{"gene":"PSMB2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"PSMB2 (C7-I) was identified as one of 17 protein subunits of the mouse 20S proteasome core; its identity was verified by two-dimensional NEPHGE-PAGE using specific antisera, establishing it as a structural beta subunit of the 20S proteolytic core.","method":"cDNA cloning, 2D gel electrophoresis (NEPHGE-PAGE), immunological verification with antisera","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical verification by 2D-PAGE and antisera, single lab but multiple orthogonal methods (cDNA cloning + protein-level confirmation)","pmids":["10436176"],"is_preprint":false},{"year":1997,"finding":"The PSMB2 gene was mapped by fluorescence in situ hybridization to human chromosome band 1p34.2, and its independent chromosomal location from other beta subunit genes is consistent with independent regulation of expression and a role for proteasome assembly in coordinating the complex.","method":"Fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental chromosomal mapping by FISH, single lab, single method","pmids":["9344661"],"is_preprint":false},{"year":2009,"finding":"PSMB2 was identified as a gene capable of inducing oncogenic focus formation in a retroviral expression library screen using 3T3 fibroblasts, suggesting a transforming/oncogenic activity for PSMB2 in ovarian carcinogenesis.","method":"Retroviral expression library focus formation assay","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (focus formation assay), no mechanistic follow-up on how PSMB2 drives transformation","pmids":["19787249"],"is_preprint":false},{"year":2018,"finding":"NUDT21 knockdown increases usage of the proximal polyadenylation site in PSMB2 3' UTR, resulting in a shortened 3' UTR and marked increase in PSMB2 expression; knockdown of PSMB2 in turn suppressed HCC cell proliferation and invasion, placing PSMB2 downstream of the NUDT21-regulated alternative polyadenylation pathway.","method":"Global APA site profiling, NUDT21 knockdown, PSMB2 knockdown, cell proliferation and invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by APA profiling plus functional knockdown experiments, single lab, multiple orthogonal methods","pmids":["29780166"],"is_preprint":false},{"year":2011,"finding":"RNAi silencing of PSMB2 in multiple myeloma cells synergistically potentiated the growth-inhibitory effects of bortezomib, identifying PSMB2 as a proteasome subunit whose suppression sensitizes myeloma cells to proteasome inhibition.","method":"Genome-wide RNAi screen with siRNA library in MM cells, proliferation assay with bortezomib","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-throughput RNAi screen with internal validation (multiple proteasome subunit hits), single lab","pmids":["21289309"],"is_preprint":false},{"year":2022,"finding":"PSMB2 knockdown in gastric cancer cells suppressed proteasome activity, inhibited cell proliferation, promoted apoptosis, and blocked NRF1 activation; PSMB2 overexpression promoted proteasome activity and cell proliferation, effects reversed by proteasome inhibitor MG132. PSMB2 knockdown also inhibited tumor growth in vivo.","method":"siRNA knockdown and overexpression in gastric cancer cell lines, proteasome activity assay, EdU staining, TUNEL assay, tumor xenograft assay, Western blotting","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (activity assay, proliferation, apoptosis, in vivo xenograft), single lab","pmids":["36110152"],"is_preprint":false},{"year":2024,"finding":"Stable PSMB2 knockdown in glioma cell lines weakened proliferation, invasion, and migration, establishing PSMB2 as a functional driver of glioma cell growth and invasiveness.","method":"Stable PSMB2 knockdown, plate colony formation assay, transwell assay, wound healing assay, flow cytometry, qPCR and Western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in stable knockdown lines, single lab","pmids":["38467767"],"is_preprint":false},{"year":2025,"finding":"In a CSFV uncoating model, PSMB2 (along with PSMD2) was identified as a direct engagement partner for VCP/p97-directed proteasomal degradation of SUMO1-modified viral Core protein; this SUMOylation-dependent, ubiquitin-independent proteolytic mechanism was essential for viral uncoating, demonstrating that PSMB2 can mediate SUMO1-VCP-dependent substrate degradation.","method":"Co-immunoprecipitation, site-directed mutagenesis of SUMOylation motif, fluorescent virion tracking (molecular beacon and quantum dot labeling), VCP depletion assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction validation and mutagenesis plus functional virion tracking, single lab, multiple orthogonal methods; caveat: PSMB2 role is part of a larger mechanistic study on viral uncoating","pmids":["41288382"],"is_preprint":false},{"year":2026,"finding":"Drug affinity responsive target stability (CETSA) profiling in macrophages identified PSMB2 (along with PSMA7) as a direct binding target stabilized by the anti-inflammatory compound Handelin, suggesting physical interaction between Handelin and the PSMB2 subunit of the 26S proteasome.","method":"DIA-CETSA (drug affinity responsive target stability with data-independent acquisition mass spectrometry), molecular docking and dynamics simulations","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CETSA is a direct binding assay but single lab, no mutagenesis or reconstitution to confirm binding site; molecular docking is computational","pmids":["41939900"],"is_preprint":false},{"year":2023,"finding":"In ARID1A-deficient iPSCs, CRISPRi whole-genome screen identified PSMB2 as a selective dependency, and this was replicated by pharmacological proteasome inhibition, establishing a synthetic lethal/dosage-sensitive interaction between ARID1A loss and PSMB2 function.","method":"Whole-genome CRISPRi screen in iPSCs, pharmacological proteasome inhibition (replication experiment)","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen hit replicated by orthogonal pharmacological method, single lab","pmids":["37028423"],"is_preprint":false},{"year":2025,"finding":"In H/R-injured cardiomyocytes, PSMB2 was identified as a downstream target gene of miR-671-5p; LINC00339 negatively regulated miR-671-5p, leading to increased PSMB2 expression, and PSMB2 overexpression inhibited the cardioprotective effect of sevoflurane postconditioning. This places PSMB2 as the effector in a LINC00339/miR-671-5p/PSMB2 regulatory axis modulating cardiomyocyte injury.","method":"qRT-PCR, luciferase reporter assay (implied by miRNA-target interaction), cell viability and apoptosis assays, overexpression experiments in AC16 cells","journal":"Journal of biochemical and molecular toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional overexpression assay without direct biochemical validation of miRNA-target binding in the abstract","pmids":["40143635"],"is_preprint":false}],"current_model":"PSMB2 encodes the beta-2 subunit of the 20S proteasome core, where it contributes to proteasome assembly and proteolytic activity; its expression level directly regulates proteasome activity in cells, and its loss-of-function suppresses proliferation and promotes apoptosis in multiple cancer cell types (glioma, gastric cancer) partly through blocking NRF1 activation, while its expression is post-transcriptionally controlled by NUDT21-mediated alternative polyadenylation; PSMB2 also participates in VCP/p97-directed, SUMOylation-dependent proteasomal substrate degradation and shows synthetic lethality with ARID1A deficiency."},"narrative":{"mechanistic_narrative":"PSMB2 encodes a structural beta subunit of the 20S proteasome proteolytic core, originally identified as one of 17 subunits of the mouse 20S proteasome and verified at the protein level [PMID:10436176]. Its cellular dosage directly sets proteasome activity: knockdown suppresses proteasome activity, proliferation, and invasion while promoting apoptosis, and overexpression elevates proteasome activity and proliferation in a manner reversed by the proteasome inhibitor MG132, with loss-of-function additionally blocking NRF1 activation [PMID:36110152]. These effects extend across multiple cancer contexts including hepatocellular carcinoma, gastric cancer, and glioma, where PSMB2 acts as a functional driver of growth and invasiveness [PMID:29780166, PMID:36110152, PMID:38467767]. PSMB2 expression is post-transcriptionally controlled through NUDT21-dependent alternative polyadenylation, where loss of NUDT21 shifts to a proximal polyadenylation site, shortens the 3' UTR, and elevates PSMB2 [PMID:29780166]. Beyond bulk degradation, PSMB2 serves as a direct engagement partner in VCP/p97-directed, SUMOylation-dependent and ubiquitin-independent proteolysis of a SUMO1-modified substrate [PMID:41288382]. PSMB2 function is a selective dependency in ARID1A-deficient cells, and its suppression sensitizes cells to proteasome inhibition [PMID:21289309, PMID:37028423].","teleology":[{"year":1997,"claim":"Establishing the genomic location of PSMB2 distinguished it from other beta-subunit genes and framed the question of how core subunit expression is independently coordinated.","evidence":"FISH mapping to human chromosome 1p34.2","pmids":["9344661"],"confidence":"Medium","gaps":["Does not address protein function or assembly","No link between chromosomal location and regulation tested directly"]},{"year":1999,"claim":"Defining PSMB2 as a bona fide subunit of the 20S core answered whether it is a structural component of the proteasome rather than an accessory factor.","evidence":"cDNA cloning, 2D NEPHGE-PAGE, and antisera verification of mouse 20S proteasome subunits","pmids":["10436176"],"confidence":"Medium","gaps":["No catalytic role assigned to PSMB2 itself","Assembly order and partner subunits within the core not resolved"]},{"year":2009,"claim":"A transformation screen raised the possibility that PSMB2 dosage contributes to oncogenesis, prompting later functional cancer studies.","evidence":"Retroviral expression library focus formation assay in 3T3 fibroblasts","pmids":["19787249"],"confidence":"Low","gaps":["No mechanistic follow-up on how PSMB2 drives transformation","Single assay, no validation in tumor models"]},{"year":2011,"claim":"An RNAi screen showed that lowering PSMB2 sensitizes cells to proteasome inhibition, linking subunit dosage to drug response.","evidence":"Genome-wide siRNA screen in multiple myeloma cells with bortezomib co-treatment","pmids":["21289309"],"confidence":"Medium","gaps":["Synergy mechanism not dissected","Does not distinguish PSMB2-specific from general core-subunit depletion effects"]},{"year":2018,"claim":"Identifying NUDT21-dependent alternative polyadenylation as a regulator of PSMB2 answered how its expression is post-transcriptionally tuned and connected this to tumor cell behavior.","evidence":"Global APA profiling with NUDT21 and PSMB2 knockdown plus proliferation/invasion assays in HCC cells","pmids":["29780166"],"confidence":"Medium","gaps":["Mechanism by which elevated PSMB2 promotes proliferation not resolved","Does not establish whether 3' UTR shortening alters protein stability versus translation"]},{"year":2022,"claim":"Bidirectional perturbation established that PSMB2 dosage directly governs proteasome activity and downstream NRF1 activation, defining its causal role in cancer cell survival.","evidence":"siRNA knockdown and overexpression in gastric cancer cells with proteasome activity, EdU, TUNEL, MG132 rescue, and xenograft assays","pmids":["36110152"],"confidence":"Medium","gaps":["Mechanism linking PSMB2 to NRF1 activation not detailed","Whether effects are core-assembly-dependent versus subunit-specific unresolved"]},{"year":2023,"claim":"A CRISPRi screen identified PSMB2 as a selective dependency in ARID1A-deficient cells, defining a synthetic lethal relationship exploitable by proteasome inhibition.","evidence":"Whole-genome CRISPRi screen in iPSCs replicated by pharmacological proteasome inhibition","pmids":["37028423"],"confidence":"Medium","gaps":["Molecular basis of the ARID1A-PSMB2 dependency not defined","Whether dependency is PSMB2-specific or generic to proteasome function unclear"]},{"year":2024,"claim":"Stable knockdown in glioma confirmed PSMB2 as a functional driver of proliferation, invasion, and migration beyond a single tumor type.","evidence":"Stable knockdown with colony formation, transwell, wound healing, and flow cytometry assays in glioma lines","pmids":["38467767"],"confidence":"Medium","gaps":["Downstream effectors in glioma not identified","No in vivo confirmation reported"]},{"year":2025,"claim":"Identifying PSMB2 as a direct engagement partner in VCP/p97-directed degradation of a SUMO1-modified substrate revealed a ubiquitin-independent proteolytic route involving this subunit.","evidence":"Co-IP, SUMOylation-motif mutagenesis, fluorescent virion tracking, and VCP depletion in a CSFV uncoating model","pmids":["41288382"],"confidence":"Medium","gaps":["Generality of SUMO1-VCP-PSMB2 degradation beyond viral Core protein unknown","Whether PSMB2 contributes catalytically or as a docking site not resolved"]},{"year":2025,"claim":"A regulatory axis study placed PSMB2 as the downstream effector of a LINC00339/miR-671-5p circuit modulating cardiomyocyte injury.","evidence":"qRT-PCR, reporter and viability/apoptosis assays with overexpression in H/R-injured AC16 cardiomyocytes","pmids":["40143635"],"confidence":"Low","gaps":["Direct miRNA-PSMB2 binding not biochemically confirmed in the available evidence","Mechanism connecting PSMB2 to cardioprotection not defined"]},{"year":2026,"claim":"Target-engagement profiling proposed PSMB2 as a direct binding target of an anti-inflammatory small molecule, raising it as a druggable proteasome subunit.","evidence":"DIA-CETSA in macrophages with molecular docking and dynamics simulations","pmids":["41939900"],"confidence":"Low","gaps":["Binding site not confirmed by mutagenesis or reconstitution","Functional consequence of compound binding to PSMB2 not established"]},{"year":null,"claim":"How PSMB2 dosage mechanistically couples to NRF1 activation, ARID1A synthetic lethality, and SUMO1-VCP-directed degradation, and whether these reflect a shared subunit-specific function or general proteasome assembly, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PSMB2 within the assembled core in these contexts","No demonstration that observed phenotypes are PSMB2-specific versus generic core-subunit loss"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,7]}],"complexes":["20S proteasome core","26S proteasome"],"partners":["VCP","PSMD2","PSMA7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49721","full_name":"Proteasome subunit beta type-2","aliases":["Macropain subunit C7-I","Multicatalytic endopeptidase complex subunit C7-I","Proteasome component C7-I","Proteasome subunit beta-4","beta-4"],"length_aa":201,"mass_kda":22.8,"function":"Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P49721/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMB2","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000126067","cell_line_id":"CID000126","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMD4","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMC1","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSME1","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"UCHL5","stoichiometry":10.0},{"gene":"PSMD13","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000126","total_profiled":1310},"omim":[{"mim_id":"604030","title":"PROTEASOME SUBUNIT, BETA-TYPE, 7; PSMB7","url":"https://www.omim.org/entry/604030"},{"mim_id":"602176","title":"PROTEASOME SUBUNIT, BETA-TYPE, 3; PSMB3","url":"https://www.omim.org/entry/602176"},{"mim_id":"602175","title":"PROTEASOME SUBUNIT, BETA-TYPE, 2; PSMB2","url":"https://www.omim.org/entry/602175"},{"mim_id":"602017","title":"PROTEASOME SUBUNIT, BETA-TYPE, 1; PSMB1","url":"https://www.omim.org/entry/602017"},{"mim_id":"600306","title":"PROTEASOME SUBUNIT, BETA-TYPE, 5; PSMB5","url":"https://www.omim.org/entry/600306"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMB2"},"hgnc":{"alias_symbol":["HC7-I"],"prev_symbol":[]},"alphafold":{"accession":"P49721","domains":[{"cath_id":"3.60.20.10","chopping":"3-194","consensus_level":"high","plddt":97.7644,"start":3,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49721","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49721-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49721-F1-predicted_aligned_error_v6.png","plddt_mean":96.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMB2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMB2"},"sequence":{"accession":"P49721","fasta_url":"https://rest.uniprot.org/uniprotkb/P49721.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49721/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49721"}},"corpus_meta":[{"pmid":"21948970","id":"PMC_21948970","title":"AGR2 is a novel surface antigen that 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neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39066974","citation_count":5,"is_preprint":false},{"pmid":"41316520","id":"PMC_41316520","title":"METTL14 Regulates the Expression of Genes Related to Interferon, Interleukin and MHC Class I in Nasopharyngeal Carcinoma Cells.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41316520","citation_count":2,"is_preprint":false},{"pmid":"36639418","id":"PMC_36639418","title":"Genome-wide siRNA screens identify RBBP9 function as a potential target in Fanconi anaemia-deficient head-and-neck squamous cell carcinoma.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36639418","citation_count":2,"is_preprint":false},{"pmid":"40143635","id":"PMC_40143635","title":"Sevoflurane Mediates LINC00339/miR-671-5p/PSMB2 Axis to Improve Cardiomyocytes Against Hypoxia/Reoxygenation Injury.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40143635","citation_count":1,"is_preprint":false},{"pmid":"41939900","id":"PMC_41939900","title":"Multi-omic profiling converges on proteasome subunits PSMA7/PSMB2 as targets of the sepsis-protective agent Handelin.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41939900","citation_count":0,"is_preprint":false},{"pmid":"41288382","id":"PMC_41288382","title":"SUMOylation-dependent degradation of nucleocapsid is responsible for Pestivirus uncoating.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/41288382","citation_count":0,"is_preprint":false},{"pmid":"41034841","id":"PMC_41034841","title":"Bronchoalveolar lavage proteomics in exacerbation of bronchiectasis.","date":"2025","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41034841","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25686,"output_tokens":2649,"usd":0.058396,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9855,"output_tokens":3213,"usd":0.0648,"stage2_stop_reason":"end_turn"},"total_usd":0.123196,"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\": 1999,\n      \"finding\": \"PSMB2 (C7-I) was identified as one of 17 protein subunits of the mouse 20S proteasome core; its identity was verified by two-dimensional NEPHGE-PAGE using specific antisera, establishing it as a structural beta subunit of the 20S proteolytic core.\",\n      \"method\": \"cDNA cloning, 2D gel electrophoresis (NEPHGE-PAGE), immunological verification with antisera\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical verification by 2D-PAGE and antisera, single lab but multiple orthogonal methods (cDNA cloning + protein-level confirmation)\",\n      \"pmids\": [\"10436176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The PSMB2 gene was mapped by fluorescence in situ hybridization to human chromosome band 1p34.2, and its independent chromosomal location from other beta subunit genes is consistent with independent regulation of expression and a role for proteasome assembly in coordinating the complex.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental chromosomal mapping by FISH, single lab, single method\",\n      \"pmids\": [\"9344661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMB2 was identified as a gene capable of inducing oncogenic focus formation in a retroviral expression library screen using 3T3 fibroblasts, suggesting a transforming/oncogenic activity for PSMB2 in ovarian carcinogenesis.\",\n      \"method\": \"Retroviral expression library focus formation assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (focus formation assay), no mechanistic follow-up on how PSMB2 drives transformation\",\n      \"pmids\": [\"19787249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUDT21 knockdown increases usage of the proximal polyadenylation site in PSMB2 3' UTR, resulting in a shortened 3' UTR and marked increase in PSMB2 expression; knockdown of PSMB2 in turn suppressed HCC cell proliferation and invasion, placing PSMB2 downstream of the NUDT21-regulated alternative polyadenylation pathway.\",\n      \"method\": \"Global APA site profiling, NUDT21 knockdown, PSMB2 knockdown, cell proliferation and invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by APA profiling plus functional knockdown experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29780166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNAi silencing of PSMB2 in multiple myeloma cells synergistically potentiated the growth-inhibitory effects of bortezomib, identifying PSMB2 as a proteasome subunit whose suppression sensitizes myeloma cells to proteasome inhibition.\",\n      \"method\": \"Genome-wide RNAi screen with siRNA library in MM cells, proliferation assay with bortezomib\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-throughput RNAi screen with internal validation (multiple proteasome subunit hits), single lab\",\n      \"pmids\": [\"21289309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMB2 knockdown in gastric cancer cells suppressed proteasome activity, inhibited cell proliferation, promoted apoptosis, and blocked NRF1 activation; PSMB2 overexpression promoted proteasome activity and cell proliferation, effects reversed by proteasome inhibitor MG132. PSMB2 knockdown also inhibited tumor growth in vivo.\",\n      \"method\": \"siRNA knockdown and overexpression in gastric cancer cell lines, proteasome activity assay, EdU staining, TUNEL assay, tumor xenograft assay, Western blotting\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (activity assay, proliferation, apoptosis, in vivo xenograft), single lab\",\n      \"pmids\": [\"36110152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Stable PSMB2 knockdown in glioma cell lines weakened proliferation, invasion, and migration, establishing PSMB2 as a functional driver of glioma cell growth and invasiveness.\",\n      \"method\": \"Stable PSMB2 knockdown, plate colony formation assay, transwell assay, wound healing assay, flow cytometry, qPCR and Western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in stable knockdown lines, single lab\",\n      \"pmids\": [\"38467767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a CSFV uncoating model, PSMB2 (along with PSMD2) was identified as a direct engagement partner for VCP/p97-directed proteasomal degradation of SUMO1-modified viral Core protein; this SUMOylation-dependent, ubiquitin-independent proteolytic mechanism was essential for viral uncoating, demonstrating that PSMB2 can mediate SUMO1-VCP-dependent substrate degradation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of SUMOylation motif, fluorescent virion tracking (molecular beacon and quantum dot labeling), VCP depletion assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction validation and mutagenesis plus functional virion tracking, single lab, multiple orthogonal methods; caveat: PSMB2 role is part of a larger mechanistic study on viral uncoating\",\n      \"pmids\": [\"41288382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Drug affinity responsive target stability (CETSA) profiling in macrophages identified PSMB2 (along with PSMA7) as a direct binding target stabilized by the anti-inflammatory compound Handelin, suggesting physical interaction between Handelin and the PSMB2 subunit of the 26S proteasome.\",\n      \"method\": \"DIA-CETSA (drug affinity responsive target stability with data-independent acquisition mass spectrometry), molecular docking and dynamics simulations\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CETSA is a direct binding assay but single lab, no mutagenesis or reconstitution to confirm binding site; molecular docking is computational\",\n      \"pmids\": [\"41939900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In ARID1A-deficient iPSCs, CRISPRi whole-genome screen identified PSMB2 as a selective dependency, and this was replicated by pharmacological proteasome inhibition, establishing a synthetic lethal/dosage-sensitive interaction between ARID1A loss and PSMB2 function.\",\n      \"method\": \"Whole-genome CRISPRi screen in iPSCs, pharmacological proteasome inhibition (replication experiment)\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen hit replicated by orthogonal pharmacological method, single lab\",\n      \"pmids\": [\"37028423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In H/R-injured cardiomyocytes, PSMB2 was identified as a downstream target gene of miR-671-5p; LINC00339 negatively regulated miR-671-5p, leading to increased PSMB2 expression, and PSMB2 overexpression inhibited the cardioprotective effect of sevoflurane postconditioning. This places PSMB2 as the effector in a LINC00339/miR-671-5p/PSMB2 regulatory axis modulating cardiomyocyte injury.\",\n      \"method\": \"qRT-PCR, luciferase reporter assay (implied by miRNA-target interaction), cell viability and apoptosis assays, overexpression experiments in AC16 cells\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional overexpression assay without direct biochemical validation of miRNA-target binding in the abstract\",\n      \"pmids\": [\"40143635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMB2 encodes the beta-2 subunit of the 20S proteasome core, where it contributes to proteasome assembly and proteolytic activity; its expression level directly regulates proteasome activity in cells, and its loss-of-function suppresses proliferation and promotes apoptosis in multiple cancer cell types (glioma, gastric cancer) partly through blocking NRF1 activation, while its expression is post-transcriptionally controlled by NUDT21-mediated alternative polyadenylation; PSMB2 also participates in VCP/p97-directed, SUMOylation-dependent proteasomal substrate degradation and shows synthetic lethality with ARID1A deficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMB2 encodes a structural beta subunit of the 20S proteasome proteolytic core, originally identified as one of 17 subunits of the mouse 20S proteasome and verified at the protein level [#0]. Its cellular dosage directly sets proteasome activity: knockdown suppresses proteasome activity, proliferation, and invasion while promoting apoptosis, and overexpression elevates proteasome activity and proliferation in a manner reversed by the proteasome inhibitor MG132, with loss-of-function additionally blocking NRF1 activation [#5]. These effects extend across multiple cancer contexts including hepatocellular carcinoma, gastric cancer, and glioma, where PSMB2 acts as a functional driver of growth and invasiveness [#3, #5, #6]. PSMB2 expression is post-transcriptionally controlled through NUDT21-dependent alternative polyadenylation, where loss of NUDT21 shifts to a proximal polyadenylation site, shortens the 3' UTR, and elevates PSMB2 [#3]. Beyond bulk degradation, PSMB2 serves as a direct engagement partner in VCP/p97-directed, SUMOylation-dependent and ubiquitin-independent proteolysis of a SUMO1-modified substrate [#7]. PSMB2 function is a selective dependency in ARID1A-deficient cells, and its suppression sensitizes cells to proteasome inhibition [#4, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic location of PSMB2 distinguished it from other beta-subunit genes and framed the question of how core subunit expression is independently coordinated.\",\n      \"evidence\": \"FISH mapping to human chromosome 1p34.2\",\n      \"pmids\": [\"9344661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function or assembly\", \"No link between chromosomal location and regulation tested directly\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining PSMB2 as a bona fide subunit of the 20S core answered whether it is a structural component of the proteasome rather than an accessory factor.\",\n      \"evidence\": \"cDNA cloning, 2D NEPHGE-PAGE, and antisera verification of mouse 20S proteasome subunits\",\n      \"pmids\": [\"10436176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic role assigned to PSMB2 itself\", \"Assembly order and partner subunits within the core not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A transformation screen raised the possibility that PSMB2 dosage contributes to oncogenesis, prompting later functional cancer studies.\",\n      \"evidence\": \"Retroviral expression library focus formation assay in 3T3 fibroblasts\",\n      \"pmids\": [\"19787249\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic follow-up on how PSMB2 drives transformation\", \"Single assay, no validation in tumor models\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"An RNAi screen showed that lowering PSMB2 sensitizes cells to proteasome inhibition, linking subunit dosage to drug response.\",\n      \"evidence\": \"Genome-wide siRNA screen in multiple myeloma cells with bortezomib co-treatment\",\n      \"pmids\": [\"21289309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synergy mechanism not dissected\", \"Does not distinguish PSMB2-specific from general core-subunit depletion effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying NUDT21-dependent alternative polyadenylation as a regulator of PSMB2 answered how its expression is post-transcriptionally tuned and connected this to tumor cell behavior.\",\n      \"evidence\": \"Global APA profiling with NUDT21 and PSMB2 knockdown plus proliferation/invasion assays in HCC cells\",\n      \"pmids\": [\"29780166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which elevated PSMB2 promotes proliferation not resolved\", \"Does not establish whether 3' UTR shortening alters protein stability versus translation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Bidirectional perturbation established that PSMB2 dosage directly governs proteasome activity and downstream NRF1 activation, defining its causal role in cancer cell survival.\",\n      \"evidence\": \"siRNA knockdown and overexpression in gastric cancer cells with proteasome activity, EdU, TUNEL, MG132 rescue, and xenograft assays\",\n      \"pmids\": [\"36110152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PSMB2 to NRF1 activation not detailed\", \"Whether effects are core-assembly-dependent versus subunit-specific unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A CRISPRi screen identified PSMB2 as a selective dependency in ARID1A-deficient cells, defining a synthetic lethal relationship exploitable by proteasome inhibition.\",\n      \"evidence\": \"Whole-genome CRISPRi screen in iPSCs replicated by pharmacological proteasome inhibition\",\n      \"pmids\": [\"37028423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the ARID1A-PSMB2 dependency not defined\", \"Whether dependency is PSMB2-specific or generic to proteasome function unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Stable knockdown in glioma confirmed PSMB2 as a functional driver of proliferation, invasion, and migration beyond a single tumor type.\",\n      \"evidence\": \"Stable knockdown with colony formation, transwell, wound healing, and flow cytometry assays in glioma lines\",\n      \"pmids\": [\"38467767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors in glioma not identified\", \"No in vivo confirmation reported\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying PSMB2 as a direct engagement partner in VCP/p97-directed degradation of a SUMO1-modified substrate revealed a ubiquitin-independent proteolytic route involving this subunit.\",\n      \"evidence\": \"Co-IP, SUMOylation-motif mutagenesis, fluorescent virion tracking, and VCP depletion in a CSFV uncoating model\",\n      \"pmids\": [\"41288382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of SUMO1-VCP-PSMB2 degradation beyond viral Core protein unknown\", \"Whether PSMB2 contributes catalytically or as a docking site not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A regulatory axis study placed PSMB2 as the downstream effector of a LINC00339/miR-671-5p circuit modulating cardiomyocyte injury.\",\n      \"evidence\": \"qRT-PCR, reporter and viability/apoptosis assays with overexpression in H/R-injured AC16 cardiomyocytes\",\n      \"pmids\": [\"40143635\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct miRNA-PSMB2 binding not biochemically confirmed in the available evidence\", \"Mechanism connecting PSMB2 to cardioprotection not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Target-engagement profiling proposed PSMB2 as a direct binding target of an anti-inflammatory small molecule, raising it as a druggable proteasome subunit.\",\n      \"evidence\": \"DIA-CETSA in macrophages with molecular docking and dynamics simulations\",\n      \"pmids\": [\"41939900\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding site not confirmed by mutagenesis or reconstitution\", \"Functional consequence of compound binding to PSMB2 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMB2 dosage mechanistically couples to NRF1 activation, ARID1A synthetic lethality, and SUMO1-VCP-directed degradation, and whether these reflect a shared subunit-specific function or general proteasome assembly, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PSMB2 within the assembled core in these contexts\", \"No demonstration that observed phenotypes are PSMB2-specific versus generic core-subunit loss\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"complexes\": [\"20S proteasome core\", \"26S proteasome\"],\n    \"partners\": [\"VCP\", \"PSMD2\", \"PSMA7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}