{"gene":"PSMD10","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2015,"finding":"PSMD10/gankyrin physically associates with ATG7 in the cytoplasm, and this interaction is enhanced by nutrient deprivation; PSMD10 also translocates to the nucleus and cooperatively binds with HSF1 on the ATG7 promoter to upregulate ATG7 expression, thereby promoting autophagy in hepatocellular carcinoma independent of the proteasome system.","method":"Co-immunoprecipitation, nuclear fractionation, chromatin immunoprecipitation, promoter reporter assay, loss-of-function in HCC cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for cytoplasmic interaction, ChIP for nuclear binding, multiple orthogonal methods in a single study with functional validation","pmids":["25905985"],"is_preprint":false},{"year":2021,"finding":"PSMD10 directly interacts with the bacterial effector NleE (EPEC) via its N-terminus, as shown by genetically incorporated crosslinkers in living cells; PSMD10 homodimerization is required for its interaction with ATG7 and promotion of autophagy, but not for its interaction with ATG12; NleE stabilizes PSMD10 in monomeric form, thereby attenuating host autophagosome formation.","method":"Genetically incorporated crosslinkers (in-cell crosslinking), pairwise chemical crosslinking, co-immunoprecipitation, loss-of-function assays measuring autophagosome formation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — novel crosslinking method with multiple orthogonal validation approaches (chemical crosslinking, Co-IP, functional autophagy assays) in a single rigorous study","pmids":["34254583"],"is_preprint":false},{"year":2021,"finding":"PSMD10 physically interacts with GRP78, and this interaction accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine; silencing PSMD10 suppresses ER stress indicators and apoptosis-associated proteins under homocysteine treatment.","method":"Co-immunoprecipitation, siRNA knockdown with western blot readout of ER stress and apoptosis markers, luciferase reporter assay (miR-212-5p targeting PSMD10)","journal":"Gut pathogens","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP demonstrates interaction, knockdown phenotype supports functional role, but single lab with limited orthogonal methods","pmids":["34666830"],"is_preprint":false},{"year":2016,"finding":"PSMD10 expression is transcriptionally upregulated by the histone demethylase JMJD2A/KDM4A and its interaction partner ETV1 in prostate cancer cells; PSMD10 knockdown impairs LNCaP cell growth, and PSMD10 can cooperate with YAP1 to stimulate cell growth.","method":"Gene expression analysis in JMJD2A transgenic mice, siRNA knockdown with proliferation assay, co-expression analysis, overexpression cooperation assay","journal":"International journal of clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo transgenic model plus KD phenotype, but no direct mechanistic binding assay between JMJD2A and PSMD10 promoter shown in abstract","pmids":["28883898"],"is_preprint":false},{"year":2019,"finding":"Conditional gankyrin/PSMD10 knockout in non-parenchymal liver cells (but not parenchymal cells alone) reduces STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, attenuating tumorigenic potential in a diethylnitrosamine hepatocarcinogenesis model; similar results were found in the colitis-associated cancer model with intestinal/myeloid cell-specific deletion.","method":"Conditional knockout mouse models (Alb-Cre;gankyrinf/f, Mx1-Cre;gankyrinf/f, Villin-Cre;Gankyrinf/f), STAT3 activity assay, cytokine measurement, cancer stem cell marker analysis","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined molecular readouts (STAT3, IL-6), but single research group and the abstract is a review/book chapter summarizing prior work","pmids":["31576540"],"is_preprint":false},{"year":2021,"finding":"Doxorubicin binds to a druggable pocket on PSMD10/gankyrin involving residues K116 and R41, which also serve as key binding energy contributors for the peptide EEVD and the interacting protein CLIC1; PSMD10 is confirmed as an intended cellular target of doxorubicin.","method":"Virtual screening, Microscale Thermophoresis, limited trypsinolysis, SPR, ITC, MTT cytotoxicity assay","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multiple biophysical binding assays (MST, SPR, ITC) plus mutational mapping of binding residues in a single study","pmids":["34953804"],"is_preprint":false},{"year":2019,"finding":"Overexpression of PSMD10/gankyrin in human neural progenitor cells facilitates neuronal differentiation via the β-catenin/Ngn1 pathway, indicating a role for PSMD10 in neural cell fate decisions beyond its proteasome assembly chaperone function.","method":"Overexpression in human neural progenitor cells, microarray gene expression profiling, network analysis, differentiation assays with pathway marker readout","journal":"International journal of stem cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with pathway inference, no direct binding or epistasis for the β-catenin/Ngn1 mechanism","pmids":["31474027"],"is_preprint":false},{"year":2022,"finding":"PSMD10 is required for optimal phosphorylation and transcriptional activation of NFκB (RELA) in TNF-α-treated colon cancer cells; PSMD10 knockdown reduces expression of anti-apoptotic NFκB target genes (TNFAIP3/A20, BIRC2/cIAP1, BIRC3/cIAP2, XIAP) and sensitizes cells to TNF-α-induced cell death; PSMD10 also transcriptionally regulates β-catenin and RB1 to promote survival.","method":"siRNA knockdown, western blot for phospho-NFκB and target gene expression, apoptosis assay in TNF-α-treated cells, qPCR for target genes","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with defined molecular phenotype across multiple anti-apoptotic readouts, single lab but two orthogonal methods (WB and qPCR)","pmids":["35378311"],"is_preprint":false},{"year":2020,"finding":"PSMD10 overexpression induces phosphorylation of STAT3 and retinoblastoma protein (Rb1), and promotes cell cycle progression by elevating cyclin A, cyclin D1, and cyclin E in liver cancer cells.","method":"Overexpression and siRNA knockdown in liver cancer cells, western blot, flow cytometry for cell cycle, MTT assay, in vivo xenograft","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression/KD approach with western blot readout, no direct binding mechanism established","pmids":["32437796"],"is_preprint":false},{"year":2025,"finding":"EBV nuclear antigen 1 (EBNA1) upregulates PSMD10 transcription in HeLa cells, as demonstrated by transfection of the EBNA1 gene and real-time PCR measurement of PSMD10 mRNA levels.","method":"Plasmid transfection of EBNA1, real-time PCR","journal":"Genes & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (qPCR), no mechanistic detail on how EBNA1 activates PSMD10 expression","pmids":["40771905"],"is_preprint":false}],"current_model":"PSMD10/gankyrin is a proteasome assembly chaperone that also functions as an oncoprotein through proteasome-independent mechanisms: it physically interacts with ATG7 in the cytoplasm and co-binds with HSF1 on the ATG7 promoter to drive autophagy; it requires homodimerization to interact with ATG7 (but not ATG12) and promote autophagosome formation, a process subverted by the bacterial effector NleE; it activates NFκB (RELA) phosphorylation and transcriptionally regulates β-catenin, RB1, and anti-apoptotic genes to promote survival; it interacts with GRP78 to modulate ER stress-mediated apoptosis; its expression is transcriptionally upregulated by JMJD2A/ETV1 and by EBV EBNA1; and a druggable pocket involving K116/R41 accommodates binding partners (EEVD peptide, CLIC1) and the drug doxorubicin."},"narrative":{"mechanistic_narrative":"PSMD10/gankyrin is an oncoprotein that drives tumor cell survival, proliferation, and autophagy through proteasome-independent activities in hepatocellular, colon, and prostate cancers [PMID:25905985, PMID:35378311]. In the cytoplasm it physically associates with ATG7 in a manner enhanced by nutrient deprivation, and it also translocates to the nucleus where it co-binds with HSF1 on the ATG7 promoter to upregulate ATG7 and promote autophagy [PMID:25905985]; this autophagy-promoting function requires PSMD10 homodimerization for the ATG7 interaction (but not for binding ATG12) and is antagonized by the bacterial effector NleE, which traps PSMD10 as a monomer [PMID:34254583]. PSMD10 supports survival signaling by enabling TNF-α-induced phosphorylation and transcriptional activation of NFκB (RELA), thereby sustaining anti-apoptotic target genes (TNFAIP3, BIRC2, BIRC3, XIAP), and by transcriptionally regulating β-catenin and RB1 [PMID:35378311]. In non-parenchymal liver and intestinal/myeloid cells it promotes tumorigenesis via STAT3 activity and IL-6 production [PMID:31576540], and it physically interacts with GRP78 to modulate ER stress-mediated hepatic apoptosis [PMID:34666830]. Its expression is transcriptionally upregulated by JMJD2A/ETV1 in prostate cancer [PMID:28883898], and a druggable pocket centered on residues K116 and R41 accommodates the EEVD peptide, the partner CLIC1, and the drug doxorubicin [PMID:34953804].","teleology":[{"year":2015,"claim":"Established that PSMD10 acts outside the proteasome by directly coupling to the autophagy machinery, resolving how this oncoprotein promotes autophagy in liver cancer.","evidence":"Co-IP, nuclear fractionation, ChIP, and promoter reporter with loss-of-function in HCC cells","pmids":["25905985"],"confidence":"High","gaps":["Does not define the structural basis of the ATG7 interaction","Does not establish how nuclear translocation is triggered"]},{"year":2016,"claim":"Identified upstream transcriptional drivers of PSMD10, showing its expression is induced by JMJD2A/ETV1 and contributes to prostate cancer cell growth.","evidence":"JMJD2A transgenic mice, siRNA knockdown with proliferation assay, co-expression and overexpression cooperation with YAP1","pmids":["28883898"],"confidence":"Medium","gaps":["No direct binding of JMJD2A/ETV1 to the PSMD10 promoter demonstrated","Mechanism of YAP1 cooperation not defined"]},{"year":2019,"claim":"Defined the cell-type context of PSMD10 oncogenic function, showing tumorigenesis depends on its action in non-parenchymal/myeloid cells through STAT3 and IL-6.","evidence":"Conditional knockout mouse models in DEN hepatocarcinogenesis and colitis-associated cancer, STAT3 and cytokine readouts","pmids":["31576540"],"confidence":"Medium","gaps":["Direct molecular link between PSMD10 and STAT3 activation not established","Review/book-chapter summary limits primary-data resolution"]},{"year":2019,"claim":"Extended PSMD10 function beyond cancer, implicating it in neuronal differentiation via the β-catenin/Ngn1 pathway.","evidence":"Overexpression in human neural progenitor cells with microarray profiling and differentiation assays","pmids":["31474027"],"confidence":"Low","gaps":["No direct binding or epistasis for the β-catenin/Ngn1 mechanism","Relies solely on overexpression and pathway inference"]},{"year":2020,"claim":"Linked PSMD10 to cell cycle progression, showing it elevates cyclins and phosphorylates STAT3 and Rb1 in liver cancer cells.","evidence":"Overexpression/knockdown in liver cancer cells, western blot, flow cytometry, xenograft","pmids":["32437796"],"confidence":"Low","gaps":["No direct binding mechanism established","Single-lab, single overexpression/KD approach"]},{"year":2021,"claim":"Resolved the structural requirement for PSMD10's autophagy function and identified a pathogen that subverts it, showing homodimerization is needed for ATG7 binding and that NleE locks PSMD10 as an inactive monomer.","evidence":"In-cell genetically incorporated crosslinkers, pairwise chemical crosslinking, Co-IP, and autophagosome formation assays","pmids":["34254583"],"confidence":"High","gaps":["Does not explain why ATG12 binding is dimerization-independent","Physiological context of NleE-driven autophagy suppression in infection not fully mapped"]},{"year":2021,"claim":"Added an ER-stress dimension, showing PSMD10 interacts with GRP78 to accelerate homocysteine-induced hepatic apoptosis.","evidence":"Co-IP, siRNA knockdown with ER-stress/apoptosis marker western blots, miR-212-5p luciferase reporter","pmids":["34666830"],"confidence":"Medium","gaps":["Single lab with limited orthogonal validation","Direct effect of the GRP78 interaction on UPR signaling not mechanistically dissected"]},{"year":2021,"claim":"Mapped a druggable pocket on PSMD10 and identified it as a doxorubicin target, defining residues that govern partner binding.","evidence":"Virtual screening, MST, SPR, ITC, limited trypsinolysis, and mutational mapping of K116/R41","pmids":["34953804"],"confidence":"Medium","gaps":["Functional consequence of doxorubicin binding on PSMD10 oncogenic activity not established","Cellular CLIC1/EEVD interplay at this pocket not validated in cells"]},{"year":2022,"claim":"Connected PSMD10 to NFκB survival signaling, showing it is required for RELA activation and maintenance of anti-apoptotic gene expression under TNF-α.","evidence":"siRNA knockdown, phospho-NFκB western blot, qPCR of target genes, apoptosis assays in TNF-α-treated colon cancer cells","pmids":["35378311"],"confidence":"Medium","gaps":["Direct molecular step by which PSMD10 promotes RELA phosphorylation not identified","Single-lab study"]},{"year":2025,"claim":"Implicated viral oncogenesis in PSMD10 regulation, showing EBV EBNA1 upregulates PSMD10 transcription.","evidence":"EBNA1 plasmid transfection and real-time PCR in HeLa cells","pmids":["40771905"],"confidence":"Low","gaps":["Single method (qPCR) with no mechanistic detail on EBNA1-driven activation","No demonstration that EBNA1 acts directly on the PSMD10 promoter"]},{"year":null,"claim":"How PSMD10's proteasome-independent oncogenic activities are structurally and temporally coordinated with its proteasome-assembly chaperone role remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model integrating ATG7, GRP78, CLIC1, and NFκB-related interactions","Direct biochemical link between PSMD10 and the kinases/signaling nodes it activates is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7]}],"complexes":[],"partners":["ATG7","HSF1","NLEE","GRP78","CLIC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75832","full_name":"26S proteasome non-ATPase regulatory subunit 10","aliases":["26S proteasome regulatory subunit p28","Gankyrin","p28(GANK)"],"length_aa":226,"mass_kda":24.4,"function":"Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O75832/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD10","classification":"Not Classified","n_dependent_lines":65,"n_total_lines":1208,"dependency_fraction":0.05380794701986755},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101843","cell_line_id":"CID001933","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMD12","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":4.0},{"gene":"PSMC4","stoichiometry":4.0},{"gene":"PSMD1","stoichiometry":4.0},{"gene":"PSMD11","stoichiometry":4.0},{"gene":"PSMD3","stoichiometry":4.0},{"gene":"PSMD2","stoichiometry":4.0},{"gene":"PSMC6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001933","total_profiled":1310},"omim":[{"mim_id":"603481","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 13; PSMD13","url":"https://www.omim.org/entry/603481"},{"mim_id":"300880","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 10; PSMD10","url":"https://www.omim.org/entry/300880"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mid piece","reliability":"Supported"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD10"},"hgnc":{"alias_symbol":["p28"],"prev_symbol":[]},"alphafold":{"accession":"O75832","domains":[{"cath_id":"1.25.40.20","chopping":"1-97","consensus_level":"medium","plddt":92.5008,"start":1,"end":97}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75832","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75832-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75832-F1-predicted_aligned_error_v6.png","plddt_mean":95.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD10","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD10"},"sequence":{"accession":"O75832","fasta_url":"https://rest.uniprot.org/uniprotkb/O75832.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75832/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75832"}},"corpus_meta":[{"pmid":"25905985","id":"PMC_25905985","title":"PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25905985","citation_count":121,"is_preprint":false},{"pmid":"25231260","id":"PMC_25231260","title":"A miR-199a/miR-214 self-regulatory network via PSMD10, TP53 and DNMT1 in testicular germ cell tumor.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25231260","citation_count":56,"is_preprint":false},{"pmid":"30272290","id":"PMC_30272290","title":"miR-214 regulates papillary thyroid carcinoma cell proliferation and metastasis by targeting PSMD10.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30272290","citation_count":51,"is_preprint":false},{"pmid":"25131931","id":"PMC_25131931","title":"MiR-605 represses PSMD10/Gankyrin and inhibits intrahepatic cholangiocarcinoma cell progression.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25131931","citation_count":38,"is_preprint":false},{"pmid":"32048306","id":"PMC_32048306","title":"The lncRNA SNHG3 accelerates papillary thyroid carcinoma progression via the miR-214-3p/PSMD10 axis.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32048306","citation_count":27,"is_preprint":false},{"pmid":"26313366","id":"PMC_26313366","title":"Involvement of PSMD10, CDK4, and Tumor Suppressors in Development of Intrahepatic Cholangiocarcinoma of Syrian Golden Hamsters Induced by Clonorchis sinensis and N-Nitrosodimethylamine.","date":"2015","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26313366","citation_count":26,"is_preprint":false},{"pmid":"26394032","id":"PMC_26394032","title":"Association between functional PSMD10 Rs111638916 variant regulated by MiR-505 and gastric cancer risk in a Chinese population.","date":"2015","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26394032","citation_count":26,"is_preprint":false},{"pmid":"33284947","id":"PMC_33284947","title":"Quantitative expression of Ikaros, IRF4, and PSMD10 proteins predicts survival in VRD-treated patients with multiple myeloma.","date":"2020","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33284947","citation_count":21,"is_preprint":false},{"pmid":"32764956","id":"PMC_32764956","title":"LINC00665 Promotes the Progression of Multiple Myeloma by Adsorbing miR-214-3p and Positively Regulating the Expression of PSMD10 and ASF1B.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32764956","citation_count":16,"is_preprint":false},{"pmid":"28883898","id":"PMC_28883898","title":"Upregulation of PSMD10 caused by the JMJD2A histone demethylase.","date":"2016","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28883898","citation_count":14,"is_preprint":false},{"pmid":"28296190","id":"PMC_28296190","title":"MicroRNA-1254 inhibits the migration of colon adenocarcinoma cells by targeting PSMD10.","date":"2017","source":"Journal of digestive diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28296190","citation_count":14,"is_preprint":false},{"pmid":"31576540","id":"PMC_31576540","title":"The Oncoprotein Gankyrin/PSMD10 as a Target of Cancer Therapy.","date":"2019","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/31576540","citation_count":11,"is_preprint":false},{"pmid":"34254583","id":"PMC_34254583","title":"Genetically incorporated crosslinkers reveal NleE attenuates host autophagy dependent on 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cardiomyopathy","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.14.24317129","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15893,"output_tokens":2707,"usd":0.044142,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9938,"output_tokens":3285,"usd":0.065907,"stage2_stop_reason":"end_turn"},"total_usd":0.110049,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMD10/gankyrin physically associates with ATG7 in the cytoplasm, and this interaction is enhanced by nutrient deprivation; PSMD10 also translocates to the nucleus and cooperatively binds with HSF1 on the ATG7 promoter to upregulate ATG7 expression, thereby promoting autophagy in hepatocellular carcinoma independent of the proteasome system.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, chromatin immunoprecipitation, promoter reporter assay, loss-of-function in HCC cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for cytoplasmic interaction, ChIP for nuclear binding, multiple orthogonal methods in a single study with functional validation\",\n      \"pmids\": [\"25905985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD10 directly interacts with the bacterial effector NleE (EPEC) via its N-terminus, as shown by genetically incorporated crosslinkers in living cells; PSMD10 homodimerization is required for its interaction with ATG7 and promotion of autophagy, but not for its interaction with ATG12; NleE stabilizes PSMD10 in monomeric form, thereby attenuating host autophagosome formation.\",\n      \"method\": \"Genetically incorporated crosslinkers (in-cell crosslinking), pairwise chemical crosslinking, co-immunoprecipitation, loss-of-function assays measuring autophagosome formation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — novel crosslinking method with multiple orthogonal validation approaches (chemical crosslinking, Co-IP, functional autophagy assays) in a single rigorous study\",\n      \"pmids\": [\"34254583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD10 physically interacts with GRP78, and this interaction accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine; silencing PSMD10 suppresses ER stress indicators and apoptosis-associated proteins under homocysteine treatment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with western blot readout of ER stress and apoptosis markers, luciferase reporter assay (miR-212-5p targeting PSMD10)\",\n      \"journal\": \"Gut pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP demonstrates interaction, knockdown phenotype supports functional role, but single lab with limited orthogonal methods\",\n      \"pmids\": [\"34666830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PSMD10 expression is transcriptionally upregulated by the histone demethylase JMJD2A/KDM4A and its interaction partner ETV1 in prostate cancer cells; PSMD10 knockdown impairs LNCaP cell growth, and PSMD10 can cooperate with YAP1 to stimulate cell growth.\",\n      \"method\": \"Gene expression analysis in JMJD2A transgenic mice, siRNA knockdown with proliferation assay, co-expression analysis, overexpression cooperation assay\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo transgenic model plus KD phenotype, but no direct mechanistic binding assay between JMJD2A and PSMD10 promoter shown in abstract\",\n      \"pmids\": [\"28883898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional gankyrin/PSMD10 knockout in non-parenchymal liver cells (but not parenchymal cells alone) reduces STAT3 activity, interleukin-6 production, and cancer stem cell marker expression, attenuating tumorigenic potential in a diethylnitrosamine hepatocarcinogenesis model; similar results were found in the colitis-associated cancer model with intestinal/myeloid cell-specific deletion.\",\n      \"method\": \"Conditional knockout mouse models (Alb-Cre;gankyrinf/f, Mx1-Cre;gankyrinf/f, Villin-Cre;Gankyrinf/f), STAT3 activity assay, cytokine measurement, cancer stem cell marker analysis\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined molecular readouts (STAT3, IL-6), but single research group and the abstract is a review/book chapter summarizing prior work\",\n      \"pmids\": [\"31576540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Doxorubicin binds to a druggable pocket on PSMD10/gankyrin involving residues K116 and R41, which also serve as key binding energy contributors for the peptide EEVD and the interacting protein CLIC1; PSMD10 is confirmed as an intended cellular target of doxorubicin.\",\n      \"method\": \"Virtual screening, Microscale Thermophoresis, limited trypsinolysis, SPR, ITC, MTT cytotoxicity assay\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple biophysical binding assays (MST, SPR, ITC) plus mutational mapping of binding residues in a single study\",\n      \"pmids\": [\"34953804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of PSMD10/gankyrin in human neural progenitor cells facilitates neuronal differentiation via the β-catenin/Ngn1 pathway, indicating a role for PSMD10 in neural cell fate decisions beyond its proteasome assembly chaperone function.\",\n      \"method\": \"Overexpression in human neural progenitor cells, microarray gene expression profiling, network analysis, differentiation assays with pathway marker readout\",\n      \"journal\": \"International journal of stem cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with pathway inference, no direct binding or epistasis for the β-catenin/Ngn1 mechanism\",\n      \"pmids\": [\"31474027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMD10 is required for optimal phosphorylation and transcriptional activation of NFκB (RELA) in TNF-α-treated colon cancer cells; PSMD10 knockdown reduces expression of anti-apoptotic NFκB target genes (TNFAIP3/A20, BIRC2/cIAP1, BIRC3/cIAP2, XIAP) and sensitizes cells to TNF-α-induced cell death; PSMD10 also transcriptionally regulates β-catenin and RB1 to promote survival.\",\n      \"method\": \"siRNA knockdown, western blot for phospho-NFκB and target gene expression, apoptosis assay in TNF-α-treated cells, qPCR for target genes\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with defined molecular phenotype across multiple anti-apoptotic readouts, single lab but two orthogonal methods (WB and qPCR)\",\n      \"pmids\": [\"35378311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMD10 overexpression induces phosphorylation of STAT3 and retinoblastoma protein (Rb1), and promotes cell cycle progression by elevating cyclin A, cyclin D1, and cyclin E in liver cancer cells.\",\n      \"method\": \"Overexpression and siRNA knockdown in liver cancer cells, western blot, flow cytometry for cell cycle, MTT assay, in vivo xenograft\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression/KD approach with western blot readout, no direct binding mechanism established\",\n      \"pmids\": [\"32437796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EBV nuclear antigen 1 (EBNA1) upregulates PSMD10 transcription in HeLa cells, as demonstrated by transfection of the EBNA1 gene and real-time PCR measurement of PSMD10 mRNA levels.\",\n      \"method\": \"Plasmid transfection of EBNA1, real-time PCR\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (qPCR), no mechanistic detail on how EBNA1 activates PSMD10 expression\",\n      \"pmids\": [\"40771905\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD10/gankyrin is a proteasome assembly chaperone that also functions as an oncoprotein through proteasome-independent mechanisms: it physically interacts with ATG7 in the cytoplasm and co-binds with HSF1 on the ATG7 promoter to drive autophagy; it requires homodimerization to interact with ATG7 (but not ATG12) and promote autophagosome formation, a process subverted by the bacterial effector NleE; it activates NFκB (RELA) phosphorylation and transcriptionally regulates β-catenin, RB1, and anti-apoptotic genes to promote survival; it interacts with GRP78 to modulate ER stress-mediated apoptosis; its expression is transcriptionally upregulated by JMJD2A/ETV1 and by EBV EBNA1; and a druggable pocket involving K116/R41 accommodates binding partners (EEVD peptide, CLIC1) and the drug doxorubicin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD10/gankyrin is an oncoprotein that drives tumor cell survival, proliferation, and autophagy through proteasome-independent activities in hepatocellular, colon, and prostate cancers [#0, #7]. In the cytoplasm it physically associates with ATG7 in a manner enhanced by nutrient deprivation, and it also translocates to the nucleus where it co-binds with HSF1 on the ATG7 promoter to upregulate ATG7 and promote autophagy [#0]; this autophagy-promoting function requires PSMD10 homodimerization for the ATG7 interaction (but not for binding ATG12) and is antagonized by the bacterial effector NleE, which traps PSMD10 as a monomer [#1]. PSMD10 supports survival signaling by enabling TNF-\\u03b1-induced phosphorylation and transcriptional activation of NF\\u03baB (RELA), thereby sustaining anti-apoptotic target genes (TNFAIP3, BIRC2, BIRC3, XIAP), and by transcriptionally regulating \\u03b2-catenin and RB1 [#7]. In non-parenchymal liver and intestinal/myeloid cells it promotes tumorigenesis via STAT3 activity and IL-6 production [#4], and it physically interacts with GRP78 to modulate ER stress-mediated hepatic apoptosis [#2]. Its expression is transcriptionally upregulated by JMJD2A/ETV1 in prostate cancer [#3], and a druggable pocket centered on residues K116 and R41 accommodates the EEVD peptide, the partner CLIC1, and the drug doxorubicin [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that PSMD10 acts outside the proteasome by directly coupling to the autophagy machinery, resolving how this oncoprotein promotes autophagy in liver cancer.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, ChIP, and promoter reporter with loss-of-function in HCC cells\",\n      \"pmids\": [\"25905985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis of the ATG7 interaction\", \"Does not establish how nuclear translocation is triggered\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified upstream transcriptional drivers of PSMD10, showing its expression is induced by JMJD2A/ETV1 and contributes to prostate cancer cell growth.\",\n      \"evidence\": \"JMJD2A transgenic mice, siRNA knockdown with proliferation assay, co-expression and overexpression cooperation with YAP1\",\n      \"pmids\": [\"28883898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding of JMJD2A/ETV1 to the PSMD10 promoter demonstrated\", \"Mechanism of YAP1 cooperation not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the cell-type context of PSMD10 oncogenic function, showing tumorigenesis depends on its action in non-parenchymal/myeloid cells through STAT3 and IL-6.\",\n      \"evidence\": \"Conditional knockout mouse models in DEN hepatocarcinogenesis and colitis-associated cancer, STAT3 and cytokine readouts\",\n      \"pmids\": [\"31576540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PSMD10 and STAT3 activation not established\", \"Review/book-chapter summary limits primary-data resolution\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PSMD10 function beyond cancer, implicating it in neuronal differentiation via the \\u03b2-catenin/Ngn1 pathway.\",\n      \"evidence\": \"Overexpression in human neural progenitor cells with microarray profiling and differentiation assays\",\n      \"pmids\": [\"31474027\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or epistasis for the \\u03b2-catenin/Ngn1 mechanism\", \"Relies solely on overexpression and pathway inference\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked PSMD10 to cell cycle progression, showing it elevates cyclins and phosphorylates STAT3 and Rb1 in liver cancer cells.\",\n      \"evidence\": \"Overexpression/knockdown in liver cancer cells, western blot, flow cytometry, xenograft\",\n      \"pmids\": [\"32437796\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding mechanism established\", \"Single-lab, single overexpression/KD approach\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the structural requirement for PSMD10's autophagy function and identified a pathogen that subverts it, showing homodimerization is needed for ATG7 binding and that NleE locks PSMD10 as an inactive monomer.\",\n      \"evidence\": \"In-cell genetically incorporated crosslinkers, pairwise chemical crosslinking, Co-IP, and autophagosome formation assays\",\n      \"pmids\": [\"34254583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain why ATG12 binding is dimerization-independent\", \"Physiological context of NleE-driven autophagy suppression in infection not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added an ER-stress dimension, showing PSMD10 interacts with GRP78 to accelerate homocysteine-induced hepatic apoptosis.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with ER-stress/apoptosis marker western blots, miR-212-5p luciferase reporter\",\n      \"pmids\": [\"34666830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with limited orthogonal validation\", \"Direct effect of the GRP78 interaction on UPR signaling not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a druggable pocket on PSMD10 and identified it as a doxorubicin target, defining residues that govern partner binding.\",\n      \"evidence\": \"Virtual screening, MST, SPR, ITC, limited trypsinolysis, and mutational mapping of K116/R41\",\n      \"pmids\": [\"34953804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of doxorubicin binding on PSMD10 oncogenic activity not established\", \"Cellular CLIC1/EEVD interplay at this pocket not validated in cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PSMD10 to NF\\u03baB survival signaling, showing it is required for RELA activation and maintenance of anti-apoptotic gene expression under TNF-\\u03b1.\",\n      \"evidence\": \"siRNA knockdown, phospho-NF\\u03baB western blot, qPCR of target genes, apoptosis assays in TNF-\\u03b1-treated colon cancer cells\",\n      \"pmids\": [\"35378311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular step by which PSMD10 promotes RELA phosphorylation not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated viral oncogenesis in PSMD10 regulation, showing EBV EBNA1 upregulates PSMD10 transcription.\",\n      \"evidence\": \"EBNA1 plasmid transfection and real-time PCR in HeLa cells\",\n      \"pmids\": [\"40771905\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (qPCR) with no mechanistic detail on EBNA1-driven activation\", \"No demonstration that EBNA1 acts directly on the PSMD10 promoter\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMD10's proteasome-independent oncogenic activities are structurally and temporally coordinated with its proteasome-assembly chaperone role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model integrating ATG7, GRP78, CLIC1, and NF\\u03baB-related interactions\", \"Direct biochemical link between PSMD10 and the kinases/signaling nodes it activates is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATG7\", \"HSF1\", \"NleE\", \"GRP78\", \"CLIC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}