{"gene":"PSME1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"Overexpression of PA28alpha (PSME1) at levels similar to IFN-gamma induction markedly enhanced MHC class I-restricted presentation of murine cytomegalovirus pp89 epitope and influenza nucleoprotein in mouse fibroblasts, demonstrating an in vivo role for PA28alpha in antigen processing.","method":"Stable transfection of murine fibroblasts with human or murine PA28alpha gene, followed by cytotoxic T cell recognition assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function in intact cells with specific functional readout, replicated across two antigen systems","pmids":["8610016"],"is_preprint":false},{"year":1997,"finding":"Crystal structure of human REGalpha (PA28alpha/PSME1) at 2.8 Å resolution revealed a heptameric barrel-shaped assembly with a central channel (20 Å opening at one end, 30 Å at the proteasome-binding surface), suggesting that REG binding causes conformational changes that open a pore in proteasome alpha-subunits to allow substrate/product passage.","method":"X-ray crystallography of human recombinant REGalpha heptamer","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with mechanistic interpretation validated by known biochemistry","pmids":["9403698"],"is_preprint":false},{"year":1999,"finding":"The human PSME1 gene (encoding PA28alpha) comprises 11 exons and maps to chromosome 14q11.2, near PSME2 (PA28beta) and ISGF3G, consistent with gene duplication during vertebrate evolution; both genes are induced by IFN-gamma.","method":"Genomic sequencing and chromosomal mapping of PSME1 and PSME2","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic characterization, single lab","pmids":["10199920"],"is_preprint":false},{"year":1999,"finding":"PA28 (including PA28alpha/PSME1) concentrates at the centrosome under basal conditions along with the 20S proteasome, PA700, ubiquitin, Hsp70, and Hsp90; this centrosomal complex enlarges in response to proteasome inhibition or accumulation of misfolded proteins, indicating that the centrosome acts as a scaffold for the proteasome-activator machinery during protein quality control.","method":"Immunofluorescence colocalization with gamma-tubulin, density gradient fractionation of purified centrosomes, and proteasome inhibitor challenge in HEK293 and HeLa cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — orthogonal localization methods (immunofluorescence + fractionation) with functional perturbation, replicated across cell lines","pmids":["10225950"],"is_preprint":false},{"year":2000,"finding":"PA28alpha/beta (including PSME1) can enhance MHC class I-restricted antigen presentation independently of changes in 20S proteasome subunit composition or immunoproteasome assembly, as shown by enhanced pp89 epitope presentation in fibroblast transfectants overexpressing both PA28 subunits with unchanged proteasome subunit composition.","method":"Stable co-transfection of PA28alpha and PA28beta in fibroblasts, proteasome subunit composition analysis, and cytotoxic T cell recognition assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with multiple controls ruling out alternative explanation, clear functional readout","pmids":["11169410"],"is_preprint":false},{"year":2001,"finding":"PA28alpha/beta double-knockout mice retain immunoproteasome assembly after IFN-gamma treatment and show normal antigen presentation for most antigens but almost completely lose the ability to process the melanoma antigen TRP2-derived peptide, demonstrating that PA28alpha/beta is essential for processing of certain specific antigens but not required globally for antigen presentation.","method":"Generation of PA28alpha/PA28beta double-knockout mice, IFN-gamma stimulation, ovalbumin and influenza antigen processing assays, TRP2 peptide presentation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with specific immunological phenotypes, orthogonal antigen systems tested, in vivo model","pmids":["11689430"],"is_preprint":false},{"year":2001,"finding":"During dendritic cell maturation, PA28alpha/beta coprecipitates with 13S/16S proteasome precursor complexes and associates equally with mature constitutive and immunoproteasomes, suggesting PA28alpha (PSME1) participates in proteasome assembly intermediates but does not preferentially drive immunoproteasome assembly in DC.","method":"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor complexes in maturing dendritic cells, quantitative mRNA and protein analysis","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP experiment with moderate mechanistic follow-up in one cell type","pmids":["11745344"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of PA28alpha and PA28beta protected diabetic mice from renal and retinal microvascular injury; PA28-mediated proteasome activity in mesangial cells and retinal pericytes under high glucose promotes expression of OPN and MCP-1; this was suppressed by peptides blocking PA28 binding to the 20S proteasome, demonstrating that PA28alpha (PSME1) drives diabetic microvascular injury through modulation of proteasome activity.","method":"PA28alpha/PA28beta double-knockout mice in STZ-induced diabetes model, cultured mesangial cells and retinal pericytes under high glucose, PA28-blocking peptides, OPN/MCP-1 expression analysis","journal":"International journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with specific pathway inhibition by blocking peptides, moderate mechanistic depth","pmids":["27830089"],"is_preprint":false},{"year":2019,"finding":"PA28alpha/beta (PSME1/PSME2) promotes breast cancer cell migration, invasion, and metastasis by downregulating CDK15 protein; knockdown of PA28alpha/beta or immunoproteasome subunit beta5i upregulates CDK15, and loss of CDK15 is important for tumor invasion, placing PSME1 upstream of CDK15 in a proteasome-dependent invasion pathway.","method":"siRNA knockdown of PA28alpha/beta and beta5i in breast cancer cells, migration/invasion assays, western blot for CDK15 protein levels","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with clear cellular phenotype and pathway placement, single lab","pmids":["31824858"],"is_preprint":false},{"year":2020,"finding":"PA28alpha (PSME1) is upregulated in multiple myeloma cells and is required for myeloma cell growth and proliferation; downregulation of PA28alpha reduces both proteasomal load and activity, shifting protein homeostasis away from proteasome dependence and causing resistance to proteasome inhibitors.","method":"shRNA/siRNA knockdown of PA28alpha in MM cell lines, cell proliferation assays, proteasome activity assays, proteasome inhibitor sensitivity assays","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with proteasome activity measurement and drug resistance phenotype, single lab","pmids":["33318477"],"is_preprint":false},{"year":2021,"finding":"Overexpression of PA28alpha (PSME1) in female mice enhances hippocampal ability to prevent protein aggregation throughout aging and improves cognitive function (memory in young, exploratory behavior in old mice), while paradoxically lowering PA28-dependent proteasome capacity in heart and hippocampus, suggesting that PA28alpha's anti-aggregation effect is partially independent of its role in boosting proteasome peptidase activity.","method":"PA28alpha transgenic overexpression in C57BL/6N×BALB/c mice, behavioral testing (Morris water maze, open field), protein aggregation assays on hippocampal extracts, proteasome activity assays across ages","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain-of-function with orthogonal behavioral and biochemical readouts, single lab","pmids":["33720528"],"is_preprint":false},{"year":2021,"finding":"PSME1/2 recombinant protein inhibits osteogenesis and promotes osteoclast formation in vitro, and PSME1/2 suppresses beta-catenin protein levels to limit Wnt/beta-catenin signaling; the proteasome inhibitor carfilzomib inhibits PSME1/2 proteasome activities, increases beta-catenin levels and promotes its nuclear translocation, thereby activating Wnt signaling and promoting osteogenesis in vitro and in an OVX mouse model.","method":"Recombinant PSME1/2 protein treatment of osteoblast/osteoclast cultures, siRNA knockdown, western blot for beta-catenin, carfilzomib treatment, OVX mouse model with micro-CT","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro reconstitution with recombinant protein plus in vivo validation, multiple readouts, single lab","pmids":["34838695"],"is_preprint":false},{"year":2024,"finding":"CCDC92 promotes degradation of ABCA1 by regulating PA28alpha (PSME1)-mediated proteasome activity, thereby reducing cholesterol efflux and causing lipid accumulation in podocytes; this defines a CCDC92/PA28alpha/ABCA1/cholesterol efflux axis contributing to diabetic kidney disease.","method":"Podocyte-specific Ccdc92 knockout mice, co-immunoprecipitation, cholesterol efflux assays, ABCA1 protein stability assays, western blot in high-glucose-treated podocytes","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with co-IP and functional cholesterol efflux assay, single lab","pmids":["38228909"],"is_preprint":false},{"year":2023,"finding":"PSME1 interacts directly with HBV core protein (HBc) and inhibits its degradation by the 26S proteasome, thereby stabilizing HBc and promoting HBV replication; PSME1 knockdown decreases HBc protein levels and inhibits HBV transcription.","method":"APEX2-based proximity labeling to identify HBc-interacting proteins, co-immunoprecipitation, PSME1 siRNA knockdown, HBc protein stability assays, HBV transcription assays in HBV infection system","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling plus Co-IP plus functional knockdown with mechanistic readout, single lab","pmids":["39281837"],"is_preprint":false}],"current_model":"PSME1 (PA28alpha) forms a heptameric ring that binds the ends of the 20S proteasome barrel (as revealed by crystal structure), activates its peptidase activity, and functions as an IFN-gamma-inducible regulator of antigen processing for MHC class I presentation; it also stabilizes substrates such as HBV core protein against 26S proteasome-mediated degradation, suppresses Wnt/beta-catenin signaling by promoting beta-catenin degradation, drives invasion in cancer cells by degrading CDK15, localizes constitutively to the centrosome as part of the protein quality-control machinery, and regulates proteasome load to govern sensitivity to proteasome inhibitors in multiple myeloma."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that PA28α has an in vivo function in antigen processing resolved whether this proteasome activator operates only in vitro, showing that physiological-level overexpression directly enhances MHC class I–restricted epitope presentation.","evidence":"Stable transfection of PA28α in murine fibroblasts with CTL recognition assays for two viral antigens","pmids":["8610016"],"confidence":"High","gaps":["Mechanism by which PA28α alters the peptide repertoire was unknown","Relative contribution of PA28α versus PA28β was not separated","Whether PA28α acts on all antigens or only a subset was untested"]},{"year":1997,"claim":"Solving the crystal structure of the PA28α heptamer answered how the activator physically engages the proteasome, revealing a barrel that opens a gated pore in the 20S α-ring to allow substrate/product transit.","evidence":"2.8 Å X-ray crystallography of recombinant human PA28α","pmids":["9403698"],"confidence":"High","gaps":["Structure of the PA28α–20S complex itself was not determined","Whether the heteromeric PA28α/β ring adopts the same architecture was unresolved","Conformational dynamics during gating remained unknown"]},{"year":1999,"claim":"Localizing PA28α/β to the centrosome together with the 20S proteasome and chaperones revealed a constitutive proteasome quality-control platform at this organelle, expanding PA28α's role beyond antigen processing.","evidence":"Immunofluorescence colocalization with γ-tubulin, density-gradient fractionation of purified centrosomes, and proteasome inhibitor challenge in HEK293 and HeLa cells","pmids":["10225950"],"confidence":"High","gaps":["The substrates degraded at the centrosome by PA28-activated proteasomes were not identified","Whether centrosomal localization is essential for PA28α's antigen-processing role was unclear"]},{"year":2000,"claim":"Demonstrating that PA28α/β enhances antigen presentation without altering proteasome subunit composition showed that the activator acts directly on 20S peptidase activity rather than by promoting immunoproteasome assembly.","evidence":"Co-transfection of PA28α/β in fibroblasts with proteasome subunit composition analysis and CTL assays","pmids":["11169410"],"confidence":"High","gaps":["The precise cleavage products altered by PA28 binding were not characterized","Whether PA28 changes cleavage site preference or only product release rate was unresolved"]},{"year":2001,"claim":"PA28α/β double-knockout mice showed that the activator is dispensable for most antigen presentation but essential for processing specific epitopes (e.g., TRP2), defining PA28 as a substrate-selective processing factor rather than a global antigen-processing requirement.","evidence":"Genetic double-KO mice with IFN-γ stimulation and antigen-specific CTL assays for multiple antigens","pmids":["11689430"],"confidence":"High","gaps":["Rules governing which epitopes require PA28 were not defined","Compensatory roles of PA28γ in vivo were not assessed","Whether PA28 dependence maps to primary sequence or proteasome cleavage kinetics was unknown"]},{"year":2016,"claim":"Finding that PA28α/β deletion protects against diabetic microvascular injury extended PSME1's physiological relevance to chronic metabolic disease, linking its proteasome-activating function to inflammatory mediator expression under high glucose.","evidence":"PA28α/β double-KO mice in STZ-induced diabetes, mesangial and retinal pericyte cultures, PA28-blocking peptides, OPN/MCP-1 readouts","pmids":["27830089"],"confidence":"Medium","gaps":["The specific proteasome substrates mediating OPN/MCP-1 upregulation were not identified","Whether PA28α or PA28β is the rate-limiting subunit in this context was not determined","Blocking peptide specificity in vivo was not fully validated"]},{"year":2019,"claim":"Identification of CDK15 as a target degraded via PA28α/β-activated immunoproteasome placed PSME1 in a pro-invasive axis in breast cancer, establishing a proteasome-dependent mechanism for metastasis promotion.","evidence":"siRNA knockdown of PA28α/β and β5i in breast cancer cells with migration/invasion assays and CDK15 protein level measurement","pmids":["31824858"],"confidence":"Medium","gaps":["Direct ubiquitination or proteasomal degradation of CDK15 was not reconstituted","In vivo metastasis data were limited","Whether CDK15 degradation is immunoproteasome-specific was not conclusively shown"]},{"year":2020,"claim":"Showing that PA28α knockdown reduces proteasome load and confers resistance to proteasome inhibitors in myeloma revealed PSME1 as a determinant of proteasome dependence in cancer, with therapeutic implications.","evidence":"shRNA/siRNA knockdown in MM cell lines with proteasome activity and bortezomib/carfilzomib sensitivity assays","pmids":["33318477"],"confidence":"Medium","gaps":["The mechanism linking reduced PA28α to decreased proteasome load was not delineated","Clinical correlation with patient drug response was not established","Whether PA28α overexpression is sufficient to resensitize resistant cells was not tested"]},{"year":2021,"claim":"Two studies in 2021 expanded PSME1's non-immune roles: PA28α overexpression in vivo reduced hippocampal protein aggregation and improved cognition independently of boosted proteasome peptidase activity, while recombinant PSME1/2 suppressed β-catenin to inhibit Wnt signaling and osteogenesis, establishing PA28α as a modulator of proteostasis and developmental signaling beyond antigen processing.","evidence":"PA28α transgenic mice with behavioral testing and aggregation assays; recombinant PSME1/2 in osteoblast/osteoclast cultures with β-catenin western blot and OVX mouse model","pmids":["33720528","34838695"],"confidence":"Medium","gaps":["The anti-aggregation mechanism independent of proteasome activation was not identified","Whether β-catenin is a direct proteasomal substrate of PA28-activated proteasomes was not shown","Sex-specific effects (female-only cognitive benefit) were unexplained mechanistically"]},{"year":2023,"claim":"Discovery that PSME1 directly binds HBV core protein and shields it from 26S proteasome degradation revealed a virus-co-opted stabilization function, demonstrating that PA28α can also inhibit specific substrate degradation rather than only promote it.","evidence":"APEX2 proximity labeling, co-IP, siRNA knockdown with HBc stability and HBV transcription assays","pmids":["39281837"],"confidence":"Medium","gaps":["Structural basis for PA28α–HBc interaction was not determined","Whether stabilization requires the assembled heptamer or monomeric PA28α was not tested","Relevance to HBV pathogenesis in vivo was not demonstrated"]},{"year":2024,"claim":"Identification of a CCDC92–PA28α–ABCA1 axis in podocytes showed that upstream regulators can channel PSME1 activity toward degradation of specific membrane transporters, broadening the list of physiologically relevant PA28α substrates.","evidence":"Podocyte-specific Ccdc92 KO mice, co-IP, cholesterol efflux and ABCA1 stability assays under high glucose","pmids":["38228909"],"confidence":"Medium","gaps":["Whether PA28α activates 20S proteasomes or an alternative pathway for ABCA1 degradation was not distinguished","Direct ubiquitination status of ABCA1 in this axis was not characterized"]},{"year":null,"claim":"Key open questions include the structural basis of heteromeric PA28α/β ring assembly on the 20S proteasome, the rules determining which substrates require PA28-activated versus 26S-mediated degradation, and the mechanism underlying PA28α's proteasome-activity-independent anti-aggregation function.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the PA28α/β–20S holocomplex","No systematic identification of PA28-dependent proteasomal substrates","Anti-aggregation mechanism independent of peptidase activation is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4,5,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,9,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,13]}],"complexes":["PA28 (11S REG)","PA28-20S hybrid proteasome"],"partners":["PSME2","PSMB8","CTNNB1","CDK15","CCDC92","ABCA1","HBC (HBV CORE PROTEIN)"],"other_free_text":[]},"mechanistic_narrative":"PSME1 (PA28α) is a subunit of the PA28 proteasome activator complex that forms a heptameric ring capping the 20S proteasome core particle, stimulating its peptidase activity and shaping the repertoire of peptides available for MHC class I antigen presentation and broader protein homeostasis. The crystal structure reveals a barrel-shaped heptamer whose binding opens a gated pore in the proteasome α-ring to permit substrate and product passage [PMID:9403698]; overexpression at IFN-γ–inducible levels enhances class I–restricted antigen presentation independently of immunoproteasome subunit exchange, while double-knockout mice lose processing of select antigens such as TRP2 [PMID:8610016, PMID:11169410, PMID:11689430]. Beyond antigen processing, PSME1-mediated proteasome activation degrades β-catenin to suppress Wnt signaling in bone cells [PMID:34838695], degrades CDK15 to promote breast cancer invasion [PMID:31824858], regulates proteasome load and sensitivity to proteasome inhibitors in multiple myeloma [PMID:33318477], and stabilizes HBV core protein against 26S proteasome degradation to facilitate viral replication [PMID:39281837]. PSME1 constitutively localizes to the centrosome together with the 20S proteasome and chaperones, where the complex expands upon proteasome inhibition or accumulation of misfolded proteins, implicating it in centrosome-based protein quality control [PMID:10225950]."},"prefetch_data":{"uniprot":{"accession":"Q06323","full_name":"Proteasome activator complex subunit 1","aliases":["11S regulator complex subunit alpha","REG-alpha","Activator of multicatalytic protease subunit 1","Interferon gamma up-regulated I-5111 protein","IGUP I-5111","Proteasome activator 28 subunit alpha","PA28a","PA28alpha"],"length_aa":249,"mass_kda":28.7,"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/Q06323/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSME1","classification":"Not Classified","n_dependent_lines":125,"n_total_lines":1208,"dependency_fraction":0.10347682119205298},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000092010","cell_line_id":"CID000135","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSME2","stoichiometry":10.0},{"gene":"PSMA1","stoichiometry":4.0},{"gene":"PSMA4","stoichiometry":4.0},{"gene":"PSMB1","stoichiometry":4.0},{"gene":"PSMB7","stoichiometry":4.0},{"gene":"PSMA5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000135","total_profiled":1310},"omim":[{"mim_id":"617858","title":"PROTEASOME INHIBITOR SUBUNIT 1; PSMF1","url":"https://www.omim.org/entry/617858"},{"mim_id":"612024","title":"OTU DOMAIN-CONTAINING PROTEIN 7A; OTUD7A","url":"https://www.omim.org/entry/612024"},{"mim_id":"605129","title":"PROTEASOME ACTIVATOR SUBUNIT 3; PSME3","url":"https://www.omim.org/entry/605129"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSME1"},"hgnc":{"alias_symbol":["IFI5111","PA28alpha"],"prev_symbol":[]},"alphafold":{"accession":"Q06323","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06323","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06323-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06323-F1-predicted_aligned_error_v6.png","plddt_mean":90.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSME1","jax_strain_url":"https://www.jax.org/strain/search?query=PSME1"},"sequence":{"accession":"Q06323","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06323.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06323/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06323"}},"corpus_meta":[{"pmid":"8610016","id":"PMC_8610016","title":"A role for the proteasome regulator PA28alpha in antigen 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11169410","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11745344","id":"PMC_11745344","title":"Pronounced up-regulation of the PA28alpha/beta proteasome regulator but little increase in the steady-state content of immunoproteasome during dendritic cell maturation.","date":"2001","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11745344","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10199920","id":"PMC_10199920","title":"Organization of the genes encoding the human proteasome activators PA28alpha and beta.","date":"1999","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10199920","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31824858","id":"PMC_31824858","title":"PA28α/β Promote Breast Cancer Cell Invasion and Metastasis via Down-Regulation of CDK15.","date":"2019","source":"Frontiers in 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myeloma.","date":"2020","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/33318477","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38228909","id":"PMC_38228909","title":"CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38228909","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33720528","id":"PMC_33720528","title":"PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/33720528","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15373739","id":"PMC_15373739","title":"Sequence characterization, polymorphism and chromosomal localizations of the porcine PSME1 and PSME2 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predicting response and survival in neoadjuvant chemoimmunotherapy for resectable NSCLC.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41035633","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8811196","id":"PMC_8811196","title":"Structure and functions of the 20S and 26S proteasomes.","date":"1996","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8811196","citation_count":2108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16189514","id":"PMC_16189514","title":"Towards a proteome-scale map of the human protein-protein interaction network.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16189514","citation_count":2090,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12167863","id":"PMC_12167863","title":"Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif 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network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12808465","id":"PMC_12808465","title":"The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808465","citation_count":912,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23503661","id":"PMC_23503661","title":"Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23503661","citation_count":870,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528300","id":"PMC_14528300","title":"The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.","date":"2003","source":"Nature 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 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":"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":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, 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CB","url":"https://pubmed.ncbi.nlm.nih.gov/14614829","citation_count":405,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8763,"output_tokens":2737,"usd":0.033672},"stage2":{"model":"claude-opus-4-6","input_tokens":6108,"output_tokens":2649,"usd":0.145148},"total_usd":0.412459,"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":19910,"output_tokens":4227,"usd":0.061567},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7103,"output_tokens":3168,"usd":0.172072}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PA28alpha (PSME1) overexpression at IFN-gamma-inducible levels enhances MHC class I-restricted presentation of viral antigens (murine cytomegalovirus pp89 and influenza nucleoprotein) in mouse fibroblasts, demonstrating a direct in vivo role for PA28alpha in antigen processing through activation of the 20S proteasome's peptide-hydrolysing activity.\",\n      \"method\": \"Transfection of PA28alpha (human or murine) into fibroblast cell lines expressing viral antigen, followed by cytotoxic T cell recognition assays; in vitro peptide-hydrolysis activation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro functional assay plus in vivo CTL recognition, replicated across two viral antigens, foundational study with 294 citations\",\n      \"pmids\": [\"8610016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of human REGalpha (PA28alpha/PSME1) at 2.8 Å resolution reveals a heptameric barrel-shaped assembly with a central channel (20 Å opening at one end, 30 Å at the proteasome-binding surface), suggesting REG binding causes conformational changes that open a pore in proteasome alpha-subunits to allow substrate/product passage.\",\n      \"method\": \"X-ray crystallography at 2.8 Å resolution of recombinant human REGalpha\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional interpretation, 150 citations, single rigorous study\",\n      \"pmids\": [\"9403698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) heteromeric complex enhances MHC class I-restricted antigen presentation independently of changes in 20S proteasome subunit composition; fibroblasts overexpressing both PA28alpha and PA28beta show enhanced pp89 epitope presentation with unchanged 20S proteasome subunit makeup.\",\n      \"method\": \"Fibroblast transfection with PA28alpha and PA28beta; proteasome subunit composition analysis; CTL recognition assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (subunit composition analysis + functional CTL assay), mechanistically distinguishes PA28 activator role from immunoproteasome subunit exchange\",\n      \"pmids\": [\"11169410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) double-knockout mice retain general antigen presentation but completely lose the ability to process the melanoma antigen TRP2-derived peptide, demonstrating that PA28alpha/beta is essential for processing of specific antigens. Also, loss of PA28alpha/beta reduces ATP-dependent proteolytic activities, implicating hybrid proteasomes in protein degradation.\",\n      \"method\": \"Gene-targeted double-knockout mice (PA28alpha-/-/beta-/-); CTL assays; immunoproteasome induction with IFN-gamma; proteolytic activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double-KO genetic model with defined antigen-specific phenotypic readout and biochemical activity measurements, 132 citations\",\n      \"pmids\": [\"11689430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) co-precipitates with 13S/16S proteasome precursor complexes and associates with mature constitutive and immunoproteasomes to the same extent in dendritic cells, suggesting PA28alpha/beta interacts with proteasome precursors during assembly.\",\n      \"method\": \"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor and mature complexes in dendritic cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-precipitation experiment, single lab, but specific to proteasome precursor association\",\n      \"pmids\": [\"11745344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) promote breast cancer cell invasion and metastasis via down-regulation of CDK15; silencing PA28alpha/beta or immunoproteasome core subunit beta5i upregulates CDK15 protein, and loss of CDK15 is required for the pro-invasive effect.\",\n      \"method\": \"siRNA knockdown of PA28alpha/beta and beta5i in breast cancer cells; migration/invasion assays; CDK15 protein level measurement\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined cellular phenotype and pathway placement via CDK15, single lab, single method per component\",\n      \"pmids\": [\"31824858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2)-mediated alteration of proteasome activity in mesangial cells and retinal pericytes under high glucose conditions promotes expression of OPN and MCP-1, contributing to diabetic microvascular injury; peptides inhibiting PA28 binding to the 20S proteasome suppressed OPN expression.\",\n      \"method\": \"Genetic deletion of PA28alpha/PA28beta in STZ-induced diabetic mice; cultured mesangial cells and retinal pericytes from knockout mice grown in high glucose; peptide inhibition of PA28-20S binding\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout plus in vitro inhibitor experiments with specific molecular readouts (OPN, MCP-1), but single lab\",\n      \"pmids\": [\"27830089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSME1/PA28alpha inhibits β-catenin protein levels by promoting its proteasomal degradation; treatment with PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation, while carfilzomib inhibition of PSME1/2 proteasome activities increased β-catenin protein and activated Wnt/β-catenin signaling.\",\n      \"method\": \"Recombinant PSME1/2 protein treatment of osteoblast/osteoclast cultures; carfilzomib inhibition; β-catenin protein level and nuclear translocation measurement; OVX mouse model\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vitro recombinant protein assay plus in vivo model, but mechanism of β-catenin degradation via PA28 not fully reconstituted\",\n      \"pmids\": [\"34838695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PA28alpha (PSME1) is upregulated in multiple myeloma cells and regulates proteasome load and activity; its downregulation shifts protein homeostasis away from proteasome dependence and confers resistance to proteasome inhibitors.\",\n      \"method\": \"siRNA knockdown of PA28alpha in MM cell lines; proteasome activity assays; cell proliferation and proteasome inhibitor sensitivity assays\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with specific biochemical (proteasome activity) and cellular (drug resistance) readouts, single lab\",\n      \"pmids\": [\"33318477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSME1 interacts with HBV core protein (HBc) and inhibits its degradation by the 26S proteasome, thereby stabilizing HBc and promoting HBV replication; PSME1 knockdown reduces HBc protein levels and HBV transcription.\",\n      \"method\": \"APEX2 proximity labeling to identify HBc-interacting proteins; co-immunoprecipitation of PSME1 with HBc; PSME1 siRNA knockdown with measurement of HBc protein stability and HBV transcription\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proximity labeling plus co-IP plus KD with mechanistic follow-up, single lab, single paper\",\n      \"pmids\": [\"39281837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC92 promotes degradation of ABCA1 by regulating PA28alpha (PSME1)-mediated proteasome activity, leading to reduced cholesterol efflux and podocyte lipotoxicity in diabetic kidney disease.\",\n      \"method\": \"Podocyte-specific Ccdc92 deletion in diabetic mice; ABCA1 protein stability assays; cholesterol efflux measurements; PA28alpha activity modulation\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo genetic model plus in vitro mechanistic assays, single lab, places PSME1 in CCDC92/ABCA1/cholesterol axis\",\n      \"pmids\": [\"38228909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME1 (PA28alpha) forms a heptameric ring that caps the 20S proteasome (structure resolved at 2.8 Å), activating peptide-hydrolysing activity and altering cleavage patterns to enhance MHC class I antigen presentation for specific epitopes; as part of the PA28alpha/beta heteromer it also regulates protein homeostasis more broadly—modulating proteasomal degradation of substrates such as β-catenin and ABCA1, stabilizing interacting proteins like HBV core protein against 26S proteasome degradation, and influencing cancer cell invasion, myeloma cell proteasome load, and diabetic microvascular injury through pathway-specific substrate regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:8610016 - KEEP (PA28alpha/PSME1 in antigen presentation)\n2. PMID:9403698 - KEEP (REGalpha/PA28alpha structure)\n3. PMID:11689430 - KEEP (PA28alpha/beta knockout mice)\n4. PMID:11169410 - KEEP (PA28alpha/beta enhances antigen presentation)\n5. PMID:11745344 - KEEP (PA28alpha/beta in dendritic cells)\n6. PMID:10199920 - KEEP (PSME1 gene organization)\n7. PMID:31824858 - KEEP (PA28alpha/beta in breast cancer)\n8. PMID:34838695 - KEEP (PSME1/2 in osteoporosis)\n9. PMID:27830089 - KEEP (PA28alpha in diabetic nephropathy)\n10. PMID:33318477 - KEEP (PA28alpha in multiple myeloma)\n11. PMID:38228909 - KEEP (PA28alpha/ABCA1 axis)\n12. PMID:33720528 - KEEP (PA28alpha overexpression in mice)\n13. PMID:15373739 - KEEP (porcine PSME1 characterization, ortholog)\n14. PMID:23916540 - KEEP (fish PA28alpha ortholog characterization)\n15. PMID:39281837 - KEEP (PSME1 and HBV core protein)\n16. PMID:41035633 - EXCLUDE (biomarker/IHC/survival study, no mechanistic findings)\n\nGene2pubmed additional papers:\n- PMID:8811196 - KEEP (review with mechanistic content on proteasome regulators)\n- PMID:16189514, 16169070, 32296183, 28514442, 26496610, 33961781, 22939629, 26344197 - EXCLUDE (interactome maps, PSME1 appears incidentally)\n- PMID:12167863, 12808466, 12809610, 14564014, 14528300, 12859895, 14527406, 12750511, 14528301, 13103906 - EXCLUDE (APOBEC3G/CEM15 papers - alias collision, CEM15 ≠ PSME1)\n- PMID:12477932, 15489334 - EXCLUDE (cDNA collection papers)\n- PMID:21873635 - EXCLUDE (GO annotation methodology)\n- PMID:23503661 - EXCLUDE (PARKIN ubiquitylome)\n- PMID:26638075 - EXCLUDE (centrosome-cilium BioID map)\n- PMID:35271311 - EXCLUDE (OpenCell proteome map)\n- PMID:10225950 - KEEP (PA28 localization at centrosome with functional consequence)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Overexpression of PA28alpha (PSME1) at levels similar to IFN-gamma induction markedly enhanced MHC class I-restricted presentation of murine cytomegalovirus pp89 epitope and influenza nucleoprotein in mouse fibroblasts, demonstrating an in vivo role for PA28alpha in antigen processing.\",\n      \"method\": \"Stable transfection of murine fibroblasts with human or murine PA28alpha gene, followed by cytotoxic T cell recognition assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function in intact cells with specific functional readout, replicated across two antigen systems\",\n      \"pmids\": [\"8610016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of human REGalpha (PA28alpha/PSME1) at 2.8 Å resolution revealed a heptameric barrel-shaped assembly with a central channel (20 Å opening at one end, 30 Å at the proteasome-binding surface), suggesting that REG binding causes conformational changes that open a pore in proteasome alpha-subunits to allow substrate/product passage.\",\n      \"method\": \"X-ray crystallography of human recombinant REGalpha heptamer\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with mechanistic interpretation validated by known biochemistry\",\n      \"pmids\": [\"9403698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human PSME1 gene (encoding PA28alpha) comprises 11 exons and maps to chromosome 14q11.2, near PSME2 (PA28beta) and ISGF3G, consistent with gene duplication during vertebrate evolution; both genes are induced by IFN-gamma.\",\n      \"method\": \"Genomic sequencing and chromosomal mapping of PSME1 and PSME2\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic characterization, single lab\",\n      \"pmids\": [\"10199920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PA28 (including PA28alpha/PSME1) concentrates at the centrosome under basal conditions along with the 20S proteasome, PA700, ubiquitin, Hsp70, and Hsp90; this centrosomal complex enlarges in response to proteasome inhibition or accumulation of misfolded proteins, indicating that the centrosome acts as a scaffold for the proteasome-activator machinery during protein quality control.\",\n      \"method\": \"Immunofluorescence colocalization with gamma-tubulin, density gradient fractionation of purified centrosomes, and proteasome inhibitor challenge in HEK293 and HeLa cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal localization methods (immunofluorescence + fractionation) with functional perturbation, replicated across cell lines\",\n      \"pmids\": [\"10225950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PA28alpha/beta (including PSME1) can enhance MHC class I-restricted antigen presentation independently of changes in 20S proteasome subunit composition or immunoproteasome assembly, as shown by enhanced pp89 epitope presentation in fibroblast transfectants overexpressing both PA28 subunits with unchanged proteasome subunit composition.\",\n      \"method\": \"Stable co-transfection of PA28alpha and PA28beta in fibroblasts, proteasome subunit composition analysis, and cytotoxic T cell recognition assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple controls ruling out alternative explanation, clear functional readout\",\n      \"pmids\": [\"11169410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PA28alpha/beta double-knockout mice retain immunoproteasome assembly after IFN-gamma treatment and show normal antigen presentation for most antigens but almost completely lose the ability to process the melanoma antigen TRP2-derived peptide, demonstrating that PA28alpha/beta is essential for processing of certain specific antigens but not required globally for antigen presentation.\",\n      \"method\": \"Generation of PA28alpha/PA28beta double-knockout mice, IFN-gamma stimulation, ovalbumin and influenza antigen processing assays, TRP2 peptide presentation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with specific immunological phenotypes, orthogonal antigen systems tested, in vivo model\",\n      \"pmids\": [\"11689430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"During dendritic cell maturation, PA28alpha/beta coprecipitates with 13S/16S proteasome precursor complexes and associates equally with mature constitutive and immunoproteasomes, suggesting PA28alpha (PSME1) participates in proteasome assembly intermediates but does not preferentially drive immunoproteasome assembly in DC.\",\n      \"method\": \"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor complexes in maturing dendritic cells, quantitative mRNA and protein analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP experiment with moderate mechanistic follow-up in one cell type\",\n      \"pmids\": [\"11745344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of PA28alpha and PA28beta protected diabetic mice from renal and retinal microvascular injury; PA28-mediated proteasome activity in mesangial cells and retinal pericytes under high glucose promotes expression of OPN and MCP-1; this was suppressed by peptides blocking PA28 binding to the 20S proteasome, demonstrating that PA28alpha (PSME1) drives diabetic microvascular injury through modulation of proteasome activity.\",\n      \"method\": \"PA28alpha/PA28beta double-knockout mice in STZ-induced diabetes model, cultured mesangial cells and retinal pericytes under high glucose, PA28-blocking peptides, OPN/MCP-1 expression analysis\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with specific pathway inhibition by blocking peptides, moderate mechanistic depth\",\n      \"pmids\": [\"27830089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) promotes breast cancer cell migration, invasion, and metastasis by downregulating CDK15 protein; knockdown of PA28alpha/beta or immunoproteasome subunit beta5i upregulates CDK15, and loss of CDK15 is important for tumor invasion, placing PSME1 upstream of CDK15 in a proteasome-dependent invasion pathway.\",\n      \"method\": \"siRNA knockdown of PA28alpha/beta and beta5i in breast cancer cells, migration/invasion assays, western blot for CDK15 protein levels\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with clear cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"31824858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PA28alpha (PSME1) is upregulated in multiple myeloma cells and is required for myeloma cell growth and proliferation; downregulation of PA28alpha reduces both proteasomal load and activity, shifting protein homeostasis away from proteasome dependence and causing resistance to proteasome inhibitors.\",\n      \"method\": \"shRNA/siRNA knockdown of PA28alpha in MM cell lines, cell proliferation assays, proteasome activity assays, proteasome inhibitor sensitivity assays\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with proteasome activity measurement and drug resistance phenotype, single lab\",\n      \"pmids\": [\"33318477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of PA28alpha (PSME1) in female mice enhances hippocampal ability to prevent protein aggregation throughout aging and improves cognitive function (memory in young, exploratory behavior in old mice), while paradoxically lowering PA28-dependent proteasome capacity in heart and hippocampus, suggesting that PA28alpha's anti-aggregation effect is partially independent of its role in boosting proteasome peptidase activity.\",\n      \"method\": \"PA28alpha transgenic overexpression in C57BL/6N×BALB/c mice, behavioral testing (Morris water maze, open field), protein aggregation assays on hippocampal extracts, proteasome activity assays across ages\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with orthogonal behavioral and biochemical readouts, single lab\",\n      \"pmids\": [\"33720528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSME1/2 recombinant protein inhibits osteogenesis and promotes osteoclast formation in vitro, and PSME1/2 suppresses beta-catenin protein levels to limit Wnt/beta-catenin signaling; the proteasome inhibitor carfilzomib inhibits PSME1/2 proteasome activities, increases beta-catenin levels and promotes its nuclear translocation, thereby activating Wnt signaling and promoting osteogenesis in vitro and in an OVX mouse model.\",\n      \"method\": \"Recombinant PSME1/2 protein treatment of osteoblast/osteoclast cultures, siRNA knockdown, western blot for beta-catenin, carfilzomib treatment, OVX mouse model with micro-CT\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro reconstitution with recombinant protein plus in vivo validation, multiple readouts, single lab\",\n      \"pmids\": [\"34838695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC92 promotes degradation of ABCA1 by regulating PA28alpha (PSME1)-mediated proteasome activity, thereby reducing cholesterol efflux and causing lipid accumulation in podocytes; this defines a CCDC92/PA28alpha/ABCA1/cholesterol efflux axis contributing to diabetic kidney disease.\",\n      \"method\": \"Podocyte-specific Ccdc92 knockout mice, co-immunoprecipitation, cholesterol efflux assays, ABCA1 protein stability assays, western blot in high-glucose-treated podocytes\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with co-IP and functional cholesterol efflux assay, single lab\",\n      \"pmids\": [\"38228909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSME1 interacts directly with HBV core protein (HBc) and inhibits its degradation by the 26S proteasome, thereby stabilizing HBc and promoting HBV replication; PSME1 knockdown decreases HBc protein levels and inhibits HBV transcription.\",\n      \"method\": \"APEX2-based proximity labeling to identify HBc-interacting proteins, co-immunoprecipitation, PSME1 siRNA knockdown, HBc protein stability assays, HBV transcription assays in HBV infection system\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling plus Co-IP plus functional knockdown with mechanistic readout, single lab\",\n      \"pmids\": [\"39281837\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME1 (PA28alpha) forms a heptameric ring that binds the ends of the 20S proteasome barrel (as revealed by crystal structure), activates its peptidase activity, and functions as an IFN-gamma-inducible regulator of antigen processing for MHC class I presentation; it also stabilizes substrates such as HBV core protein against 26S proteasome-mediated degradation, suppresses Wnt/beta-catenin signaling by promoting beta-catenin degradation, drives invasion in cancer cells by degrading CDK15, localizes constitutively to the centrosome as part of the protein quality-control machinery, and regulates proteasome load to govern sensitivity to proteasome inhibitors in multiple myeloma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSME1 (PA28α) is a proteasome activator that assembles into a heptameric ring capping the 20S proteasome core, enhancing peptide hydrolysis and modulating antigen processing for MHC class I presentation. The 2.8 Å crystal structure reveals a barrel-shaped heptamer with a central channel that opens a gated pore in the proteasome α-ring to permit substrate and product transit [PMID:9403698]. As a homocomplex or as a PA28α/β heteromer with PSME2, PSME1 enhances presentation of specific viral and tumor-associated epitopes independently of immunoproteasome subunit exchange, and PA28α/β double-knockout mice selectively lose processing of the melanoma antigen TRP2 while retaining general antigen presentation [PMID:8610016, PMID:11169410, PMID:11689430]. Beyond immune function, PSME1-mediated proteasome activation regulates degradation of β-catenin, ABCA1, and CDK15, thereby influencing Wnt signaling, cholesterol efflux, osteogenesis, cancer cell invasion, and myeloma proteasome inhibitor sensitivity [PMID:34838695, PMID:38228909, PMID:31824858, PMID:33318477].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that PA28α directly enhances MHC class I antigen presentation resolved how this IFN-γ-inducible activator connects proteasome biochemistry to adaptive immunity in vivo.\",\n      \"evidence\": \"Transfection of PA28α into fibroblasts expressing viral antigens (MCMV pp89, influenza NP) with CTL recognition readout and in vitro peptide hydrolysis assays\",\n      \"pmids\": [\"8610016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Homomeric vs. heteromeric activator contribution not distinguished\", \"Structural basis of proteasome activation unknown\", \"Epitope specificity of enhancement not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Solving the crystal structure of the PA28α heptamer revealed the gating mechanism by which the activator ring opens the proteasome α-ring pore to allow substrate access.\",\n      \"evidence\": \"X-ray crystallography of recombinant human PA28α at 2.8 Å resolution\",\n      \"pmids\": [\"9403698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the PA28α/β heteromer not determined\", \"No co-structure with the 20S proteasome to visualize pore opening directly\", \"Functional residues mediating activation not mutationally mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that PA28α/β enhances antigen presentation without altering 20S subunit composition separated the activator's role from immunoproteasome assembly.\",\n      \"evidence\": \"Co-transfection of PA28α and PA28β in fibroblasts; proteasome subunit composition analysis combined with CTL assays\",\n      \"pmids\": [\"11169410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PA28α/β directly alters cleavage site usage or simply increases throughput not resolved\", \"Contribution of hybrid 19S-20S-PA28 proteasomes unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"PA28α/β double-knockout mice revealed that the activator is essential for processing specific antigens (TRP2) but dispensable for general antigen presentation, establishing epitope selectivity as a key feature of PA28 function.\",\n      \"evidence\": \"Gene-targeted PA28α−/−/β−/− mice; CTL assays against multiple epitopes; biochemical proteolytic activity measurements\",\n      \"pmids\": [\"11689430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing which epitopes require PA28 not defined\", \"Reduced ATP-dependent activity implies hybrid proteasome involvement but hybrid stoichiometry uncharacterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Co-precipitation of PA28α/β with proteasome precursor complexes suggested a role in proteasome assembly or maturation beyond simple capping of mature particles.\",\n      \"evidence\": \"Co-immunoprecipitation from dendritic cell lysates identifying PA28α/β with 13S/16S proteasome precursors\",\n      \"pmids\": [\"11745344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal validation\", \"Functional consequence of precursor association not tested\", \"Unclear whether association is direct or bridged\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking PA28α/β to diabetic microvascular injury via OPN and MCP-1 induction under high glucose extended PSME1 function beyond immunity to metabolic disease pathology.\",\n      \"evidence\": \"PA28α/β knockout mice with STZ-induced diabetes; mesangial cells and pericytes in high glucose; peptide inhibitors of PA28-20S binding\",\n      \"pmids\": [\"27830089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteasome substrates mediating OPN/MCP-1 upregulation not identified\", \"Peptide inhibitor specificity not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying CDK15 as a substrate whose PA28α/β-dependent degradation drives breast cancer invasion placed PSME1 in a specific oncogenic signaling axis.\",\n      \"evidence\": \"siRNA knockdown of PA28α/β and β5i in breast cancer cells; invasion assays; CDK15 protein measurement\",\n      \"pmids\": [\"31824858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitin-independent degradation of CDK15 by PA28-proteasome not reconstituted in vitro\", \"Generalizability across cancer types untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that PSME1 regulates proteasome load in myeloma and that its loss confers proteasome inhibitor resistance revealed a clinically relevant role in protein homeostasis capacity.\",\n      \"evidence\": \"siRNA knockdown in multiple myeloma cell lines; proteasome activity assays; drug sensitivity profiling\",\n      \"pmids\": [\"33318477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which reduced PA28α shifts proteostasis away from proteasome dependence not defined\", \"In vivo relevance to drug resistance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that PA28α/β promotes β-catenin proteasomal degradation connected PSME1 to Wnt signaling regulation and bone homeostasis.\",\n      \"evidence\": \"Recombinant PSME1/2 treatment of osteoblast/osteoclast cultures; carfilzomib inhibition; β-catenin levels and nuclear translocation; OVX mouse model\",\n      \"pmids\": [\"34838695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether β-catenin degradation is ubiquitin-dependent or PA28-mediated ubiquitin-independent not determined\", \"Direct interaction between PA28-proteasome and β-catenin not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of PSME1 as a stabilizer of HBV core protein—protecting it from 26S proteasome degradation—revealed a virus-exploitation mechanism distinct from PSME1's canonical proteasome-activating role.\",\n      \"evidence\": \"APEX2 proximity labeling; co-IP of PSME1–HBc; siRNA knockdown with HBc stability and HBV transcription readouts\",\n      \"pmids\": [\"39281837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PA28α binding shields HBc from 26S degradation unknown\", \"Whether this involves PA28-20S competition with 26S for core particle not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing PSME1 downstream of CCDC92 in promoting ABCA1 degradation and podocyte lipotoxicity extended the activator's substrate repertoire to cholesterol efflux regulation in diabetic kidney disease.\",\n      \"evidence\": \"Podocyte-specific Ccdc92 deletion in diabetic mice; ABCA1 stability and cholesterol efflux assays; PA28α activity modulation\",\n      \"pmids\": [\"38228909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CCDC92 regulates PA28α activity mechanistically not resolved\", \"Whether ABCA1 is a direct PA28-proteasome substrate or degraded indirectly unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The rules determining substrate selectivity of the PA28α/β-20S proteasome—whether degradation is ubiquitin-independent, which substrates are directly engaged, and how hybrid proteasome stoichiometry is regulated—remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No reconstituted in vitro system demonstrating direct substrate selection by PA28-proteasome\", \"Co-structure of PA28α/β heteromer bound to 20S proteasome not available\", \"Ubiquitin-independent vs. ubiquitin-dependent substrate channeling by PA28 not mechanistically separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"complexes\": [\n      \"PA28 (11S REG)\",\n      \"PA28alpha/beta heteromer\"\n    ],\n    \"partners\": [\n      \"PSME2\",\n      \"PSMB8\",\n      \"HBc\",\n      \"CCDC92\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSME1 (PA28α) is a subunit of the PA28 proteasome activator complex that forms a heptameric ring capping the 20S proteasome core particle, stimulating its peptidase activity and shaping the repertoire of peptides available for MHC class I antigen presentation and broader protein homeostasis. The crystal structure reveals a barrel-shaped heptamer whose binding opens a gated pore in the proteasome α-ring to permit substrate and product passage [PMID:9403698]; overexpression at IFN-γ–inducible levels enhances class I–restricted antigen presentation independently of immunoproteasome subunit exchange, while double-knockout mice lose processing of select antigens such as TRP2 [PMID:8610016, PMID:11169410, PMID:11689430]. Beyond antigen processing, PSME1-mediated proteasome activation degrades β-catenin to suppress Wnt signaling in bone cells [PMID:34838695], degrades CDK15 to promote breast cancer invasion [PMID:31824858], regulates proteasome load and sensitivity to proteasome inhibitors in multiple myeloma [PMID:33318477], and stabilizes HBV core protein against 26S proteasome degradation to facilitate viral replication [PMID:39281837]. PSME1 constitutively localizes to the centrosome together with the 20S proteasome and chaperones, where the complex expands upon proteasome inhibition or accumulation of misfolded proteins, implicating it in centrosome-based protein quality control [PMID:10225950].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that PA28α has an in vivo function in antigen processing resolved whether this proteasome activator operates only in vitro, showing that physiological-level overexpression directly enhances MHC class I–restricted epitope presentation.\",\n      \"evidence\": \"Stable transfection of PA28α in murine fibroblasts with CTL recognition assays for two viral antigens\",\n      \"pmids\": [\"8610016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PA28α alters the peptide repertoire was unknown\", \"Relative contribution of PA28α versus PA28β was not separated\", \"Whether PA28α acts on all antigens or only a subset was untested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Solving the crystal structure of the PA28α heptamer answered how the activator physically engages the proteasome, revealing a barrel that opens a gated pore in the 20S α-ring to allow substrate/product transit.\",\n      \"evidence\": \"2.8 Å X-ray crystallography of recombinant human PA28α\",\n      \"pmids\": [\"9403698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the PA28α–20S complex itself was not determined\", \"Whether the heteromeric PA28α/β ring adopts the same architecture was unresolved\", \"Conformational dynamics during gating remained unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Localizing PA28α/β to the centrosome together with the 20S proteasome and chaperones revealed a constitutive proteasome quality-control platform at this organelle, expanding PA28α's role beyond antigen processing.\",\n      \"evidence\": \"Immunofluorescence colocalization with γ-tubulin, density-gradient fractionation of purified centrosomes, and proteasome inhibitor challenge in HEK293 and HeLa cells\",\n      \"pmids\": [\"10225950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The substrates degraded at the centrosome by PA28-activated proteasomes were not identified\", \"Whether centrosomal localization is essential for PA28α's antigen-processing role was unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that PA28α/β enhances antigen presentation without altering proteasome subunit composition showed that the activator acts directly on 20S peptidase activity rather than by promoting immunoproteasome assembly.\",\n      \"evidence\": \"Co-transfection of PA28α/β in fibroblasts with proteasome subunit composition analysis and CTL assays\",\n      \"pmids\": [\"11169410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The precise cleavage products altered by PA28 binding were not characterized\", \"Whether PA28 changes cleavage site preference or only product release rate was unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"PA28α/β double-knockout mice showed that the activator is dispensable for most antigen presentation but essential for processing specific epitopes (e.g., TRP2), defining PA28 as a substrate-selective processing factor rather than a global antigen-processing requirement.\",\n      \"evidence\": \"Genetic double-KO mice with IFN-γ stimulation and antigen-specific CTL assays for multiple antigens\",\n      \"pmids\": [\"11689430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing which epitopes require PA28 were not defined\", \"Compensatory roles of PA28γ in vivo were not assessed\", \"Whether PA28 dependence maps to primary sequence or proteasome cleavage kinetics was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Finding that PA28α/β deletion protects against diabetic microvascular injury extended PSME1's physiological relevance to chronic metabolic disease, linking its proteasome-activating function to inflammatory mediator expression under high glucose.\",\n      \"evidence\": \"PA28α/β double-KO mice in STZ-induced diabetes, mesangial and retinal pericyte cultures, PA28-blocking peptides, OPN/MCP-1 readouts\",\n      \"pmids\": [\"27830089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific proteasome substrates mediating OPN/MCP-1 upregulation were not identified\", \"Whether PA28α or PA28β is the rate-limiting subunit in this context was not determined\", \"Blocking peptide specificity in vivo was not fully validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of CDK15 as a target degraded via PA28α/β-activated immunoproteasome placed PSME1 in a pro-invasive axis in breast cancer, establishing a proteasome-dependent mechanism for metastasis promotion.\",\n      \"evidence\": \"siRNA knockdown of PA28α/β and β5i in breast cancer cells with migration/invasion assays and CDK15 protein level measurement\",\n      \"pmids\": [\"31824858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination or proteasomal degradation of CDK15 was not reconstituted\", \"In vivo metastasis data were limited\", \"Whether CDK15 degradation is immunoproteasome-specific was not conclusively shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that PA28α knockdown reduces proteasome load and confers resistance to proteasome inhibitors in myeloma revealed PSME1 as a determinant of proteasome dependence in cancer, with therapeutic implications.\",\n      \"evidence\": \"shRNA/siRNA knockdown in MM cell lines with proteasome activity and bortezomib/carfilzomib sensitivity assays\",\n      \"pmids\": [\"33318477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mechanism linking reduced PA28α to decreased proteasome load was not delineated\", \"Clinical correlation with patient drug response was not established\", \"Whether PA28α overexpression is sufficient to resensitize resistant cells was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies in 2021 expanded PSME1's non-immune roles: PA28α overexpression in vivo reduced hippocampal protein aggregation and improved cognition independently of boosted proteasome peptidase activity, while recombinant PSME1/2 suppressed β-catenin to inhibit Wnt signaling and osteogenesis, establishing PA28α as a modulator of proteostasis and developmental signaling beyond antigen processing.\",\n      \"evidence\": \"PA28α transgenic mice with behavioral testing and aggregation assays; recombinant PSME1/2 in osteoblast/osteoclast cultures with β-catenin western blot and OVX mouse model\",\n      \"pmids\": [\"33720528\", \"34838695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The anti-aggregation mechanism independent of proteasome activation was not identified\", \"Whether β-catenin is a direct proteasomal substrate of PA28-activated proteasomes was not shown\", \"Sex-specific effects (female-only cognitive benefit) were unexplained mechanistically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that PSME1 directly binds HBV core protein and shields it from 26S proteasome degradation revealed a virus-co-opted stabilization function, demonstrating that PA28α can also inhibit specific substrate degradation rather than only promote it.\",\n      \"evidence\": \"APEX2 proximity labeling, co-IP, siRNA knockdown with HBc stability and HBV transcription assays\",\n      \"pmids\": [\"39281837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for PA28α–HBc interaction was not determined\", \"Whether stabilization requires the assembled heptamer or monomeric PA28α was not tested\", \"Relevance to HBV pathogenesis in vivo was not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of a CCDC92–PA28α–ABCA1 axis in podocytes showed that upstream regulators can channel PSME1 activity toward degradation of specific membrane transporters, broadening the list of physiologically relevant PA28α substrates.\",\n      \"evidence\": \"Podocyte-specific Ccdc92 KO mice, co-IP, cholesterol efflux and ABCA1 stability assays under high glucose\",\n      \"pmids\": [\"38228909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PA28α activates 20S proteasomes or an alternative pathway for ABCA1 degradation was not distinguished\", \"Direct ubiquitination status of ABCA1 in this axis was not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of heteromeric PA28α/β ring assembly on the 20S proteasome, the rules determining which substrates require PA28-activated versus 26S-mediated degradation, and the mechanism underlying PA28α's proteasome-activity-independent anti-aggregation function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the PA28α/β–20S holocomplex\", \"No systematic identification of PA28-dependent proteasomal substrates\", \"Anti-aggregation mechanism independent of peptidase activation is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4, 5, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 9, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 13]}\n    ],\n    \"complexes\": [\n      \"PA28 (11S REG)\",\n      \"PA28-20S hybrid proteasome\"\n    ],\n    \"partners\": [\n      \"PSME2\",\n      \"PSMB8\",\n      \"CTNNB1\",\n      \"CDK15\",\n      \"CCDC92\",\n      \"ABCA1\",\n      \"HBc (HBV core protein)\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}