{"gene":"PSMA2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2022,"finding":"PSMA2 is required for influenza A virus (IAV) maturation: PSMA2 knockdown in A549 cells significantly reduced extracellular progeny IAV titers without affecting intracellular viral protein translation or viral RNA transcription, indicating PSMA2 acts at a post-transcriptional/maturation stage. Additionally, PSMA2 is required for NRF2-mediated ROS neutralization; IAV uses PSMA2 to suppress NRF2 nuclear translocation and dampen the oxidative stress response, thereby escaping viral clearance.","method":"siRNA knockdown in A549 cells, SomaScan proteomics (1307 proteins), NRF2 nuclear translocation assay, ROS measurement","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal proteomic and functional readouts in a single lab","pmids":["35019712"],"is_preprint":false},{"year":2022,"finding":"PSMA2 knockdown in human lung epithelial A549 cells dysregulates 52 proteins involved in immune response, cytokine signaling, autophagy, unfolded protein response, and cancer-related signaling, establishing PSMA2 as a broad regulator of cellular proteostasis and immune signaling.","method":"siRNA knockdown, SOMAScan aptamer-based multiplexed proteomics measuring >1300 proteins","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with proteome-wide functional readout, single lab, single method","pmids":["36481484"],"is_preprint":false},{"year":2022,"finding":"PSMA2 acts as a restriction factor for Zika virus (ZIKV) replication in astrocytic cells: siRNA-mediated knockdown of PSMA2 increased ZIKV titers and viral protein synthesis in U251 glioblastoma cells.","method":"siRNA knockdown, ZIKV titer measurement, viral protein synthesis assay","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined virology phenotype, single lab, single method","pmids":["36680137"],"is_preprint":false},{"year":2024,"finding":"Corynoline binds directly to PSMA2 (identified by Lip-SMap and validated by DARTS), and siRNA knockdown of PSMA2 abrogates the anti-fibrotic effect of corynoline in pancreatic stellate cells, placing PSMA2 in the NF-κB signaling pathway as the molecular target mediating corynoline's inhibition of pancreatic fibrosis.","method":"Lip-SMap (limited proteolysis–small molecule mapping), DARTS (drug affinity responsive target stability), siRNA knockdown, in vitro collagen synthesis assay, NF-κB pathway analysis","journal":"Journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding validated by two orthogonal methods (Lip-SMap + DARTS) plus functional epistasis via siRNA, single lab","pmids":["39145797"],"is_preprint":false},{"year":2024,"finding":"PSMA2 promotes glioma cell proliferation and migration via the epithelial-mesenchymal transition (EMT) pathway. Co-IP mass spectrometry identified PSMA2-binding proteins enriched in cell adhesion molecule binding and cadherin binding; PSMA2 knockdown suppressed EMT markers as confirmed by Western blot, and inhibited tumor growth in vivo.","method":"Co-immunoprecipitation mass spectrometry (Co-IP MS), CCK-8/colony formation/transwell assays, Western blot for EMT markers, xenograft mouse model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP MS for interaction partners, in vitro and in vivo loss-of-function with defined molecular readout (EMT markers), single lab","pmids":["38574629"],"is_preprint":false},{"year":2021,"finding":"PSMA2 promotes cervical cancer cell proliferation; psma2-shRNA knockdown decreased cell proliferation in vitro and reduced tumor volume and Ki67 expression in vivo. GLP-1R silencing decreased PSMA2 expression, and Exendin-4 decreased PSMA2 expression and attenuated phospho-p65 and phospho-IκB in the NF-κB pathway.","method":"shRNA knockdown, in vitro proliferation assay, xenograft mouse model, Ki67 immunostaining, siRNA silencing of GLP-1R, Western blot for NF-κB pathway components","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined molecular and phenotypic readouts, pathway placement via NF-κB, single lab","pmids":["33684886"],"is_preprint":false},{"year":2021,"finding":"PSMA2 is a direct target of miR-132: luciferase reporter assay confirmed that miR-132 directly regulates PSMA2 expression, and miR-132 mimic reduced CRC cell proliferation, establishing PSMA2 as a downstream effector of miR-132 in colorectal cancer.","method":"Luciferase reporter assay, miRNA mimic transfection, loss-of-function experiments in CRC cell lines","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay directly validates miR-132 targeting of PSMA2, functional epistasis via mimic, single lab","pmids":["33537240"],"is_preprint":false},{"year":2025,"finding":"PSMA2 regulates cell cycle progression, mitochondrial dysfunction, and mitophagy in OSCC cells, contributing to chemo- and radioresistance. PSMA2 overexpression in a xenograft model was countered by mitophagy inducers, demonstrating that PSMA2-mediated suppression of mitophagy is the mechanistic basis of treatment resistance.","method":"PSMA2 knockdown/overexpression, cell cycle analysis, mitochondrial function assays, xenograft mouse model with mitophagy inducer treatment","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (mitophagy) and pharmacological rescue, single lab","pmids":["39794329"],"is_preprint":false},{"year":2025,"finding":"PSMA2 overexpression accelerates HSP90 turnover and hypersensitizes the androgen receptor (AR) to residual androgen under castration conditions, driving AR nuclear activity and conferring enzalutamide resistance in prostate cancer. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes cells to androgen, and re-sensitizes resistant cells to enzalutamide. PSMA2 also promotes transcriptional and phenotypic neuroendocrine lineage conversion (tNEPC).","method":"PSMA2 overexpression and siRNA knockdown, HSP90 stability assay, AR nuclear translocation/activity assay, androgen sensitivity assay, enzalutamide resistance/re-sensitization assay, neuroendocrine marker analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (HSP90 turnover, AR activity, drug resistance rescue), single lab preprint not yet peer-reviewed","pmids":["41394666"],"is_preprint":true},{"year":2025,"finding":"PRRSV nonstructural protein Nsp12 promotes autophagy-dependent degradation of PSMA2 protein to suppress host proteasome activity. PSMA2 overexpression enhances cellular proteasome activity and upregulates immunoproteasome activator subunits PSME1, PSME2, and PSME3, while PSMA2 silencing reduces proteasome activity and promotes PRRSV replication, establishing PSMA2 as an antiviral host restriction factor.","method":"Overexpression and siRNA knockdown, proteasome activity assay, PSME1/2/3 transcription analysis, Nsp12 interaction screen, autophagy inhibitor experiments","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined molecular mechanism (autophagy-mediated degradation by Nsp12), proteasome activity readout, single lab","pmids":["41475191"],"is_preprint":false},{"year":2018,"finding":"A t(7;13)(p14;q12) chromosomal translocation in MDS/AML generates an out-of-frame PAN3-PSMA2 fusion transcript, disrupting the PSMA2 reading frame and implicating loss of normal PSMA2 function (as part of the 20S proteasome) in disease pathogenesis.","method":"RNA sequencing, RT-PCR, Sanger sequencing, interphase FISH","journal":"Experimental hematology & oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization of a fusion transcript by sequencing, single case, no functional reconstitution of PSMA2 activity","pmids":["29560286"],"is_preprint":false}],"current_model":"PSMA2 is a structural subunit of the 20S proteasome core particle that regulates cellular protein quality control through proteolytic degradation; mechanistically, it promotes viral replication (IAV maturation, NRF2/ROS suppression) or restricts other viruses (ZIKV, PRRSV) depending on context, is directly targeted by miR-132, binds the drug corynoline to modulate NF-κB signaling and fibrosis, accelerates HSP90 turnover to hypersensitize the androgen receptor under castration conditions, and promotes EMT and mitophagy suppression to drive cancer cell proliferation, migration, and therapy resistance."},"narrative":{"mechanistic_narrative":"PSMA2 is a structural subunit of the 20S proteasome core particle whose dosage tunes cellular proteasome capacity and broad proteostasis: knockdown reshapes a network of proteins governing immune response, cytokine signaling, autophagy, and the unfolded protein response [PMID:36481484], while overexpression raises bulk proteasome activity and induces the immunoproteasome activator subunits PSME1/2/3 [PMID:41475191]. Through this proteolytic control PSMA2 acts as a host factor in viral infection with context-dependent direction — it is required for influenza A virus maturation and is exploited by IAV to suppress NRF2 nuclear translocation and the oxidative-stress response [PMID:35019712], yet it restricts Zika virus replication in astrocytic cells [PMID:36680137] and restrains PRRSV, which counters this defense by driving autophagy-dependent degradation of PSMA2 via its Nsp12 protein [PMID:41475191]. In cancer, PSMA2 promotes proliferation and migration: it drives glioma growth through an EMT program with cadherin- and adhesion-molecule-binding partners [PMID:38574629], promotes cervical cancer proliferation downstream of GLP-1R/NF-κB signaling [PMID:33684886], and suppresses mitophagy to confer chemo- and radioresistance in oral squamous cell carcinoma [PMID:39794329]. PSMA2 expression is held in check by miR-132, which binds its transcript directly to limit colorectal cancer proliferation [PMID:33537240]. The small molecule corynoline binds PSMA2 directly to exert anti-fibrotic effects through NF-κB signaling in pancreatic stellate cells [PMID:39145797].","teleology":[{"year":2021,"claim":"Established PSMA2 as a pro-proliferative effector in cancer and placed it downstream of upstream regulators, answering whether a proteasome subunit can act as a node in oncogenic signaling.","evidence":"shRNA knockdown with in vitro proliferation and xenograft readouts, GLP-1R silencing and Exendin-4 treatment with NF-κB Western blots in cervical cancer; luciferase reporter showing direct miR-132 targeting in CRC","pmids":["33684886","33537240"],"confidence":"Medium","gaps":["Does not resolve whether the proliferative effect depends on PSMA2's proteasome activity or a moonlighting function","Mechanistic link between GLP-1R, PSMA2 levels, and NF-κB not biochemically defined"]},{"year":2022,"claim":"Defined PSMA2 as a broad proteostasis and immune-signaling regulator and revealed opposing roles across viruses, reframing it as a context-dependent host factor rather than a passive structural subunit.","evidence":"siRNA knockdown in A549 cells with SOMAScan proteome-wide profiling, IAV titer/NRF2 translocation/ROS assays, and ZIKV titer/protein-synthesis assays in U251 cells","pmids":["35019712","36481484","36680137"],"confidence":"Medium","gaps":["The molecular basis of the IAV-versus-ZIKV directional difference is unexplained","Whether NRF2 suppression is a direct proteasome-dependent event is not established","Single-lab, single-method (knockdown) for each phenotype"]},{"year":2024,"claim":"Identified direct small-molecule and protein interactions of PSMA2, advancing it from a phenotypic correlate to a druggable molecular target and EMT driver.","evidence":"Lip-SMap and DARTS showing direct corynoline binding plus siRNA epistasis in pancreatic stellate cells; Co-IP mass spectrometry, EMT-marker Western blots, and xenograft loss-of-function in glioma","pmids":["39145797","38574629"],"confidence":"Medium","gaps":["Corynoline binding site on PSMA2 and its effect on proteasome activity not mapped","EMT partners identified by Co-IP MS not individually validated","Connection between PSMA2's proteasome role and EMT induction unresolved"]},{"year":2025,"claim":"Linked PSMA2 to mitophagy, HSP90/AR signaling, and proteasome activity control, extending its mechanistic reach into therapy resistance and antiviral defense.","evidence":"Knockdown/overexpression with mitophagy inducers and xenografts in OSCC; HSP90 turnover, AR activity, and enzalutamide re-sensitization assays in prostate cancer (preprint); proteasome activity, PSME1/2/3 induction, and Nsp12-mediated autophagic degradation assays for PRRSV restriction","pmids":["39794329","41394666","41475191"],"confidence":"Medium","gaps":["How a proteasome subunit suppresses mitophagy mechanistically is undefined","HSP90/AR finding is from a preprint not yet peer-reviewed","Whether PSME1/2/3 induction is transcriptionally direct is not shown"]},{"year":null,"claim":"It remains unknown how PSMA2 dosage and its 20S-core function are mechanistically partitioned among its many context-dependent roles (antiviral restriction, viral maturation, EMT, mitophagy, AR signaling).","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical account of how PSMA2 perturbation selectively rewires distinct pathways","No demonstration that the opposing viral phenotypes share a common proteasome-dependent mechanism","Disease causality of the PAN3-PSMA2 fusion not functionally tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,9]}],"complexes":["20S proteasome core particle"],"partners":["CORYNOLINE","HSP90","PRRSV NSP12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25787","full_name":"Proteasome subunit alpha type-2","aliases":["Macropain subunit C3","Multicatalytic endopeptidase complex subunit C3","Proteasome component C3","Proteasome subunit alpha-2","alpha-2"],"length_aa":234,"mass_kda":25.9,"function":"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/P25787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA2","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000106588","cell_line_id":"CID000113","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMD3","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000113","total_profiled":1310},"omim":[{"mim_id":"602017","title":"PROTEASOME SUBUNIT, BETA-TYPE, 1; PSMB1","url":"https://www.omim.org/entry/602017"},{"mim_id":"176846","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 4; PSMA4","url":"https://www.omim.org/entry/176846"},{"mim_id":"176843","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 3; PSMA3","url":"https://www.omim.org/entry/176843"},{"mim_id":"176842","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 2; PSMA2","url":"https://www.omim.org/entry/176842"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA2"},"hgnc":{"alias_symbol":["MU","HC3","PMSA2"],"prev_symbol":[]},"alphafold":{"accession":"P25787","domains":[{"cath_id":"3.60.20.10","chopping":"33-234","consensus_level":"medium","plddt":95.9588,"start":33,"end":234}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25787","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25787-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25787-F1-predicted_aligned_error_v6.png","plddt_mean":94.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA2"},"sequence":{"accession":"P25787","fasta_url":"https://rest.uniprot.org/uniprotkb/P25787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25787"}},"corpus_meta":[{"pmid":"33684886","id":"PMC_33684886","title":"Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study.","date":"2021","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/33684886","citation_count":28,"is_preprint":false},{"pmid":"36481484","id":"PMC_36481484","title":"PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells.","date":"2022","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36481484","citation_count":15,"is_preprint":false},{"pmid":"33537240","id":"PMC_33537240","title":"Comprehensively Analyzed Macrophage-Regulated Genes Indicate That PSMA2 Promotes Colorectal Cancer Progression.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33537240","citation_count":15,"is_preprint":false},{"pmid":"35019712","id":"PMC_35019712","title":"Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35019712","citation_count":14,"is_preprint":false},{"pmid":"29560286","id":"PMC_29560286","title":"PAN3-PSMA2 fusion resulting from a novel t(7;13)(p14;q12) chromosome translocation in a myelodysplastic syndrome that evolved into acute myeloid leukemia.","date":"2018","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29560286","citation_count":11,"is_preprint":false},{"pmid":"39145797","id":"PMC_39145797","title":"Corynoline protects chronic pancreatitis via binding to PSMA2 and alleviating pancreatic fibrosis.","date":"2024","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/39145797","citation_count":9,"is_preprint":false},{"pmid":"38574629","id":"PMC_38574629","title":"PSMA2 promotes glioma proliferation and migration via EMT.","date":"2024","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/38574629","citation_count":6,"is_preprint":false},{"pmid":"36680137","id":"PMC_36680137","title":"HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36680137","citation_count":6,"is_preprint":false},{"pmid":"39794329","id":"PMC_39794329","title":"PSMA2 promotes chemo- and radioresistance of oral squamous cell carcinoma by modulating mitophagy pathway.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39794329","citation_count":5,"is_preprint":false},{"pmid":"41475191","id":"PMC_41475191","title":"PRRSV Nsp12 targets PSMA2 to suppress host proteasome activity and promote viral survival.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41475191","citation_count":0,"is_preprint":false},{"pmid":"41394666","id":"PMC_41394666","title":"Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage Transformation.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41394666","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.14.24317129","title":"Comprehensive analysis of key m6A RNA modification-related genes and immune infiltrates in hypertrophic 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":9079,"output_tokens":2893,"usd":0.035316,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10261,"output_tokens":2286,"usd":0.054227,"stage2_stop_reason":"end_turn"},"total_usd":0.089543,"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\": 2022,\n      \"finding\": \"PSMA2 is required for influenza A virus (IAV) maturation: PSMA2 knockdown in A549 cells significantly reduced extracellular progeny IAV titers without affecting intracellular viral protein translation or viral RNA transcription, indicating PSMA2 acts at a post-transcriptional/maturation stage. Additionally, PSMA2 is required for NRF2-mediated ROS neutralization; IAV uses PSMA2 to suppress NRF2 nuclear translocation and dampen the oxidative stress response, thereby escaping viral clearance.\",\n      \"method\": \"siRNA knockdown in A549 cells, SomaScan proteomics (1307 proteins), NRF2 nuclear translocation assay, ROS measurement\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple orthogonal proteomic and functional readouts in a single lab\",\n      \"pmids\": [\"35019712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMA2 knockdown in human lung epithelial A549 cells dysregulates 52 proteins involved in immune response, cytokine signaling, autophagy, unfolded protein response, and cancer-related signaling, establishing PSMA2 as a broad regulator of cellular proteostasis and immune signaling.\",\n      \"method\": \"siRNA knockdown, SOMAScan aptamer-based multiplexed proteomics measuring >1300 proteins\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with proteome-wide functional readout, single lab, single method\",\n      \"pmids\": [\"36481484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMA2 acts as a restriction factor for Zika virus (ZIKV) replication in astrocytic cells: siRNA-mediated knockdown of PSMA2 increased ZIKV titers and viral protein synthesis in U251 glioblastoma cells.\",\n      \"method\": \"siRNA knockdown, ZIKV titer measurement, viral protein synthesis assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined virology phenotype, single lab, single method\",\n      \"pmids\": [\"36680137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Corynoline binds directly to PSMA2 (identified by Lip-SMap and validated by DARTS), and siRNA knockdown of PSMA2 abrogates the anti-fibrotic effect of corynoline in pancreatic stellate cells, placing PSMA2 in the NF-κB signaling pathway as the molecular target mediating corynoline's inhibition of pancreatic fibrosis.\",\n      \"method\": \"Lip-SMap (limited proteolysis–small molecule mapping), DARTS (drug affinity responsive target stability), siRNA knockdown, in vitro collagen synthesis assay, NF-κB pathway analysis\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding validated by two orthogonal methods (Lip-SMap + DARTS) plus functional epistasis via siRNA, single lab\",\n      \"pmids\": [\"39145797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMA2 promotes glioma cell proliferation and migration via the epithelial-mesenchymal transition (EMT) pathway. Co-IP mass spectrometry identified PSMA2-binding proteins enriched in cell adhesion molecule binding and cadherin binding; PSMA2 knockdown suppressed EMT markers as confirmed by Western blot, and inhibited tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation mass spectrometry (Co-IP MS), CCK-8/colony formation/transwell assays, Western blot for EMT markers, xenograft mouse model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP MS for interaction partners, in vitro and in vivo loss-of-function with defined molecular readout (EMT markers), single lab\",\n      \"pmids\": [\"38574629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMA2 promotes cervical cancer cell proliferation; psma2-shRNA knockdown decreased cell proliferation in vitro and reduced tumor volume and Ki67 expression in vivo. GLP-1R silencing decreased PSMA2 expression, and Exendin-4 decreased PSMA2 expression and attenuated phospho-p65 and phospho-IκB in the NF-κB pathway.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation assay, xenograft mouse model, Ki67 immunostaining, siRNA silencing of GLP-1R, Western blot for NF-κB pathway components\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with defined molecular and phenotypic readouts, pathway placement via NF-κB, single lab\",\n      \"pmids\": [\"33684886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMA2 is a direct target of miR-132: luciferase reporter assay confirmed that miR-132 directly regulates PSMA2 expression, and miR-132 mimic reduced CRC cell proliferation, establishing PSMA2 as a downstream effector of miR-132 in colorectal cancer.\",\n      \"method\": \"Luciferase reporter assay, miRNA mimic transfection, loss-of-function experiments in CRC cell lines\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay directly validates miR-132 targeting of PSMA2, functional epistasis via mimic, single lab\",\n      \"pmids\": [\"33537240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMA2 regulates cell cycle progression, mitochondrial dysfunction, and mitophagy in OSCC cells, contributing to chemo- and radioresistance. PSMA2 overexpression in a xenograft model was countered by mitophagy inducers, demonstrating that PSMA2-mediated suppression of mitophagy is the mechanistic basis of treatment resistance.\",\n      \"method\": \"PSMA2 knockdown/overexpression, cell cycle analysis, mitochondrial function assays, xenograft mouse model with mitophagy inducer treatment\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (mitophagy) and pharmacological rescue, single lab\",\n      \"pmids\": [\"39794329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMA2 overexpression accelerates HSP90 turnover and hypersensitizes the androgen receptor (AR) to residual androgen under castration conditions, driving AR nuclear activity and conferring enzalutamide resistance in prostate cancer. Conversely, PSMA2 silencing stabilizes HSP90, desensitizes cells to androgen, and re-sensitizes resistant cells to enzalutamide. PSMA2 also promotes transcriptional and phenotypic neuroendocrine lineage conversion (tNEPC).\",\n      \"method\": \"PSMA2 overexpression and siRNA knockdown, HSP90 stability assay, AR nuclear translocation/activity assay, androgen sensitivity assay, enzalutamide resistance/re-sensitization assay, neuroendocrine marker analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (HSP90 turnover, AR activity, drug resistance rescue), single lab preprint not yet peer-reviewed\",\n      \"pmids\": [\"41394666\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRRSV nonstructural protein Nsp12 promotes autophagy-dependent degradation of PSMA2 protein to suppress host proteasome activity. PSMA2 overexpression enhances cellular proteasome activity and upregulates immunoproteasome activator subunits PSME1, PSME2, and PSME3, while PSMA2 silencing reduces proteasome activity and promotes PRRSV replication, establishing PSMA2 as an antiviral host restriction factor.\",\n      \"method\": \"Overexpression and siRNA knockdown, proteasome activity assay, PSME1/2/3 transcription analysis, Nsp12 interaction screen, autophagy inhibitor experiments\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular mechanism (autophagy-mediated degradation by Nsp12), proteasome activity readout, single lab\",\n      \"pmids\": [\"41475191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A t(7;13)(p14;q12) chromosomal translocation in MDS/AML generates an out-of-frame PAN3-PSMA2 fusion transcript, disrupting the PSMA2 reading frame and implicating loss of normal PSMA2 function (as part of the 20S proteasome) in disease pathogenesis.\",\n      \"method\": \"RNA sequencing, RT-PCR, Sanger sequencing, interphase FISH\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization of a fusion transcript by sequencing, single case, no functional reconstitution of PSMA2 activity\",\n      \"pmids\": [\"29560286\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA2 is a structural subunit of the 20S proteasome core particle that regulates cellular protein quality control through proteolytic degradation; mechanistically, it promotes viral replication (IAV maturation, NRF2/ROS suppression) or restricts other viruses (ZIKV, PRRSV) depending on context, is directly targeted by miR-132, binds the drug corynoline to modulate NF-κB signaling and fibrosis, accelerates HSP90 turnover to hypersensitize the androgen receptor under castration conditions, and promotes EMT and mitophagy suppression to drive cancer cell proliferation, migration, and therapy resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA2 is a structural subunit of the 20S proteasome core particle whose dosage tunes cellular proteasome capacity and broad proteostasis: knockdown reshapes a network of proteins governing immune response, cytokine signaling, autophagy, and the unfolded protein response [#1], while overexpression raises bulk proteasome activity and induces the immunoproteasome activator subunits PSME1/2/3 [#9]. Through this proteolytic control PSMA2 acts as a host factor in viral infection with context-dependent direction — it is required for influenza A virus maturation and is exploited by IAV to suppress NRF2 nuclear translocation and the oxidative-stress response [#0], yet it restricts Zika virus replication in astrocytic cells [#2] and restrains PRRSV, which counters this defense by driving autophagy-dependent degradation of PSMA2 via its Nsp12 protein [#9]. In cancer, PSMA2 promotes proliferation and migration: it drives glioma growth through an EMT program with cadherin- and adhesion-molecule-binding partners [#4], promotes cervical cancer proliferation downstream of GLP-1R/NF-\\u03baB signaling [#5], and suppresses mitophagy to confer chemo- and radioresistance in oral squamous cell carcinoma [#7]. PSMA2 expression is held in check by miR-132, which binds its transcript directly to limit colorectal cancer proliferation [#6]. The small molecule corynoline binds PSMA2 directly to exert anti-fibrotic effects through NF-\\u03baB signaling in pancreatic stellate cells [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PSMA2 as a pro-proliferative effector in cancer and placed it downstream of upstream regulators, answering whether a proteasome subunit can act as a node in oncogenic signaling.\",\n      \"evidence\": \"shRNA knockdown with in vitro proliferation and xenograft readouts, GLP-1R silencing and Exendin-4 treatment with NF-\\u03baB Western blots in cervical cancer; luciferase reporter showing direct miR-132 targeting in CRC\",\n      \"pmids\": [\"33684886\", \"33537240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve whether the proliferative effect depends on PSMA2's proteasome activity or a moonlighting function\", \"Mechanistic link between GLP-1R, PSMA2 levels, and NF-\\u03baB not biochemically defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined PSMA2 as a broad proteostasis and immune-signaling regulator and revealed opposing roles across viruses, reframing it as a context-dependent host factor rather than a passive structural subunit.\",\n      \"evidence\": \"siRNA knockdown in A549 cells with SOMAScan proteome-wide profiling, IAV titer/NRF2 translocation/ROS assays, and ZIKV titer/protein-synthesis assays in U251 cells\",\n      \"pmids\": [\"35019712\", \"36481484\", \"36680137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular basis of the IAV-versus-ZIKV directional difference is unexplained\", \"Whether NRF2 suppression is a direct proteasome-dependent event is not established\", \"Single-lab, single-method (knockdown) for each phenotype\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified direct small-molecule and protein interactions of PSMA2, advancing it from a phenotypic correlate to a druggable molecular target and EMT driver.\",\n      \"evidence\": \"Lip-SMap and DARTS showing direct corynoline binding plus siRNA epistasis in pancreatic stellate cells; Co-IP mass spectrometry, EMT-marker Western blots, and xenograft loss-of-function in glioma\",\n      \"pmids\": [\"39145797\", \"38574629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Corynoline binding site on PSMA2 and its effect on proteasome activity not mapped\", \"EMT partners identified by Co-IP MS not individually validated\", \"Connection between PSMA2's proteasome role and EMT induction unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked PSMA2 to mitophagy, HSP90/AR signaling, and proteasome activity control, extending its mechanistic reach into therapy resistance and antiviral defense.\",\n      \"evidence\": \"Knockdown/overexpression with mitophagy inducers and xenografts in OSCC; HSP90 turnover, AR activity, and enzalutamide re-sensitization assays in prostate cancer (preprint); proteasome activity, PSME1/2/3 induction, and Nsp12-mediated autophagic degradation assays for PRRSV restriction\",\n      \"pmids\": [\"39794329\", \"41394666\", \"41475191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a proteasome subunit suppresses mitophagy mechanistically is undefined\", \"HSP90/AR finding is from a preprint not yet peer-reviewed\", \"Whether PSME1/2/3 induction is transcriptionally direct is not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PSMA2 dosage and its 20S-core function are mechanistically partitioned among its many context-dependent roles (antiviral restriction, viral maturation, EMT, mitophagy, AR signaling).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical account of how PSMA2 perturbation selectively rewires distinct pathways\", \"No demonstration that the opposing viral phenotypes share a common proteasome-dependent mechanism\", \"Disease causality of the PAN3-PSMA2 fusion not functionally tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 9]}\n    ],\n    \"complexes\": [\"20S proteasome core particle\"],\n    \"partners\": [\"corynoline\", \"HSP90\", \"PRRSV Nsp12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}