{"gene":"PSMA2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1994,"finding":"The human PSMA2 gene (encoding the alpha-type HC3 proteasome subunit) was isolated and characterized. The HC3 gene spans ~15 kb, contains 9 exons, lacks TATA and CAAT promoter elements but possesses GC boxes that function as promoters. A silencer element in the 5'-upstream region near exon 1 was identified that represses HC3 transcription and can repress other gene promoters in an orientation-independent manner, establishing a distinct transcriptional regulatory mechanism for PSMA2 compared to the beta-type HC5 subunit.","method":"Gene cloning, genomic structure analysis, 5'-flanking region functional assays in transfected cells","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional promoter assays with mutagenesis, single lab","pmids":["7966316"],"is_preprint":false},{"year":1996,"finding":"PSMA2 (HC3), as an alpha-type subunit of the 20S proteasome, assembles into the outer rings of the barrel-shaped 20S core particle (two heptameric alpha rings flanking two beta rings). The 20S proteasome harbors multiple distinct peptidase activities (chymotrypsin-like, trypsin-like, peptidylglutamyl-peptide hydrolase) operating via a novel threonine-based catalytic mechanism, and PSMA2 contributes to the structural integrity and gating function of the alpha ring.","method":"Biochemical reconstitution, electron microscopy, peptidase activity assays, crystallographic structural analysis of archaebacterial homologs extrapolated to eukaryotic complex","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — structural and biochemical reconstitution, foundational review integrating multiple independent studies, highly replicated","pmids":["8811196"],"is_preprint":false},{"year":2009,"finding":"PSMA2 is a subunit of the 20S proteolytic core particle (CP), which together with the 19S regulatory particle forms the 26S proteasome. The 20S CP's 28-subunit architecture (including PSMA2 in the alpha ring) provides the internal degradation chamber into which substrate polypeptides are threaded after unfolding by ATPases in the regulatory particle. The alpha-ring gate (formed by alpha subunits including PSMA2) controls substrate access to the proteolytic chamber.","method":"Structural analysis, biochemical reconstitution, genetic studies integrated in mechanistic review","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple independent structural and biochemical studies, extensively replicated","pmids":["19489727"],"is_preprint":false},{"year":2021,"finding":"PSMA2 knockdown (via shRNA) in cervical cancer cell lines decreased cell proliferation in vitro and reduced tumor volume and Ki67 expression in vivo in a xenograft model. Additionally, PSMA2 expression was found to be positively correlated with GLP-1R expression in T2D-related cervical cancer specimens, and GLP-1R silencing decreased PSMA2 expression, suggesting GLP-1R signaling regulates PSMA2 levels. Exendin-4 (GLP-1R agonist) decreased PSMA2 expression and attenuated phospho-p65 and phospho-IκB in the NF-κB pathway.","method":"shRNA knockdown, in vitro proliferation assay, in vivo xenograft model, immunohistochemistry, Western blot, pharmacological intervention with Exendin-4","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined proliferation and tumor growth phenotype, supported by in vivo data, single lab","pmids":["33684886"],"is_preprint":false},{"year":2007,"finding":"PSMA2 was identified as a component of proteasome-containing protein complexes in a large-scale human protein interaction map using immunoprecipitation of Flag-tagged proteins followed by LC-ESI-MS/MS. PSMA2 co-purified with other proteasome subunits confirming its stable integration into the 20S core particle complex in human cells.","method":"Large-scale affinity purification–mass spectrometry (AP-MS) in human cells","journal":"Molecular systems biology","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale AP-MS, systematic interactome study confirming complex membership","pmids":["17353931"],"is_preprint":false},{"year":2012,"finding":"PSMA2 was identified as a component of the 20S proteasome complex in a systematic proteome-wide census of soluble human protein complexes, confirming its stable association with other alpha and beta proteasome subunits via chromatographic co-fractionation and quantitative tandem mass spectrometry.","method":"Chromatographic co-fractionation of cell extracts combined with quantitative tandem mass spectrometry","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — systematic quantitative co-fractionation MS across >1000 fractions, large-scale validation of complex membership","pmids":["22939629"],"is_preprint":false},{"year":2015,"finding":"BioPlex affinity-purification mass spectrometry identified PSMA2 as a stable interactor within the proteasome complex network in HEK293T cells, co-purifying with multiple other proteasome alpha and beta subunits, confirming its integration into the 20S core particle in a human cellular context.","method":"High-throughput affinity-purification mass spectrometry (AP-MS), BioPlex network","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale AP-MS with systematic controls, proteome-scale coverage","pmids":["26186194"],"is_preprint":false},{"year":2021,"finding":"BioPlex 3.0 AP-MS confirmed PSMA2 interactions with other proteasome subunits in both HEK293T and HCT116 cell lines, and comparison across cell lines revealed that PSMA2's interactions within the 20S core complex are shared (core) interactions conserved between the two cell types, consistent with its constitutive role in proteasome assembly.","method":"Proteome-scale affinity-purification mass spectrometry in two human cell lines (BioPlex 3.0)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — replicated across two cell lines in systematic AP-MS study","pmids":["33961781"],"is_preprint":false},{"year":2011,"finding":"Quantitative diGly proteomics identified ubiquitylation sites on PSMA2 in human cells, and PSMA2 ubiquitylation levels changed in response to proteasome inhibition with MG-132, indicating that PSMA2 itself is subject to ubiquitin-mediated post-translational modification as part of proteasome homeostasis regulation.","method":"Quantitative diglycine (diGly) immunoenrichment proteomics with SILAC mass spectrometry","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative site-specific ubiquitylation mapping with pharmacological perturbation, large-scale study","pmids":["21890473"],"is_preprint":false}],"current_model":"PSMA2 (HC3) is an alpha-type subunit that assembles into the outer alpha rings of the 20S proteasome core particle, contributing to the gating of the proteolytic chamber through which substrates are threaded for degradation; its gene is regulated by GC-box promoters and a silencer element, its expression promotes cancer cell proliferation via NF-κB-linked mechanisms that can be attenuated by GLP-1R agonism, and PSMA2 itself undergoes ubiquitylation as part of proteasome homeostasis regulation."},"narrative":{"teleology":[{"year":1994,"claim":"Determining how PSMA2 transcription is controlled revealed an unusual promoter architecture—GC boxes instead of TATA/CAAT elements—plus a novel orientation-independent silencer, distinguishing its regulation from beta-type proteasome subunits.","evidence":"Gene cloning, promoter deletion/mutagenesis assays in transfected cells","pmids":["7966316"],"confidence":"Medium","gaps":["Identity of the trans-acting factor(s) binding the silencer element is unknown","Physiological conditions under which the silencer is relieved are uncharacterized"]},{"year":1996,"claim":"Structural and biochemical reconstitution established that PSMA2 resides in the outer alpha rings of the barrel-shaped 20S proteasome, where it contributes to gating the proteolytic chamber rather than directly catalyzing peptide bond hydrolysis.","evidence":"Electron microscopy, crystal structure of archaeal homolog, peptidase activity assays of eukaryotic 20S particles","pmids":["8811196"],"confidence":"High","gaps":["High-resolution structure of the human 20S complex with individual alpha subunit assignments was not yet available","Specific gating contacts contributed by PSMA2 versus other alpha subunits were not resolved"]},{"year":2009,"claim":"Integrated structural and genetic work consolidated the model that the alpha-ring gate formed by subunits including PSMA2 is the critical barrier controlling substrate entry into the 26S proteasome degradation chamber.","evidence":"Structural analysis, biochemical reconstitution, and yeast genetic studies synthesized in mechanistic review","pmids":["19489727"],"confidence":"High","gaps":["Relative contribution of PSMA2 N-terminal tail versus other alpha subunit tails to gate closure was not dissected in human cells"]},{"year":2007,"claim":"Large-scale interaction mapping confirmed that PSMA2 stably co-purifies with the full complement of proteasome subunits in human cells, validating its constitutive incorporation into the 20S core particle in vivo.","evidence":"Flag-tagged AP-MS in human cells (Ewing et al.); replicated by co-fractionation MS (2012) and BioPlex AP-MS (2015, 2021)","pmids":["17353931","22939629","26186194","33961781"],"confidence":"Medium","gaps":["Whether PSMA2 exists in free or assembly-intermediate pools beyond the mature 20S particle is not quantified","Cell-type-specific stoichiometric variation has not been addressed"]},{"year":2011,"claim":"The discovery that PSMA2 is ubiquitylated, with modification levels responsive to proteasome inhibition, revealed a feedback layer in which the proteasome's own subunits are marked by ubiquitin, potentially regulating proteasome turnover or remodeling.","evidence":"Quantitative diGly immunoenrichment with SILAC MS under MG-132 treatment","pmids":["21890473"],"confidence":"Medium","gaps":["The E3 ligase responsible for PSMA2 ubiquitylation is unidentified","Functional consequence of site-specific ubiquitylation (degradation, assembly, activity) is unknown"]},{"year":2021,"claim":"Loss-of-function experiments linked PSMA2 expression to cancer cell proliferation and NF-κB signaling, and showed that GLP-1R agonism downregulates PSMA2, connecting metabolic signaling to proteasome subunit expression in cervical cancer.","evidence":"shRNA knockdown in cervical cancer cells, xenograft tumor growth assay, Western blot for NF-κB pathway components, Exendin-4 pharmacological intervention","pmids":["33684886"],"confidence":"Medium","gaps":["Whether PSMA2 loss reduces proliferation by impairing global proteasome function or a specific NF-κB substrate is unclear","GLP-1R–PSMA2 regulatory axis has not been replicated in independent cancer models","Mechanism by which GLP-1R signaling modulates PSMA2 transcription or protein stability is unresolved"]},{"year":null,"claim":"The specific structural contacts PSMA2 makes in gating, the functional consequences of its ubiquitylation, and the generality of its pro-proliferative role across cancer types remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["High-resolution cryo-EM mapping of human PSMA2-specific gate contacts is needed","No mutagenesis study of PSMA2 ubiquitylation sites has been performed","Whether PSMA2 expression is selectively limiting for proteasome assembly in any tissue is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5,6,7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,8]}],"complexes":["20S proteasome core particle","26S proteasome"],"partners":["PSMA1","PSMA3","PSMA4","PSMA5","PSMA6","PSMA7","PSMB1"],"other_free_text":[]},"mechanistic_narrative":"PSMA2 (also designated HC3) is a structural alpha-type subunit of the 20S proteasome core particle, where it assembles into the outer heptameric alpha rings that gate substrate access to the internal proteolytic chamber [PMID:8811196, PMID:19489727]. Its stable integration into the 20S complex is conserved across human cell types, as confirmed by multiple independent affinity-purification and co-fractionation mass spectrometry studies [PMID:17353931, PMID:33961781]. The PSMA2 gene uses GC-box-driven promoters and harbors an orientation-independent silencer element that represses transcription [PMID:7966316]. PSMA2 itself is subject to ubiquitylation whose levels respond to proteasome inhibition, implicating it in proteasome homeostasis feedback, and its knockdown reduces cancer cell proliferation in vitro and tumor growth in vivo through a mechanism linked to NF-κB pathway attenuation [PMID:21890473, PMID:33684886]."},"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":"10842167","id":"PMC_10842167","title":"Oligomerization of mu- and delta-opioid receptors. 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complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528301","id":"PMC_14528301","title":"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14527406","id":"PMC_14527406","title":"HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14527406","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12750511","id":"PMC_12750511","title":"Hypermutation of HIV-1 DNA in the absence of the Vif protein.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12750511","citation_count":570,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21565611","id":"PMC_21565611","title":"Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21565611","citation_count":507,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43478,"output_tokens":765,"usd":0.070955},"stage2":{"model":"claude-opus-4-6","input_tokens":3748,"output_tokens":907,"usd":0.062122},"total_usd":0.351831,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":55031,"output_tokens":3029,"usd":0.105264},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5797,"output_tokens":1867,"usd":0.11349}},"stage1_raw":"Looking through the abstracts, I need to identify papers about PSMA2 (Proteasome Subunit Alpha Type 2, also known as HC3). Most papers in this corpus are about opioid receptors (mu, delta, kappa), bacteriophage Mu, calpains, or other unrelated genes that share the symbol \"mu.\" I need to find papers specifically about PSMA2.\n\nRelevant papers:\n- PMID 33684886: About PSMA2 in cervical cancer, showing psma2-shRNA decreased cell proliferation (functional KD study)\n- PMID 7966316: About isolation and characterization of the HC3 (alpha-type, which is PSMA2) gene, including promoter/silencer elements\n\nLet me extract mechanistic findings from these.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The human PSMA2 (HC3) gene is approximately 15 kb in length with 9 exons, lacks TATA and CAAT promoter elements but contains GC boxes that function coordinately as promoters, and possesses an additional silencer element in the 5'-upstream region near the first exon that can repress promoter activity of other genes (HC5, GLUT1) in an orientation-independent manner, indicating it acts as a general transcriptional silencer.\",\n      \"method\": \"Gene isolation, Southern blotting, exon-intron mapping, transfection-based promoter/silencer activity assays\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assays of regulatory elements in transfected cells, single lab\",\n      \"pmids\": [\"7966316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMA2 knockdown via psma2-shRNA decreased cervical cancer cell proliferation in vitro and reduced tumour volume and Ki67 expression in vivo; silencing GLP-1R decreased PSMA2 expression, placing PSMA2 downstream of GLP-1R/NF-κB signaling in T2D-related cervical cancer cells.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation assays, in vivo xenograft tumour volume measurement, immunohistochemistry (Ki67), siRNA epistasis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/KD with defined cellular phenotype and pathway placement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33684886\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA2 (HC3) is an alpha-type subunit of the human 20S proteasome whose gene is regulated by GC-box promoters and a general transcriptional silencer element; its expression promotes cell proliferation downstream of GLP-1R/NF-κB signaling, and its loss-of-function reduces cancer cell growth in vitro and in vivo.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe query gene is **PSMA2** (Proteasome Subunit Alpha Type-2), a subunit of the 20S proteasome core particle.\n\nFrom the main corpus (100 papers): The vast majority describe opioid receptors (mu, delta, kappa), bacteriophage Mu transposition, immunoglobulin mu chains, mu-calpain, DNA polymerase mu, or other unrelated proteins. These are all EXCLUDE (alias collision or symbol collision).\n\nOnly papers directly about PSMA2 (proteasome alpha 2 subunit):\n- **Paper [79]**: Explicitly about PSMA2 (proteasome alpha 2 subunit) in cervical cancer — KEEP\n- **Paper [43]**: iTRAQ proteomics mentioning various proteins — EXCLUDE (no specific PSMA2 mechanistic finding)\n\nFrom the gene2pubmed curated papers:\n- **[1] PMID:8811196**: Structure and functions of 20S and 26S proteasomes — KEEP (directly relevant to PSMA2's complex)\n- **[97] PMID:7966316**: Isolation/characterization of human proteasome genes including HC3 (=PSMA2) — KEEP\n- **[8] PMID:26186194**: BioPlex network — contains PSMA2 interactions — KEEP\n- **[9] PMID:28514442**: BioPlex 2.0 — KEEP\n- **[10] PMID:26496610**: Human interactome — KEEP\n- **[22] PMID:33961781**: BioPlex 3.0 — KEEP\n- **[23] PMID:22939629**: Census of human protein complexes — KEEP\n- **[21] PMID:17353931**: Large-scale MS protein interactions — KEEP\n- **[15] PMID:32296183**: HuRI reference interactome — KEEP\n- **[4] PMID:19489727**: Recognition and processing of ubiquitin-protein conjugates — KEEP (proteasome mechanism)\n- **[5] PMID:21906983**: Ubiquitin-modified proteome — KEEP\n- **[14] PMID:23503661**: PARKIN ubiquitylome — KEEP\n- **[20] PMID:21890473**: Ubiquitylation sites survey — KEEP\n- **[12] PMID:15592455**: Tyrosine phosphorylation profiling — marginal, no specific PSMA2 mechanism — EXCLUDE\n- **[27] PMID:19056867**: Urinary exosomes proteomics — KEEP (identifies PSMA2)\n- **[3] PMID:12477932**: MGC cDNA sequences — EXCLUDE (no mechanism)\n- **[2],[6],[7],[11],[13],[16],[17],[18],[19],[24],[25],[26],[28],[29],[30]**: APOBEC3G/HIV/Vif, VIRMA m6A, splicing sulfonamides, ciliopathy — EXCLUDE (not about PSMA2)\n\nNow extracting mechanistic discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The human PSMA2 gene (encoding the alpha-type HC3 proteasome subunit) was isolated and characterized. The HC3 gene spans ~15 kb, contains 9 exons, lacks TATA and CAAT promoter elements but possesses GC boxes that function as promoters. A silencer element in the 5'-upstream region near exon 1 was identified that represses HC3 transcription and can repress other gene promoters in an orientation-independent manner, establishing a distinct transcriptional regulatory mechanism for PSMA2 compared to the beta-type HC5 subunit.\",\n      \"method\": \"Gene cloning, genomic structure analysis, 5'-flanking region functional assays in transfected cells\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional promoter assays with mutagenesis, single lab\",\n      \"pmids\": [\"7966316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PSMA2 (HC3), as an alpha-type subunit of the 20S proteasome, assembles into the outer rings of the barrel-shaped 20S core particle (two heptameric alpha rings flanking two beta rings). The 20S proteasome harbors multiple distinct peptidase activities (chymotrypsin-like, trypsin-like, peptidylglutamyl-peptide hydrolase) operating via a novel threonine-based catalytic mechanism, and PSMA2 contributes to the structural integrity and gating function of the alpha ring.\",\n      \"method\": \"Biochemical reconstitution, electron microscopy, peptidase activity assays, crystallographic structural analysis of archaebacterial homologs extrapolated to eukaryotic complex\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and biochemical reconstitution, foundational review integrating multiple independent studies, highly replicated\",\n      \"pmids\": [\"8811196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMA2 is a subunit of the 20S proteolytic core particle (CP), which together with the 19S regulatory particle forms the 26S proteasome. The 20S CP's 28-subunit architecture (including PSMA2 in the alpha ring) provides the internal degradation chamber into which substrate polypeptides are threaded after unfolding by ATPases in the regulatory particle. The alpha-ring gate (formed by alpha subunits including PSMA2) controls substrate access to the proteolytic chamber.\",\n      \"method\": \"Structural analysis, biochemical reconstitution, genetic studies integrated in mechanistic review\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple independent structural and biochemical studies, extensively replicated\",\n      \"pmids\": [\"19489727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMA2 knockdown (via shRNA) in cervical cancer cell lines decreased cell proliferation in vitro and reduced tumor volume and Ki67 expression in vivo in a xenograft model. Additionally, PSMA2 expression was found to be positively correlated with GLP-1R expression in T2D-related cervical cancer specimens, and GLP-1R silencing decreased PSMA2 expression, suggesting GLP-1R signaling regulates PSMA2 levels. Exendin-4 (GLP-1R agonist) decreased PSMA2 expression and attenuated phospho-p65 and phospho-IκB in the NF-κB pathway.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation assay, in vivo xenograft model, immunohistochemistry, Western blot, pharmacological intervention with Exendin-4\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined proliferation and tumor growth phenotype, supported by in vivo data, single lab\",\n      \"pmids\": [\"33684886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PSMA2 was identified as a component of proteasome-containing protein complexes in a large-scale human protein interaction map using immunoprecipitation of Flag-tagged proteins followed by LC-ESI-MS/MS. PSMA2 co-purified with other proteasome subunits confirming its stable integration into the 20S core particle complex in human cells.\",\n      \"method\": \"Large-scale affinity purification–mass spectrometry (AP-MS) in human cells\",\n      \"journal\": \"Molecular systems biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale AP-MS, systematic interactome study confirming complex membership\",\n      \"pmids\": [\"17353931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PSMA2 was identified as a component of the 20S proteasome complex in a systematic proteome-wide census of soluble human protein complexes, confirming its stable association with other alpha and beta proteasome subunits via chromatographic co-fractionation and quantitative tandem mass spectrometry.\",\n      \"method\": \"Chromatographic co-fractionation of cell extracts combined with quantitative tandem mass spectrometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic quantitative co-fractionation MS across >1000 fractions, large-scale validation of complex membership\",\n      \"pmids\": [\"22939629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BioPlex affinity-purification mass spectrometry identified PSMA2 as a stable interactor within the proteasome complex network in HEK293T cells, co-purifying with multiple other proteasome alpha and beta subunits, confirming its integration into the 20S core particle in a human cellular context.\",\n      \"method\": \"High-throughput affinity-purification mass spectrometry (AP-MS), BioPlex network\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale AP-MS with systematic controls, proteome-scale coverage\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BioPlex 3.0 AP-MS confirmed PSMA2 interactions with other proteasome subunits in both HEK293T and HCT116 cell lines, and comparison across cell lines revealed that PSMA2's interactions within the 20S core complex are shared (core) interactions conserved between the two cell types, consistent with its constitutive role in proteasome assembly.\",\n      \"method\": \"Proteome-scale affinity-purification mass spectrometry in two human cell lines (BioPlex 3.0)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — replicated across two cell lines in systematic AP-MS study\",\n      \"pmids\": [\"33961781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Quantitative diGly proteomics identified ubiquitylation sites on PSMA2 in human cells, and PSMA2 ubiquitylation levels changed in response to proteasome inhibition with MG-132, indicating that PSMA2 itself is subject to ubiquitin-mediated post-translational modification as part of proteasome homeostasis regulation.\",\n      \"method\": \"Quantitative diglycine (diGly) immunoenrichment proteomics with SILAC mass spectrometry\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative site-specific ubiquitylation mapping with pharmacological perturbation, large-scale study\",\n      \"pmids\": [\"21890473\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA2 (HC3) is an alpha-type subunit that assembles into the outer alpha rings of the 20S proteasome core particle, contributing to the gating of the proteolytic chamber through which substrates are threaded for degradation; its gene is regulated by GC-box promoters and a silencer element, its expression promotes cancer cell proliferation via NF-κB-linked mechanisms that can be attenuated by GLP-1R agonism, and PSMA2 itself undergoes ubiquitylation as part of proteasome homeostasis regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMA2 (HC3) is an alpha-type subunit of the 20S proteasome. The PSMA2 gene lacks TATA and CAAT boxes and is instead driven by GC-box elements functioning coordinately as promoters, with an orientation-independent silencer element in the 5′-upstream region capable of repressing heterologous promoters [PMID:7966316]. PSMA2 expression is positively regulated by GLP-1R/NF-κB signaling, and its knockdown reduces cervical cancer cell proliferation in vitro and tumor growth in vivo [PMID:33684886].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining the transcriptional control architecture of PSMA2 revealed an unusual GC-box-driven promoter and a general transcriptional silencer, establishing how a constitutively needed proteasome subunit gene is regulated without canonical TATA/CAAT elements.\",\n      \"evidence\": \"Gene isolation, exon-intron mapping, and transfection-based promoter/silencer assays in human cells\",\n      \"pmids\": [\"7966316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of transcription factors binding the GC boxes and silencer element is unknown\",\n        \"Whether the silencer element regulates endogenous loci in a physiological chromatin context is untested\",\n        \"Findings from a single lab without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that PSMA2 is a proliferation-promoting effector downstream of GLP-1R/NF-κB signaling placed this proteasome subunit in a specific oncogenic signaling axis in cervical cancer.\",\n      \"evidence\": \"shRNA knockdown with in vitro proliferation assays, in vivo xenograft models, Ki67 immunohistochemistry, and siRNA epistasis in cervical cancer cells\",\n      \"pmids\": [\"33684886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the proliferative role of PSMA2 reflects general proteasome function or a subunit-specific activity is unresolved\",\n        \"The NF-κB-dependent mechanism that upregulates PSMA2 transcription has not been mapped to specific promoter elements\",\n        \"Findings limited to one cancer cell line context without validation in other tumor types\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether PSMA2 has any non-proteasomal functions, what structural contacts it makes within the 20S alpha ring, and whether the transcriptional silencer element discovered in its locus has physiological relevance at endogenous chromatin.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical studies of PSMA2 within the assembled proteasome reported in this literature\",\n        \"No disease-associated coding mutations described\",\n        \"No interactome or substrate-specificity data available\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [1]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [1]\n      }\n    ],\n    \"complexes\": [\"20S proteasome\"],\n    \"partners\": [\"GLP1R\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMA2 (also designated HC3) is a structural alpha-type subunit of the 20S proteasome core particle, where it assembles into the outer heptameric alpha rings that gate substrate access to the internal proteolytic chamber [PMID:8811196, PMID:19489727]. Its stable integration into the 20S complex is conserved across human cell types, as confirmed by multiple independent affinity-purification and co-fractionation mass spectrometry studies [PMID:17353931, PMID:33961781]. The PSMA2 gene uses GC-box-driven promoters and harbors an orientation-independent silencer element that represses transcription [PMID:7966316]. PSMA2 itself is subject to ubiquitylation whose levels respond to proteasome inhibition, implicating it in proteasome homeostasis feedback, and its knockdown reduces cancer cell proliferation in vitro and tumor growth in vivo through a mechanism linked to NF-κB pathway attenuation [PMID:21890473, PMID:33684886].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Determining how PSMA2 transcription is controlled revealed an unusual promoter architecture—GC boxes instead of TATA/CAAT elements—plus a novel orientation-independent silencer, distinguishing its regulation from beta-type proteasome subunits.\",\n      \"evidence\": \"Gene cloning, promoter deletion/mutagenesis assays in transfected cells\",\n      \"pmids\": [\"7966316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the trans-acting factor(s) binding the silencer element is unknown\",\n        \"Physiological conditions under which the silencer is relieved are uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Structural and biochemical reconstitution established that PSMA2 resides in the outer alpha rings of the barrel-shaped 20S proteasome, where it contributes to gating the proteolytic chamber rather than directly catalyzing peptide bond hydrolysis.\",\n      \"evidence\": \"Electron microscopy, crystal structure of archaeal homolog, peptidase activity assays of eukaryotic 20S particles\",\n      \"pmids\": [\"8811196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution structure of the human 20S complex with individual alpha subunit assignments was not yet available\",\n        \"Specific gating contacts contributed by PSMA2 versus other alpha subunits were not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Integrated structural and genetic work consolidated the model that the alpha-ring gate formed by subunits including PSMA2 is the critical barrier controlling substrate entry into the 26S proteasome degradation chamber.\",\n      \"evidence\": \"Structural analysis, biochemical reconstitution, and yeast genetic studies synthesized in mechanistic review\",\n      \"pmids\": [\"19489727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of PSMA2 N-terminal tail versus other alpha subunit tails to gate closure was not dissected in human cells\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Large-scale interaction mapping confirmed that PSMA2 stably co-purifies with the full complement of proteasome subunits in human cells, validating its constitutive incorporation into the 20S core particle in vivo.\",\n      \"evidence\": \"Flag-tagged AP-MS in human cells (Ewing et al.); replicated by co-fractionation MS (2012) and BioPlex AP-MS (2015, 2021)\",\n      \"pmids\": [\"17353931\", \"22939629\", \"26186194\", \"33961781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PSMA2 exists in free or assembly-intermediate pools beyond the mature 20S particle is not quantified\",\n        \"Cell-type-specific stoichiometric variation has not been addressed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The discovery that PSMA2 is ubiquitylated, with modification levels responsive to proteasome inhibition, revealed a feedback layer in which the proteasome's own subunits are marked by ubiquitin, potentially regulating proteasome turnover or remodeling.\",\n      \"evidence\": \"Quantitative diGly immunoenrichment with SILAC MS under MG-132 treatment\",\n      \"pmids\": [\"21890473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ligase responsible for PSMA2 ubiquitylation is unidentified\",\n        \"Functional consequence of site-specific ubiquitylation (degradation, assembly, activity) is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Loss-of-function experiments linked PSMA2 expression to cancer cell proliferation and NF-κB signaling, and showed that GLP-1R agonism downregulates PSMA2, connecting metabolic signaling to proteasome subunit expression in cervical cancer.\",\n      \"evidence\": \"shRNA knockdown in cervical cancer cells, xenograft tumor growth assay, Western blot for NF-κB pathway components, Exendin-4 pharmacological intervention\",\n      \"pmids\": [\"33684886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PSMA2 loss reduces proliferation by impairing global proteasome function or a specific NF-κB substrate is unclear\",\n        \"GLP-1R–PSMA2 regulatory axis has not been replicated in independent cancer models\",\n        \"Mechanism by which GLP-1R signaling modulates PSMA2 transcription or protein stability is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific structural contacts PSMA2 makes in gating, the functional consequences of its ubiquitylation, and the generality of its pro-proliferative role across cancer types remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"High-resolution cryo-EM mapping of human PSMA2-specific gate contacts is needed\",\n        \"No mutagenesis study of PSMA2 ubiquitylation sites has been performed\",\n        \"Whether PSMA2 expression is selectively limiting for proteasome assembly in any tissue is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 8]}\n    ],\n    \"complexes\": [\n      \"20S proteasome core particle\",\n      \"26S proteasome\"\n    ],\n    \"partners\": [\n      \"PSMA1\",\n      \"PSMA3\",\n      \"PSMA4\",\n      \"PSMA5\",\n      \"PSMA6\",\n      \"PSMA7\",\n      \"PSMB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}