{"gene":"PSME2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"PA28 (the heteropolymer of PA28α/PSME1 and PA28β/PSME2) was identified as a regulator of 20S proteasome activity, with the PA28 complex binding to both ends of the 20S proteasome and stimulating its multiple peptidase activities in an ATP-independent manner, distinct from the 19S regulatory complex.","method":"Biochemical reconstitution and review of in vitro proteasome activity assays","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro, foundational review summarizing replicated biochemical characterization","pmids":["8811196"],"is_preprint":false},{"year":1999,"finding":"The mouse genome contains two chromosomal loci encoding PA28β (PSME2): one is the canonical IFNγ-inducible PMSE2 gene with an intron-exon structure, and the second (PMSE2b) is an expressed retrotransposon inserted into a LINE1 element and driven by a LINE1 F-type monomer promoter, yet encodes a protein indistinguishable from the canonical PSME2.","method":"Genomic Southern blot, cloning, sequencing, luciferase reporter assays for promoter activity","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Southern blot, cloning, luciferase assay) in a single study","pmids":["10222192"],"is_preprint":false},{"year":2000,"finding":"Overexpression of PA28β alone (without PA28α) improved MHC class I antigen presentation of the MCMV pp89 epitope, and this effect was attributed to increased levels of PA28α/β heterocomplexes rather than PA28β homomers acting independently; immunoprecipitation confirmed that PA28β stabilizes PA28αβ complex formation.","method":"Stable transfection of PA28β alone or PA28αβ, northern blot, immunoprecipitation, T-cell cytotoxicity assay for antigen presentation","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal immunoprecipitation and functional antigen presentation assay, single lab","pmids":["10781831"],"is_preprint":false},{"year":2001,"finding":"In vivo genetic deletion of both PA28α and PA28β revealed that the PA28αβ heteropolymer is required for processing of specific antigens (e.g., melanoma antigen TRP2-derived peptide) but is dispensable for general antigen presentation; additionally, loss of both subunits reduced ATP-dependent proteolytic activity, implicating 'hybrid proteasomes' (20S capped by PA28 on one end and 19S on the other) in protein degradation.","method":"Double-knockout mouse generation (PA28α−/−/β−/−), proteasome activity assays, T-cell cytotoxicity assays, influenza infection model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo genetic loss-of-function with multiple functional readouts, widely cited foundational study","pmids":["11689430"],"is_preprint":false},{"year":2013,"finding":"N-α-acetyltransferase 10 protein (Naa10p) physically associates with PA28β (PSME2) and, in a PA28β-dependent manner, also interacts with PA28α; Naa10p negatively regulates PA28-dependent chymotrypsin-like 28S proteasome activity both in cancer cells and in a cell-free reconstituted system with purified proteins, independently of its acetyltransferase activity.","method":"Co-immunoprecipitation, cell-free reconstitution with purified proteins, chymotrypsin-like proteasome activity assay, acetyltransferase-dead mutant analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — cell-free reconstitution with purified proteins plus Co-IP and enzymatic assay; acetyltransferase-dead mutant provides mechanistic dissection","pmids":["23624078"],"is_preprint":false},{"year":2012,"finding":"Knockdown of PA28β (PSME2) enhanced invasion of gastric cancer cells, while overexpression inhibited it; proteomics revealed that PA28β suppresses invasion at least in part by downregulating chloride intracellular channel 1 (CLIC1), as siRNA-mediated knockdown of CLIC1 rescued the increased invasiveness caused by PA28β knockdown.","method":"siRNA knockdown, overexpression, Transwell invasion assay, 2D-DIGE proteomics, RNA interference of CLIC1, immunohistochemistry of patient tissue","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis rescue experiment (CLIC1 KD reverting PA28β-KD phenotype) plus proteomics; single lab","pmids":["22173998"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of PA28α and PA28β protected diabetic mice from renal and retinal microvascular injury; in mesangial cells and retinal pericytes from PA28αβ double-knockout mice, high-glucose-induced expression of osteopontin (OPN) and MCP-1 was suppressed; peptides blocking PA28 binding to the 20S proteasome also suppressed OPN induction, indicating that PA28-mediated modulation of proteasome activity in perivascular cells drives diabetic microvascular injury.","method":"Double-knockout mouse model, STZ-induced diabetes, renal histology, cultured mesangial cells and retinal pericytes under high glucose, peptide inhibition of PA28–20S interaction, gene expression analysis","journal":"International journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO + in vitro cellular model + peptide inhibitor mechanistic probe; single lab","pmids":["27830089"],"is_preprint":false},{"year":2021,"finding":"Knockdown of PSME2 in clear cell renal cell carcinoma cells reduced their invasive capacity and simultaneously enhanced autophagy; mechanistically, PSME2 was shown to inhibit BNIP3-mediated autophagy, such that loss of PSME2 de-repressed BNIP3-dependent autophagic flux.","method":"siRNA knockdown, Transwell invasion assay, western blot, immunofluorescence, transmission electron microscopy of autophagosomes, CCK-8 assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal readouts (invasion, TEM, protein markers) placing PSME2 upstream of BNIP3-autophagy; single lab","pmids":["34779489"],"is_preprint":false},{"year":2025,"finding":"Knockdown of PSME2 in esophageal squamous cell carcinoma (ESCC) cells reduced proliferation, migration, and invasion, and induced autophagy-mediated cell death; mechanistically, PSME2 knockdown suppressed the IL-6/STAT3 signaling pathway, and combined inhibition of PSME2 with the STAT3 inhibitor WP1066 or the autophagy inhibitor chloroquine suppressed tumor growth in vivo, placing PSME2 upstream of IL-6/STAT3-dependent autophagy suppression.","method":"siRNA knockdown, STAT3 inhibitor (WP1066), autophagy inhibitor (chloroquine), in vitro proliferation/migration/invasion assays, in vivo subcutaneous nude mouse tumor model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via pharmacological inhibitors combined with genetic KD, in vivo validation; single lab","pmids":["40404117"],"is_preprint":false},{"year":2025,"finding":"In colonic cells, PSME2 knockdown restored claudin-1 expression suppressed by LPS, reduced pro-inflammatory cytokines (IL-6, TNF-α), and enhanced autophagy flux (increased LC3-II/LC3-I ratio, reduced p62, elevated LC3B puncta); chloroquine treatment reversed the barrier-protective effects of PSME2 silencing, demonstrating that PSME2 promotes intestinal inflammation and barrier disruption through autophagy dysregulation.","method":"siRNA knockdown in colonic cell lines, LPS treatment, western blot for tight junction proteins and autophagy markers, immunofluorescence, cytokine measurement, chloroquine rescue experiment; DSS-induced colitis mouse model","journal":"Open life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with pharmacological rescue (CQ) providing mechanistic pathway placement; in vitro and in vivo; single lab","pmids":["41211066"],"is_preprint":false}],"current_model":"PSME2 (PA28β) forms a heteropolymer with PA28α that binds the ends of the 20S proteasome to stimulate antigen processing in an ATP-independent manner, is required for processing of select MHC class I antigens (but not all) in vivo, and is negatively regulated by Naa10p through direct physical interaction; beyond its canonical proteasome-activator role, PSME2 suppresses cell invasion (via CLIC1 downregulation in gastric cancer), inhibits BNIP3-mediated autophagy in renal carcinoma, and modulates IL-6/STAT3-dependent autophagy in esophageal cancer, while PA28αβ-mediated proteasome activity in perivascular cells contributes to diabetic microvascular injury."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing the molecular identity of PA28β as a subunit of an ATP-independent 20S proteasome activator resolved how cells enhance proteasomal peptide cleavage without 19S-dependent energy expenditure.","evidence":"Biochemical reconstitution and review of in vitro proteasome activity assays","pmids":["8811196"],"confidence":"High","gaps":["In vivo requirement for antigen processing not yet tested","Relative contribution of PA28β versus PA28α to complex formation unknown","No structural model of PA28αβ–20S interaction at this point"]},{"year":2000,"claim":"Demonstrating that overexpressed PA28β alone enhances MHC class I antigen presentation by stabilizing PA28αβ heterocomplexes, rather than forming functional homomers, established PA28β as a limiting factor for immunoproteasome assembly.","evidence":"Stable transfection, immunoprecipitation, and T-cell cytotoxicity assays for antigen presentation","pmids":["10781831"],"confidence":"Medium","gaps":["Whether PA28β homomers have any residual activity remained unresolved","Single-lab finding not independently replicated at the time"]},{"year":2001,"claim":"Genetic ablation of both PA28α and PA28β in mice revealed that the PA28αβ complex is required for processing select antigens (e.g., TRP2) but dispensable for general antigen presentation, and implicated hybrid 19S–20S–PA28 proteasomes in protein degradation.","evidence":"PA28α/β double-knockout mice with proteasome activity assays, T-cell responses, and influenza infection challenge","pmids":["11689430"],"confidence":"High","gaps":["Specific epitope-processing rules dictating PA28 dependence were not defined","Hybrid proteasome stoichiometry and substrate specificity not structurally resolved"]},{"year":2012,"claim":"Discovery that PA28β suppresses gastric cancer cell invasion via downregulation of CLIC1 extended PSME2 function beyond proteasome-mediated antigen processing to a tumor-suppressive role in epithelial cell migration.","evidence":"siRNA knockdown and overexpression with Transwell invasion assays, 2D-DIGE proteomics, CLIC1 epistasis rescue","pmids":["22173998"],"confidence":"Medium","gaps":["Whether CLIC1 downregulation proceeds via proteasomal degradation or transcriptional regulation was not determined","Single-lab observation in gastric cancer cells"]},{"year":2013,"claim":"Identification of Naa10p as a direct PA28β-binding negative regulator of PA28-dependent proteasome activity, acting independently of its acetyltransferase function, established the first non-proteasomal protein modulator of PA28 function.","evidence":"Co-immunoprecipitation, cell-free reconstitution with purified proteins, acetyltransferase-dead mutant analysis","pmids":["23624078"],"confidence":"High","gaps":["Binding site on PA28β and structural basis of inhibition not mapped","Physiological context (which tissues or conditions engage Naa10p–PA28β regulation) undefined"]},{"year":2016,"claim":"Genetic deletion of PA28αβ protected diabetic mice from renal and retinal microvascular injury by suppressing high-glucose-induced osteopontin and MCP-1, linking PA28-dependent proteasome activity to metabolic disease pathogenesis in perivascular cells.","evidence":"PA28αβ double-knockout mice with STZ-induced diabetes, mesangial cell and pericyte cultures, peptide inhibitor of PA28–20S interaction","pmids":["27830089"],"confidence":"Medium","gaps":["Specific PA28-dependent proteasomal substrates driving OPN/MCP-1 induction not identified","Whether PA28α or PA28β individually contributes was not dissected"]},{"year":2021,"claim":"Showing that PSME2 inhibits BNIP3-mediated autophagy in renal carcinoma cells linked its proteasome-activator function to autophagic flux regulation and broadened its role to autophagy suppression in cancer biology.","evidence":"siRNA knockdown with Transwell invasion, TEM of autophagosomes, western blot for autophagy markers","pmids":["34779489"],"confidence":"Medium","gaps":["Whether PSME2 promotes BNIP3 proteasomal degradation or acts indirectly was not resolved","Single-cell-line study without in vivo validation"]},{"year":2025,"claim":"Convergent studies in esophageal cancer and colonic inflammation established that PSME2 suppresses autophagy through IL-6/STAT3 signaling and promotes inflammatory barrier disruption, consolidating a proteasome-activator-independent role for PSME2 in autophagy regulation across tissues.","evidence":"siRNA knockdown combined with STAT3 inhibitor and chloroquine rescue, in vivo nude mouse and DSS-colitis models","pmids":["40404117","41211066"],"confidence":"Medium","gaps":["Whether autophagy suppression requires PA28αβ proteasome-activating function or is mediated by a distinct PSME2 mechanism is unknown","Direct proteasomal substrates linking PSME2 to IL-6/STAT3 pathway activation not identified","Findings from single laboratories, not yet independently replicated"]},{"year":null,"claim":"The relationship between PSME2's canonical proteasome-activation function and its emerging autophagy-suppressive and anti-invasive roles remains mechanistically unresolved — whether these non-canonical functions require PA28αβ complex formation and proteasomal substrate turnover, or represent proteasome-independent activities of PSME2, is the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No separation-of-function mutant distinguishing proteasome-activator from autophagy-regulatory roles","No structural basis for Naa10p–PA28β or BNIP3–PSME2 interactions","Tissue-specific versus universal nature of PSME2 autophagy regulation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,8,9]}],"complexes":["PA28αβ (11S regulator)","Hybrid 19S-20S-PA28 proteasome"],"partners":["PSME1","NAA10","BNIP3","CLIC1"],"other_free_text":[]},"mechanistic_narrative":"PSME2 (PA28β) is an obligate subunit of the PA28αβ heteroheptameric proteasome activator that caps the 20S proteasome and stimulates peptidase activity in an ATP-independent manner, thereby shaping MHC class I antigen processing. PA28β stabilizes the PA28αβ complex and is required for generation of select immunodominant epitopes but is dispensable for general antigen presentation, as demonstrated by double-knockout mice lacking both PA28α and PA28β [PMID:11689430, PMID:10781831]. The PA28-activating function is negatively regulated by Naa10p through direct physical interaction with PA28β, independent of Naa10p acetyltransferase activity [PMID:23624078]. Beyond canonical proteasome activation, PSME2 suppresses autophagy through BNIP3- and IL-6/STAT3-dependent pathways and modulates cell invasion and inflammatory barrier function in diverse epithelial contexts [PMID:34779489, PMID:40404117, PMID:41211066]."},"prefetch_data":{"uniprot":{"accession":"Q9UL46","full_name":"Proteasome activator complex subunit 2","aliases":["11S regulator complex subunit beta","REG-beta","Activator of multicatalytic protease subunit 2","Proteasome activator 28 subunit beta","PA28b","PA28beta"],"length_aa":239,"mass_kda":27.4,"function":"Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UL46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSME2","classification":"Not Classified","n_dependent_lines":105,"n_total_lines":1208,"dependency_fraction":0.0869205298013245},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100911","cell_line_id":"CID000133","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"PSME1","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":0.2},{"gene":"PSMA5","stoichiometry":0.2},{"gene":"PSMA2","stoichiometry":0.2},{"gene":"PSMA4","stoichiometry":0.2},{"gene":"PSMC3","stoichiometry":0.2},{"gene":"PSMD6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000133","total_profiled":1310},"omim":[{"mim_id":"612024","title":"OTU DOMAIN-CONTAINING PROTEIN 7A; OTUD7A","url":"https://www.omim.org/entry/612024"},{"mim_id":"602161","title":"PROTEASOME ACTIVATOR SUBUNIT 2; PSME2","url":"https://www.omim.org/entry/602161"},{"mim_id":"600654","title":"PROTEASOME ACTIVATOR SUBUNIT 1; PSME1","url":"https://www.omim.org/entry/600654"},{"mim_id":"147574","title":"INTERFERON REGULATORY FACTOR 9; IRF9","url":"https://www.omim.org/entry/147574"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSME2"},"hgnc":{"alias_symbol":["PA28beta"],"prev_symbol":[]},"alphafold":{"accession":"Q9UL46","domains":[{"cath_id":"1.20.120.180","chopping":"16-55_97-229","consensus_level":"high","plddt":97.7475,"start":16,"end":229}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UL46-F1-predicted_aligned_error_v6.png","plddt_mean":91.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSME2","jax_strain_url":"https://www.jax.org/strain/search?query=PSME2"},"sequence":{"accession":"Q9UL46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UL46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UL46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UL46"}},"corpus_meta":[{"pmid":"11689430","id":"PMC_11689430","title":"Immunoproteasome assembly 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528300","citation_count":798,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12859895","id":"PMC_12859895","title":"Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859895","citation_count":763,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein 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 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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":"17110338","id":"PMC_17110338","title":"Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17110338","citation_count":517,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with 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\"Tier 2 — clean double-KO mice with multiple orthogonal functional readouts, replicated across antigen substrates\",\n      \"pmids\": [\"11689430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PA28β alone (without PA28α) can enhance MHC class I antigen presentation of the MCMV pp89 epitope, but this effect is mediated through increased levels of PA28αβ heterocomplexes (driven by stabilization of PA28α), rather than PA28β acting independently.\",\n      \"method\": \"Stable transfection of PA28β alone or PA28αβ into mouse B8 cells, Northern blot, immunoprecipitation, antigen presentation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — immunoprecipitation plus functional antigen presentation assay in single study\",\n      \"pmids\": [\"10781831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The mouse genome contains a second expressed PA28β locus (PMSE2b) that is a retrotransposon inserted into a LINE1 element and driven by a LINE1 F-type monomer promoter, producing a constitutively expressed PA28β protein identical to that from the IFN-γ-inducible PMSE2 gene.\",\n      \"method\": \"Genomic Southern blot, luciferase promoter assays, cDNA cloning and sequencing\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter assay plus genomic characterization in single study\",\n      \"pmids\": [\"10222192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"N-α-acetyltransferase 10 protein (Naa10p) physically associates with PA28β (PSME2) and, in a PA28β-dependent manner, also interacts with PA28α. Naa10p negatively regulates PA28-dependent chymotrypsin-like proteasome activity (28S proteasome) in cancer cells and in a cell-free reconstituted system with purified proteins; this suppression is independent of Naa10p's acetyltransferase activity.\",\n      \"method\": \"Co-immunoprecipitation, cell-free reconstitution with purified proteins, proteasome activity assay, acetyltransferase-dead mutant\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified proteins plus mutagenesis, supported by co-IP in cells\",\n      \"pmids\": [\"23624078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of PA28α and PA28β protected diabetic mice from renal and retinal microvascular injury; the PA28-mediated expression of Osteopontin (OPN) and MCP-1 under high-glucose conditions in mesangial cells and retinal pericytes was suppressed by peptides that inhibit PA28 binding to the 20S proteasome, placing PA28 upstream of OPN/MCP-1-driven microvascular injury.\",\n      \"method\": \"PA28α/PA28β double-knockout mice, STZ-induced diabetes model, cultured mesangial cells and retinal pericytes, peptide inhibition of PA28–20S binding, gene expression analysis\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with peptide inhibitor mechanistic dissection, single study\",\n      \"pmids\": [\"27830089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of PA28β (PSME2) in gastric cancer cells enhanced invasion, while overexpression inhibited it; proteomics comparison identified CLIC1 as significantly upregulated upon PA28β knockdown, and siRNA-mediated CLIC1 knockdown reversed the invasion enhancement, placing PA28β upstream of CLIC1 in regulating cell invasion.\",\n      \"method\": \"siRNA knockdown, overexpression, 2D proteomics, RNA interference epistasis, Transwell invasion assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by rescue experiment with CLIC1 siRNA, supported by proteomics\",\n      \"pmids\": [\"22173998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of PSME2 in clear cell renal cell carcinoma cell lines (CAKI-1 and 786-O) reduced invasion and enhanced autophagy, linked to BNIP3-mediated autophagy, placing PSME2 as an inhibitor of BNIP3-dependent autophagy that promotes invasion.\",\n      \"method\": \"siRNA knockdown, Western blot, immunofluorescence, Transwell invasion assay, transmission electron microscopy for autophagy\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined phenotype and pathway placement, single lab\",\n      \"pmids\": [\"34779489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of PSME2 in esophageal squamous cell carcinoma cells reduced proliferation, migration, and invasion, and induced autophagy through the IL-6/STAT3 signaling pathway; STAT3 inhibitor WP1066 or autophagy inhibitor chloroquine combined with PSME2 knockdown suppressed tumor growth in vivo, placing PSME2 upstream of IL-6/STAT3-dependent autophagy regulation.\",\n      \"method\": \"siRNA knockdown, STAT3 inhibitor (WP1066), autophagy inhibitor (chloroquine), in vivo subcutaneous tumor model in nude mice, in vitro proliferation/migration/invasion assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis plus in vivo model, single lab\",\n      \"pmids\": [\"40404117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colonic cells, PSME2 knockdown restored LPS-suppressed claudin-1 (tight junction protein) expression, reduced inflammatory cytokines (IL-6, IL-10, TNF-α), and enhanced autophagy (increased LC3-II/LC3-I, reduced p62). Chloroquine treatment reversed these protective effects, indicating that PSME2 disrupts intestinal barrier integrity and promotes inflammation through autophagy dysregulation.\",\n      \"method\": \"siRNA knockdown in colonic cells, LPS treatment, Western blot for claudin-1/LC3/p62, ELISA for cytokines, chloroquine rescue experiment\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined molecular readouts and pharmacological rescue, single study\",\n      \"pmids\": [\"41211066\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME2 (PA28β) forms a heteropolymeric complex with PA28α that binds and activates the 20S proteasome to enhance MHC class I antigen processing; Naa10p suppresses this PA28β-dependent 28S proteasome activity through direct binding; PSME2 additionally regulates cell invasion, autophagy (via BNIP3 and IL-6/STAT3 pathways), and intestinal barrier integrity through proteasome-dependent and possibly proteasome-independent mechanisms.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\nRETRIEVED PAPERS:\n1. PMID:11689430 — KEEP (PA28α/β double KO mice, directly about PSME2/PA28β)\n2. PMID:22173998 — KEEP (PA28β/PSME2 in gastric cancer, direct KD/OE experiments)\n3. PMID:38385075 — KEEP (PSME2 pan-cancer, osteosarcoma functional studies)\n4. PMID:34779489 — KEEP (PSME2 in ccRCC, BNIP3 autophagy)\n5. PMID:16901544 — KEEP (fish PA28β ortholog, immune function)\n6. PMID:10222192 — KEEP (PSME2 gene structure, retrotransposon locus)\n7. PMID:29020885 — KEEP (PA28β/PSME2 in ESCC)\n8. PMID:23624078 — KEEP (Naa10p interacts with PA28β/PSME2, proteasome activity)\n9. PMID:20140627 — KEEP (PA28β in gastric adenocarcinoma, functional assays)\n10. PMID:27830089 — KEEP (PA28α/β double KO in diabetic nephropathy/retinopathy)\n11. PMID:14597164 — KEEP (flounder PSME2 ortholog)\n12. PMID:10781831 — KEEP (PA28β overexpression, MHC class I presentation)\n13. PMID:15373739 — KEEP (porcine PSME1/PSME2 characterization)\n14. PMID:36583022 — EXCLUDE (biomarker/expression study, no direct mechanism)\n15. PMID:23916540 — KEEP (rock bream PA28α/β ortholog characterization)\n16. PMID:37430323 — EXCLUDE (bioinformatics/expression only, no direct mechanistic experiment)\n17. PMID:40404117 — KEEP (PSME2 in ESCC, IL-6/STAT3/autophagy KD experiments)\n18. PMID:41035633 — EXCLUDE (biomarker/IHC/survival study)\n19. PMID:41211066 — KEEP (PSME2 in UC, autophagy/barrier function, KD experiments)\n\nGENE2PUBMED PAPERS:\n- PMID:8811196 — KEEP (review of 20S/26S proteasome including PA28 activator)\n- PMID:16189514 — EXCLUDE (general interactome map, PSME2 not specifically studied)\n- PMID:12167863 — EXCLUDE (APOBEC3G/CEM15, alias collision)\n- PMID:12477932 — EXCLUDE (cDNA library project, no PSME2-specific mechanism)\n- PMID:12808466 — EXCLUDE (APOBEC3G, alias collision)\n- PMID:18187620 — EXCLUDE (HIV host factors screen, not PSME2-specific)\n- PMID:12809610 — EXCLUDE (CEM15/APOBEC3G, alias collision)\n- PMID:26186194 — EXCLUDE (general interactome, not PSME2-specific)\n- PMID:26496610 — EXCLUDE (general interactome)\n- PMID:14564014 — EXCLUDE (APOBEC3G/Vif, alias collision)\n- PMID:21873635 — EXCLUDE (GO annotation methods)\n- PMID:14527406 — EXCLUDE (APOBEC3G, alias collision)\n- PMID:19056867 — EXCLUDE (urinary exosome proteomics, not PSME2-specific)\n- PMID:12750511 — EXCLUDE (APOBEC3G, alias collision)\n- PMID:17110338 — EXCLUDE (CFTR/Hsp90, not PSME2)\n- PMID:8125298 — EXCLUDE (oligo-capping method)\n- PMID:15489334 — EXCLUDE (MGC cDNA project)\n- PMID:35271311 — EXCLUDE (general cell organization atlas)\n- PMID:14614829 — EXCLUDE (APOBEC3G/Vif, alias collision)\n- PMID:11285280 — EXCLUDE (cyclin A/APC, not PSME2)\n- PMID:23503661 — EXCLUDE (PARKIN ubiquitylome, not PSME2-specific)\n- PMID:32296183 — EXCLUDE (general interactome)\n- PMID:29507755 — EXCLUDE (m6A methylation, not PSME2)\n- PMID:33961781 — EXCLUDE (BioPlex 3.0, general interactome)\n- PMID:22939629 — EXCLUDE (general protein complex census)\n- PMID:12859895 — EXCLUDE (APOBEC3G, alias collision)\n- PMID:14528300 — EXCLUDE (APOBEC3G, alias collision)\n- PMID:14528301 — EXCLUDE (APOBEC3G, alias collision)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PA28 (the heteropolymer of PA28α/PSME1 and PA28β/PSME2) was identified as a regulator of 20S proteasome activity, with the PA28 complex binding to both ends of the 20S proteasome and stimulating its multiple peptidase activities in an ATP-independent manner, distinct from the 19S regulatory complex.\",\n      \"method\": \"Biochemical reconstitution and review of in vitro proteasome activity assays\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro, foundational review summarizing replicated biochemical characterization\",\n      \"pmids\": [\"8811196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The mouse genome contains two chromosomal loci encoding PA28β (PSME2): one is the canonical IFNγ-inducible PMSE2 gene with an intron-exon structure, and the second (PMSE2b) is an expressed retrotransposon inserted into a LINE1 element and driven by a LINE1 F-type monomer promoter, yet encodes a protein indistinguishable from the canonical PSME2.\",\n      \"method\": \"Genomic Southern blot, cloning, sequencing, luciferase reporter assays for promoter activity\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Southern blot, cloning, luciferase assay) in a single study\",\n      \"pmids\": [\"10222192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of PA28β alone (without PA28α) improved MHC class I antigen presentation of the MCMV pp89 epitope, and this effect was attributed to increased levels of PA28α/β heterocomplexes rather than PA28β homomers acting independently; immunoprecipitation confirmed that PA28β stabilizes PA28αβ complex formation.\",\n      \"method\": \"Stable transfection of PA28β alone or PA28αβ, northern blot, immunoprecipitation, T-cell cytotoxicity assay for antigen presentation\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal immunoprecipitation and functional antigen presentation assay, single lab\",\n      \"pmids\": [\"10781831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In vivo genetic deletion of both PA28α and PA28β revealed that the PA28αβ heteropolymer is required for processing of specific antigens (e.g., melanoma antigen TRP2-derived peptide) but is dispensable for general antigen presentation; additionally, loss of both subunits reduced ATP-dependent proteolytic activity, implicating 'hybrid proteasomes' (20S capped by PA28 on one end and 19S on the other) in protein degradation.\",\n      \"method\": \"Double-knockout mouse generation (PA28α−/−/β−/−), proteasome activity assays, T-cell cytotoxicity assays, influenza infection model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo genetic loss-of-function with multiple functional readouts, widely cited foundational study\",\n      \"pmids\": [\"11689430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"N-α-acetyltransferase 10 protein (Naa10p) physically associates with PA28β (PSME2) and, in a PA28β-dependent manner, also interacts with PA28α; Naa10p negatively regulates PA28-dependent chymotrypsin-like 28S proteasome activity both in cancer cells and in a cell-free reconstituted system with purified proteins, independently of its acetyltransferase activity.\",\n      \"method\": \"Co-immunoprecipitation, cell-free reconstitution with purified proteins, chymotrypsin-like proteasome activity assay, acetyltransferase-dead mutant analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cell-free reconstitution with purified proteins plus Co-IP and enzymatic assay; acetyltransferase-dead mutant provides mechanistic dissection\",\n      \"pmids\": [\"23624078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of PA28β (PSME2) enhanced invasion of gastric cancer cells, while overexpression inhibited it; proteomics revealed that PA28β suppresses invasion at least in part by downregulating chloride intracellular channel 1 (CLIC1), as siRNA-mediated knockdown of CLIC1 rescued the increased invasiveness caused by PA28β knockdown.\",\n      \"method\": \"siRNA knockdown, overexpression, Transwell invasion assay, 2D-DIGE proteomics, RNA interference of CLIC1, immunohistochemistry of patient tissue\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment (CLIC1 KD reverting PA28β-KD phenotype) plus proteomics; single lab\",\n      \"pmids\": [\"22173998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of PA28α and PA28β protected diabetic mice from renal and retinal microvascular injury; in mesangial cells and retinal pericytes from PA28αβ double-knockout mice, high-glucose-induced expression of osteopontin (OPN) and MCP-1 was suppressed; peptides blocking PA28 binding to the 20S proteasome also suppressed OPN induction, indicating that PA28-mediated modulation of proteasome activity in perivascular cells drives diabetic microvascular injury.\",\n      \"method\": \"Double-knockout mouse model, STZ-induced diabetes, renal histology, cultured mesangial cells and retinal pericytes under high glucose, peptide inhibition of PA28–20S interaction, gene expression analysis\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO + in vitro cellular model + peptide inhibitor mechanistic probe; single lab\",\n      \"pmids\": [\"27830089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of PSME2 in clear cell renal cell carcinoma cells reduced their invasive capacity and simultaneously enhanced autophagy; mechanistically, PSME2 was shown to inhibit BNIP3-mediated autophagy, such that loss of PSME2 de-repressed BNIP3-dependent autophagic flux.\",\n      \"method\": \"siRNA knockdown, Transwell invasion assay, western blot, immunofluorescence, transmission electron microscopy of autophagosomes, CCK-8 assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal readouts (invasion, TEM, protein markers) placing PSME2 upstream of BNIP3-autophagy; single lab\",\n      \"pmids\": [\"34779489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of PSME2 in esophageal squamous cell carcinoma (ESCC) cells reduced proliferation, migration, and invasion, and induced autophagy-mediated cell death; mechanistically, PSME2 knockdown suppressed the IL-6/STAT3 signaling pathway, and combined inhibition of PSME2 with the STAT3 inhibitor WP1066 or the autophagy inhibitor chloroquine suppressed tumor growth in vivo, placing PSME2 upstream of IL-6/STAT3-dependent autophagy suppression.\",\n      \"method\": \"siRNA knockdown, STAT3 inhibitor (WP1066), autophagy inhibitor (chloroquine), in vitro proliferation/migration/invasion assays, in vivo subcutaneous nude mouse tumor model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via pharmacological inhibitors combined with genetic KD, in vivo validation; single lab\",\n      \"pmids\": [\"40404117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colonic cells, PSME2 knockdown restored claudin-1 expression suppressed by LPS, reduced pro-inflammatory cytokines (IL-6, TNF-α), and enhanced autophagy flux (increased LC3-II/LC3-I ratio, reduced p62, elevated LC3B puncta); chloroquine treatment reversed the barrier-protective effects of PSME2 silencing, demonstrating that PSME2 promotes intestinal inflammation and barrier disruption through autophagy dysregulation.\",\n      \"method\": \"siRNA knockdown in colonic cell lines, LPS treatment, western blot for tight junction proteins and autophagy markers, immunofluorescence, cytokine measurement, chloroquine rescue experiment; DSS-induced colitis mouse model\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with pharmacological rescue (CQ) providing mechanistic pathway placement; in vitro and in vivo; single lab\",\n      \"pmids\": [\"41211066\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME2 (PA28β) forms a heteropolymer with PA28α that binds the ends of the 20S proteasome to stimulate antigen processing in an ATP-independent manner, is required for processing of select MHC class I antigens (but not all) in vivo, and is negatively regulated by Naa10p through direct physical interaction; beyond its canonical proteasome-activator role, PSME2 suppresses cell invasion (via CLIC1 downregulation in gastric cancer), inhibits BNIP3-mediated autophagy in renal carcinoma, and modulates IL-6/STAT3-dependent autophagy in esophageal cancer, while PA28αβ-mediated proteasome activity in perivascular cells contributes to diabetic microvascular injury.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSME2 (PA28β) is a proteasome activator subunit that forms a heteropolymeric ring with PA28α (PSME1), capping the 20S proteasome to stimulate peptide hydrolysis and shape MHC class I antigen processing. The PA28αβ heterocomplex enhances chymotrypsin-like proteasome activity and is required for processing of specific antigenic peptides—such as the melanoma antigen TRP2-derived epitope—but is dispensable for general antigen presentation; PA28β overexpression alone promotes antigen presentation by stabilizing PA28α and thereby increasing PA28αβ heterocomplex levels [PMID:11689430, PMID:10781831]. Naa10p directly binds PA28β and suppresses PA28-dependent 28S proteasome activity independently of its acetyltransferase function, establishing PA28β as a regulated node in proteasome activation [PMID:23624078]. Beyond classical proteasome-mediated antigen processing, PSME2 modulates cell invasion (upstream of CLIC1), autophagy (through BNIP3- and IL-6/STAT3-dependent pathways), and intestinal epithelial barrier integrity, with knockdown consistently enhancing autophagy and reducing invasion across multiple cancer and epithelial cell models [PMID:22173998, PMID:34779489, PMID:40404117, PMID:41211066].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolving how PSME2 expression is regulated revealed that the mouse genome harbors a second PA28β locus driven by a LINE1 retrotransposon promoter, providing constitutive expression independent of IFN-γ induction.\",\n      \"evidence\": \"Genomic Southern blot, cDNA cloning, and luciferase promoter assays in mouse cells\",\n      \"pmids\": [\"10222192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of constitutive versus IFN-γ-inducible PA28β expression not established\",\n        \"Whether a comparable locus exists in humans is unknown\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Addressing whether PA28β can act independently of PA28α showed that PA28β overexpression enhances MHC class I antigen presentation, but this occurs by stabilizing PA28α protein and increasing PA28αβ heterocomplex levels rather than through a solo function.\",\n      \"evidence\": \"Stable transfection of PA28β alone or PA28αβ in mouse B8 cells with immunoprecipitation and antigen presentation assays\",\n      \"pmids\": [\"10781831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PA28β has any proteasome-independent functions was not tested\",\n        \"Mechanism of PA28α stabilization by PA28β not defined\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the in vivo requirement for PA28αβ, double-knockout mice demonstrated that the PA28αβ complex contributes to hybrid proteasome activity and is essential for processing specific antigenic peptides (e.g., TRP2) but dispensable for overall antigen presentation and viral clearance.\",\n      \"evidence\": \"PA28α/PA28β double-knockout mice with proteasome activity assays, antigen presentation assays, and viral infection models\",\n      \"pmids\": [\"11689430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of PA28α versus PA28β to hybrid proteasome function not separated\",\n        \"Full spectrum of PA28-dependent substrates not catalogued\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending PA28β function beyond antigen processing, epistasis experiments showed that PSME2 suppresses gastric cancer cell invasion by keeping CLIC1 levels low, revealing a proteasome-linked role in cell migration control.\",\n      \"evidence\": \"siRNA knockdown and overexpression of PSME2 in gastric cancer cells, 2D proteomics, CLIC1 rescue with siRNA, Transwell invasion assay\",\n      \"pmids\": [\"22173998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CLIC1 is a direct proteasomal substrate of the PA28-20S complex is unknown\",\n        \"Not replicated in non-gastric cancer models at the time\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying a direct negative regulator of PA28-dependent proteasome activation, Naa10p was shown to bind PA28β physically and suppress 28S proteasome chymotrypsin-like activity through a mechanism independent of its acetyltransferase catalytic function.\",\n      \"evidence\": \"Co-immunoprecipitation in cancer cells, cell-free reconstitution with purified proteins, acetyltransferase-dead mutant analysis\",\n      \"pmids\": [\"23624078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of Naa10p–PA28β interaction not determined\",\n        \"Physiological contexts where Naa10p regulates PA28 activity in vivo not established\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking PA28αβ to non-immune pathology, genetic deletion of PA28α/β protected diabetic mice from renal and retinal microvascular injury, and peptide-based inhibition of PA28–20S binding suppressed Osteopontin and MCP-1 expression under high-glucose conditions.\",\n      \"evidence\": \"PA28α/PA28β double-knockout mice in STZ-induced diabetes model, cultured mesangial cells and retinal pericytes with peptide inhibitor\",\n      \"pmids\": [\"27830089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether OPN/MCP-1 are direct substrates or transcriptionally regulated downstream is unclear\",\n        \"Relative contribution of PA28α versus PA28β not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting PSME2 to autophagy regulation, PSME2 knockdown in renal carcinoma cells enhanced BNIP3-mediated autophagy and reduced invasion, establishing PSME2 as an inhibitor of autophagy that promotes invasive behavior.\",\n      \"evidence\": \"siRNA knockdown in CAKI-1 and 786-O cells, Western blot, immunofluorescence, TEM for autophagy, Transwell invasion assay\",\n      \"pmids\": [\"34779489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PSME2 regulates BNIP3 at transcriptional or post-translational level is undefined\",\n        \"Proteasome dependence of the autophagy phenotype not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalizing the autophagy link and defining a signaling axis, PSME2 was placed upstream of IL-6/STAT3 signaling in esophageal cancer and shown to regulate intestinal barrier integrity through autophagy; pharmacological epistasis with STAT3 and autophagy inhibitors confirmed these pathway placements in vivo and in vitro.\",\n      \"evidence\": \"siRNA knockdown combined with STAT3 inhibitor (WP1066) and chloroquine in esophageal cancer cells and nude mouse xenografts; siRNA in colonic cells with LPS stimulation and chloroquine rescue\",\n      \"pmids\": [\"40404117\", \"41211066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct proteasomal substrate(s) mediating autophagy and barrier phenotypes not identified\",\n        \"Whether IL-6/STAT3 and BNIP3 pathways converge or represent tissue-specific mechanisms is unknown\",\n        \"No structural or biochemical basis for proteasome-independent PSME2 functions\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown which direct proteasomal substrates are responsible for PSME2's effects on autophagy, invasion, and barrier integrity, and whether any of these phenotypes are independent of PA28αβ-20S proteasome activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No substrate-level resolution for non-immune phenotypes\",\n        \"No structural model of Naa10p–PA28β interaction or PA28-regulated substrate selection\",\n        \"Proteasome-independent functions of PA28β not formally tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [\n      \"PA28αβ (11S regulator)\",\n      \"PA28αβ-20S hybrid proteasome\"\n    ],\n    \"partners\": [\n      \"PSME1\",\n      \"NAA10\",\n      \"CLIC1\",\n      \"BNIP3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSME2 (PA28β) is an obligate subunit of the PA28αβ heteroheptameric proteasome activator that caps the 20S proteasome and stimulates peptidase activity in an ATP-independent manner, thereby shaping MHC class I antigen processing. PA28β stabilizes the PA28αβ complex and is required for generation of select immunodominant epitopes but is dispensable for general antigen presentation, as demonstrated by double-knockout mice lacking both PA28α and PA28β [PMID:11689430, PMID:10781831]. The PA28-activating function is negatively regulated by Naa10p through direct physical interaction with PA28β, independent of Naa10p acetyltransferase activity [PMID:23624078]. Beyond canonical proteasome activation, PSME2 suppresses autophagy through BNIP3- and IL-6/STAT3-dependent pathways and modulates cell invasion and inflammatory barrier function in diverse epithelial contexts [PMID:34779489, PMID:40404117, PMID:41211066].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the molecular identity of PA28β as a subunit of an ATP-independent 20S proteasome activator resolved how cells enhance proteasomal peptide cleavage without 19S-dependent energy expenditure.\",\n      \"evidence\": \"Biochemical reconstitution and review of in vitro proteasome activity assays\",\n      \"pmids\": [\"8811196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo requirement for antigen processing not yet tested\",\n        \"Relative contribution of PA28β versus PA28α to complex formation unknown\",\n        \"No structural model of PA28αβ–20S interaction at this point\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that overexpressed PA28β alone enhances MHC class I antigen presentation by stabilizing PA28αβ heterocomplexes, rather than forming functional homomers, established PA28β as a limiting factor for immunoproteasome assembly.\",\n      \"evidence\": \"Stable transfection, immunoprecipitation, and T-cell cytotoxicity assays for antigen presentation\",\n      \"pmids\": [\"10781831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PA28β homomers have any residual activity remained unresolved\",\n        \"Single-lab finding not independently replicated at the time\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic ablation of both PA28α and PA28β in mice revealed that the PA28αβ complex is required for processing select antigens (e.g., TRP2) but dispensable for general antigen presentation, and implicated hybrid 19S–20S–PA28 proteasomes in protein degradation.\",\n      \"evidence\": \"PA28α/β double-knockout mice with proteasome activity assays, T-cell responses, and influenza infection challenge\",\n      \"pmids\": [\"11689430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific epitope-processing rules dictating PA28 dependence were not defined\",\n        \"Hybrid proteasome stoichiometry and substrate specificity not structurally resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that PA28β suppresses gastric cancer cell invasion via downregulation of CLIC1 extended PSME2 function beyond proteasome-mediated antigen processing to a tumor-suppressive role in epithelial cell migration.\",\n      \"evidence\": \"siRNA knockdown and overexpression with Transwell invasion assays, 2D-DIGE proteomics, CLIC1 epistasis rescue\",\n      \"pmids\": [\"22173998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CLIC1 downregulation proceeds via proteasomal degradation or transcriptional regulation was not determined\",\n        \"Single-lab observation in gastric cancer cells\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of Naa10p as a direct PA28β-binding negative regulator of PA28-dependent proteasome activity, acting independently of its acetyltransferase function, established the first non-proteasomal protein modulator of PA28 function.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-free reconstitution with purified proteins, acetyltransferase-dead mutant analysis\",\n      \"pmids\": [\"23624078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding site on PA28β and structural basis of inhibition not mapped\",\n        \"Physiological context (which tissues or conditions engage Naa10p–PA28β regulation) undefined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic deletion of PA28αβ protected diabetic mice from renal and retinal microvascular injury by suppressing high-glucose-induced osteopontin and MCP-1, linking PA28-dependent proteasome activity to metabolic disease pathogenesis in perivascular cells.\",\n      \"evidence\": \"PA28αβ double-knockout mice with STZ-induced diabetes, mesangial cell and pericyte cultures, peptide inhibitor of PA28–20S interaction\",\n      \"pmids\": [\"27830089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific PA28-dependent proteasomal substrates driving OPN/MCP-1 induction not identified\",\n        \"Whether PA28α or PA28β individually contributes was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that PSME2 inhibits BNIP3-mediated autophagy in renal carcinoma cells linked its proteasome-activator function to autophagic flux regulation and broadened its role to autophagy suppression in cancer biology.\",\n      \"evidence\": \"siRNA knockdown with Transwell invasion, TEM of autophagosomes, western blot for autophagy markers\",\n      \"pmids\": [\"34779489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PSME2 promotes BNIP3 proteasomal degradation or acts indirectly was not resolved\",\n        \"Single-cell-line study without in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Convergent studies in esophageal cancer and colonic inflammation established that PSME2 suppresses autophagy through IL-6/STAT3 signaling and promotes inflammatory barrier disruption, consolidating a proteasome-activator-independent role for PSME2 in autophagy regulation across tissues.\",\n      \"evidence\": \"siRNA knockdown combined with STAT3 inhibitor and chloroquine rescue, in vivo nude mouse and DSS-colitis models\",\n      \"pmids\": [\"40404117\", \"41211066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether autophagy suppression requires PA28αβ proteasome-activating function or is mediated by a distinct PSME2 mechanism is unknown\",\n        \"Direct proteasomal substrates linking PSME2 to IL-6/STAT3 pathway activation not identified\",\n        \"Findings from single laboratories, not yet independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The relationship between PSME2's canonical proteasome-activation function and its emerging autophagy-suppressive and anti-invasive roles remains mechanistically unresolved — whether these non-canonical functions require PA28αβ complex formation and proteasomal substrate turnover, or represent proteasome-independent activities of PSME2, is the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No separation-of-function mutant distinguishing proteasome-activator from autophagy-regulatory roles\",\n        \"No structural basis for Naa10p–PA28β or BNIP3–PSME2 interactions\",\n        \"Tissue-specific versus universal nature of PSME2 autophagy regulation untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"complexes\": [\n      \"PA28αβ (11S regulator)\",\n      \"Hybrid 19S-20S-PA28 proteasome\"\n    ],\n    \"partners\": [\n      \"PSME1\",\n      \"NAA10\",\n      \"BNIP3\",\n      \"CLIC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}