snail1 stabilization, and loss-of-function variants disrupt these DUB and protein-interaction activities to cause X-linked intellectual disability (XLID105).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP27X is a deubiquitylase that controls the stability of diverse regulatory proteins by removing polyubiquitin chains to prevent their proteasomal degradation, thereby influencing epithelial-mesenchymal transition, apoptosis, cell cycle progression, innate antiviral signaling, and tumor metabolism [#0, #1, #2]. In cancer it acts as a pro-tumorigenic stabilizer: it deubiquitylates and stabilizes Snail1 to drive TGFβ-induced EMT, migration, invasion and chemoresistance [#0], and it likewise stabilizes Cyclin E, the histone methyltransferase SETD3, MYC, and the glycolytic enzymes PFKFB3 to promote proliferation and aerobic glycolysis [#4, #6, #8, #9]. In apoptotic signaling it removes ubiquitin from ERK-phosphorylated Bim, counteracting ERK-driven Bim degradation and sensitizing cells to pathway inhibition [#1, #5]. In innate immunity USP27X exerts opposing effects on two nucleic-acid sensors: it removes K48-linked chains from cGAS to stabilize it and support IFN-β production against DNA virus, yet removes K63-linked chains from RIG-I to attenuate type I interferon signaling against RNA virus [#2, #3]. Its activity is set by upstream kinases—GSK3β phosphorylates USP27X to enhance its interaction with and stabilization of CBX2, and PIM2 phosphorylates USP27X to boost MYC deubiquitylation—and its expression is transcriptionally controlled by TGFβ and by CTCF [#7, #8, #9, #0]. Loss-of-function and missense variants that reduce USP27X deubiquitylating activity and protein-interaction capacity cause X-linked intellectual disability (XLID105) [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established USP27X as a deubiquitylase that protects a specific substrate from degradation, by showing it binds and removes ubiquitin from ERK-phosphorylated Bim to enhance apoptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays and gain/loss-of-function apoptosis readouts in melanoma and NSCLC cell lines\",\n      \"pmids\": [\"27013495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the recognition determinant linking phospho-Bim to USP27X\", \"No structural basis for substrate selection\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a pro-tumorigenic role by showing USP27X deubiquitylates and stabilizes Snail1, and is itself a TGFβ-induced gene required for TGFβ-driven EMT.\",\n      \"evidence\": \"siRNA screen, reciprocal Co-IP, ubiquitination assays, migration/invasion/metastasis and chemosensitivity readouts across cell lines\",\n      \"pmids\": [\"30341066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TGFβ induces USP27X transcription not resolved\", \"Ubiquitin linkage type on Snail1 not specified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the substrate range to cell cycle control by showing USP27X stabilizes Cyclin E to drive proliferation in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA knockdown with proliferation/migration/invasion assays and tumor IHC\",\n      \"pmids\": [\"29497124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Linkage specificity of Cyclin E deubiquitylation not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed USP27X positively regulates DNA-sensing innate immunity by cleaving K48-linked chains from cGAS to stabilize it and sustain IFN-β responses.\",\n      \"evidence\": \"Usp27x-knockout mouse macrophages, reciprocal Co-IP, K48-linkage-specific ubiquitination assay, cGAMP ELISA, phospho-immunoblot and HSV-1 infection\",\n      \"pmids\": [\"31534008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP27X regulation of cGAS occurs in non-macrophage cells unknown\", \"No structural model of the cGAS interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed USP27X downstream of a Cathepsin K/Raptor/mitochondrial ROS axis that induces its expression and thereby stabilizes Bim.\",\n      \"evidence\": \"siRNA knockdown, ROS scavenger experiments, immunoblotting and xenograft model\",\n      \"pmids\": [\"31901727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct mechanism coupling ROS to USP27X expression not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a context-dependent, opposing immune role by showing USP27X removes K63-linked chains from RIG-I to dampen RNA-virus-induced type I interferon signaling.\",\n      \"evidence\": \"siRNA library screen, Co-IP, K63-linkage-specific ubiquitination assay, IFN-β reporter and immunoblot\",\n      \"pmids\": [\"32027733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP27X stabilizes cGAS yet destabilizes RIG-I signaling within the same cell is unresolved\", \"No reconstitution of linkage selectivity\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified SETD3 as a substrate, linking USP27X to epigenetic regulation and HCC tumorigenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA knockdown with proliferation/tumorigenesis readouts\",\n      \"pmids\": [\"35018513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional consequence of SETD3 stabilization on histone methylation not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed USP27X activity is kinase-regulated, with GSK3β phosphorylating USP27X to enhance its interaction with and stabilization of CBX2.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, phosphorylation and ubiquitination assays, tumorigenesis assays\",\n      \"pmids\": [\"38030604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite on USP27X not mapped here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected USP27X to tumor metabolism by showing PIM2 phosphorylation enhances its deubiquitylation of MYC to drive aerobic glycolysis.\",\n      \"evidence\": \"Co-IP, kinase assay, ubiquitination assay, glycolysis readouts and PIM2-knockout mouse validation\",\n      \"pmids\": [\"38969771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Phosphosite mediating MYC-directed activation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated CTCF-driven transcriptional control of USP27X and stabilization of the glycolytic enzyme PFKFB3, reinforcing a metabolic-tumorigenic axis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP for CTCF promoter binding, glycolysis assays and xenograft\",\n      \"pmids\": [\"39746496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Overlap with other USP27X transcriptional inputs (TGFβ) not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked USP27X dysfunction to disease by showing patient variants causing X-linked intellectual disability disrupt DUB activity and protein interactions through distinct mechanisms.\",\n      \"evidence\": \"Clinical genetics across multiple families, in vitro DUB activity assays and Co-IP for 10 variants\",\n      \"pmids\": [\"38182161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which neuronal substrate(s) underlie the phenotype unknown\", \"No in vivo neurodevelopmental model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinforced the loss-of-function disease mechanism with a single new missense variant impairing USP27X expression and DUB activity.\",\n      \"evidence\": \"In vitro expression and deubiquitination activity assay of mutant construct\",\n      \"pmids\": [\"40596734\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab, single variant in vitro only\", \"No pathway placement beyond reduced DUB activity\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP27X selects among its many substrates and achieves opposing K48 versus K63 linkage specificity, and which substrate dysregulation drives the neurodevelopmental phenotype, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or linkage recognition\", \"Neuronal substrate underlying XLID105 unidentified\", \"Reconciliation of pro- versus anti-immune roles in vivo lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 6, 7, 8, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 6, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SNAI1\", \"BCL2L11\", \"CGAS\", \"DDX58\", \"CCNE1\", \"SETD3\", \"CBX2\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}