{"gene":"PSME1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"PA28alpha (PSME1) overexpression at IFN-gamma-inducible levels markedly enhanced MHC class I-restricted presentation of viral antigens (MCMV pp89 and influenza nucleoprotein) in mouse fibroblasts, establishing an in vivo function for PA28alpha in antigen processing. PA28alpha alone is sufficient to activate the peptide-hydrolysing activity of the 20S proteasome in vitro.","method":"Transfection of PA28alpha into fibroblasts expressing viral antigen; cytotoxic T cell recognition assay; in vitro peptide-hydrolysis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional cellular assay with defined readout (CTL recognition), in vitro biochemical activity confirmed, replicated across two viral antigens","pmids":["8610016"],"is_preprint":false},{"year":1997,"finding":"Crystal structure of human REGalpha (PA28alpha/PSME1) determined at 2.8 Å resolution, revealing 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 induces conformational changes that open a pore in proteasome alpha-subunits to allow substrate/product passage.","method":"X-ray crystallography of recombinant human REGalpha heptamer","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.8 Å resolution, heptameric assembly directly visualized with functional inference from structure","pmids":["9403698"],"is_preprint":false},{"year":2000,"finding":"PA28alpha/beta (PSME1/PSME2 heteromer) enhances MHC class I antigen presentation independently of changes in 20S proteasome subunit composition; fibroblasts overexpressing both subunits showed enhanced pp89 epitope presentation with identical 20S subunit composition to control cells.","method":"Stable transfection of PA28alpha and PA28beta; proteasome subunit composition analysis; CTL recognition assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct cellular functional assay with biochemical subunit analysis, single lab but two orthogonal methods","pmids":["11169410"],"is_preprint":false},{"year":2001,"finding":"In PA28alpha/beta double-knockout mice, ATP-dependent proteolytic activities were decreased, implicating hybrid proteasomes (containing both 19S and PA28 caps) in protein degradation. PA28alpha/beta is essential for processing the melanoma antigen TRP2 but not required for general antigen presentation (e.g., ovalbumin processing was unaffected).","method":"Genetic knockout (double PA28alpha/PA28beta KO mice); proteolytic activity assays; CTL antigen presentation assays; influenza virus infection model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in vivo with multiple defined phenotypic readouts across independent antigens, replicated in different assay contexts","pmids":["11689430"],"is_preprint":false},{"year":2001,"finding":"PA28alpha/beta co-precipitated with 13S/16S proteasome precursor complexes (assembling proteasomes) and with mature constitutive and immunoproteasomes to the same extent, indicating PA28alpha/beta associates with proteasomes throughout their assembly and maturation.","method":"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor complexes in dendritic cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-precipitation in a relevant cell type, single lab, single method but consistent result across multiple proteasome forms","pmids":["11745344"],"is_preprint":false},{"year":2016,"finding":"Genetic deletion of PA28alpha/beta (PSME1/PSME2) protected diabetic mice from renal and retinal microvascular injury; PA28-mediated proteasome activity in mesangial cells and retinal pericytes under high-glucose conditions drove expression of OPN and MCP-1, and this was suppressed by peptides that inhibit PA28 binding to the 20S proteasome.","method":"PA28alpha/beta double-knockout mice in STZ-induced diabetes model; primary cell cultures under high glucose; peptide inhibitors of PA28–20S binding; OPN/MCP-1 expression analysis","journal":"International journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype plus peptide inhibitor mechanistic follow-up, single lab","pmids":["27830089"],"is_preprint":false},{"year":2019,"finding":"PA28alpha/beta (PSME1/PSME2) promotes breast cancer cell invasion and metastasis by down-regulating CDK15 protein levels; knockdown of PA28alpha/beta or immunoproteasome subunit beta5i up-regulated CDK15, and loss of CDK15 was shown to be important for tumor cell invasion.","method":"siRNA knockdown of PA28alpha, PA28beta, and beta5i in breast cancer cells; migration/invasion assays; CDK15 protein expression analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, two orthogonal knockdown targets","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 proteasomal load and activity, shifts protein homeostasis to be less proteasome-dependent, and confers resistance to proteasome inhibitors.","method":"PA28alpha knockdown in MM cell lines; proteasome activity assays; cell growth/proliferation assays; proteasome inhibitor sensitivity assays","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KD phenotype with biochemical (proteasome activity) and cellular (growth, drug resistance) readouts, single lab","pmids":["33318477"],"is_preprint":false},{"year":2021,"finding":"PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation in vitro, and inhibited β-catenin protein levels, limiting Wnt/β-catenin signaling. Carfilzomib (CFZ) inhibited PSME1/2 proteasome activities, increased β-catenin protein levels, and promoted its nuclear translocation to activate Wnt/β-catenin signaling.","method":"Recombinant PSME1/2 protein treatment of osteoblast/osteoclast cultures; β-catenin protein level and localization assays; CFZ treatment; OVX mouse model with micro-CT","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with recombinant protein plus in vivo model, single lab, multiple readouts","pmids":["34838695"],"is_preprint":false},{"year":2021,"finding":"Overexpression of PA28alpha (PSME1) in female mice maintained hippocampal anti-aggregation capacity through aging; protein extracts from PA28alpha-overexpressing hippocampi prevented protein aggregation more efficiently than wild type, though PA28alpha overexpression paradoxically lowered PA28-dependent proteasome capacity in heart and hippocampus without reducing protein damage load.","method":"Transgenic PA28alpha overexpressing mice (C57BL/6N×BALB/c); protein aggregation assays with hippocampal extracts; proteasome activity assays; behavioral testing across age groups","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression with biochemical (aggregation, proteasome activity) and behavioral phenotypes, single lab, multiple orthogonal readouts","pmids":["33720528"],"is_preprint":false},{"year":2023,"finding":"PSME1 interacts with HBV core protein (HBc) and inhibits its degradation by the 26S proteasome, thereby stabilizing HBc; PSME1 knockdown decreased HBc protein levels and inhibited HBV transcription in an HBV infection system.","method":"APEX2-proximity labeling to identify HBc-interacting proteins; Co-immunoprecipitation of PSME1 with HBc; PSME1 knockdown with measurement of HBc stability and HBV transcription","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling plus co-IP plus functional KD, single lab, mechanistic follow-up with multiple methods","pmids":["39281837"],"is_preprint":false},{"year":2024,"finding":"CCDC92 promotes degradation of ABCA1 by regulating PA28alpha-mediated proteasome activity, thereby reducing cholesterol efflux and causing lipid accumulation in podocytes; this PA28alpha/ABCA1/cholesterol efflux axis contributes to podocyte injury in diabetic kidney disease.","method":"Podocyte-specific Ccdc92 knockout mice; ABCA1 degradation assays; cholesterol efflux assays; PA28alpha activity measurements in podocytes","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined substrate (ABCA1) and functional (cholesterol efflux) readouts, single lab","pmids":["38228909"],"is_preprint":false}],"current_model":"PSME1 (PA28alpha) is an IFN-gamma-inducible heptameric activator of the 20S proteasome that binds to the proteasome's alpha-ring face (as revealed by its crystal structure) to stimulate peptide-hydrolysing activity and alter cleavage patterns, thereby enhancing MHC class I antigen presentation for specific epitopes; beyond antigen processing, PSME1/PA28alpha regulates protein homeostasis in diverse contexts including myeloma cell survival, viral core protein stability, Wnt/β-catenin signaling via β-catenin levels, CDK15-mediated tumor invasion, and podocyte cholesterol efflux through ABCA1 degradation."},"narrative":{"mechanistic_narrative":"PSME1 (PA28alpha/REGalpha) is an IFN-gamma-inducible proteasome regulator that assembles into a heptameric, barrel-shaped activator which docks onto the alpha-ring face of the 20S proteasome to stimulate peptide hydrolysis and reshape cleavage patterns [PMID:8610016, PMID:9403698]. Its crystal structure reveals a central channel that widens toward the proteasome-binding surface, providing a structural basis for opening the alpha-subunit gate to permit substrate and product passage [PMID:9403698]. The principal characterized cellular role is enhancement of MHC class I antigen presentation: PA28alpha alone activates 20S peptide hydrolysis in vitro and, at IFN-gamma-inducible levels, boosts presentation of viral epitopes, while the PA28alpha/beta (PSME1/PSME2) heteromer augments epitope presentation without altering 20S subunit composition and is selectively required for processing particular antigens such as the melanoma antigen TRP2 [PMID:8610016, PMID:11169410, PMID:11689430]. PA28alpha/beta associates with proteasomes throughout assembly and maturation and contributes to ATP-dependent proteolysis via hybrid proteasomes [PMID:11689430, PMID:11745344]. Beyond antigen processing, PSME1-dependent proteasome activity controls protein homeostasis and the stability of specific factors in disease contexts: it supports myeloma cell proliferation and proteasome-inhibitor sensitivity [PMID:33318477], drives breast cancer invasion by lowering CDK15 [PMID:31824858], stabilizes HBV core protein to sustain viral transcription [PMID:39281837], limits Wnt/beta-catenin signaling by reducing beta-catenin levels [PMID:34838695], and promotes ABCA1 degradation to impair podocyte cholesterol efflux in diabetic kidney disease [PMID:38228909].","teleology":[{"year":1996,"claim":"Established that PA28alpha is not merely an in vitro proteasome activator but functions in cells to enhance antigen processing, answering whether its biochemical activity has an immunological consequence.","evidence":"Transfection of PA28alpha into antigen-expressing fibroblasts with CTL recognition readout and in vitro peptide-hydrolysis assay","pmids":["8610016"],"confidence":"High","gaps":["Did not resolve the structural mechanism of 20S activation","Limited to two viral epitopes; generality across the epitope repertoire unaddressed"]},{"year":1997,"claim":"Defined the heptameric architecture and central channel of PA28alpha, providing a structural model for how REG binding opens the proteasome alpha-ring gate.","evidence":"X-ray crystallography of recombinant human REGalpha heptamer at 2.8 Å","pmids":["9403698"],"confidence":"High","gaps":["Structure of the PA28-20S complex not determined","Conformational change in alpha-subunits inferred rather than directly visualized"]},{"year":2000,"claim":"Showed that the PA28alpha/beta heteromer enhances presentation without changing 20S subunit composition, distinguishing a gating/processing effect from a change in catalytic subunit makeup.","evidence":"Stable co-transfection of PA28alpha and PA28beta with subunit composition analysis and CTL recognition assay","pmids":["11169410"],"confidence":"High","gaps":["Mechanism by which cleavage specificity is altered not defined","Tested for a single epitope"]},{"year":2001,"claim":"Genetic loss-of-function established that PA28alpha/beta is required for processing specific antigens but dispensable for general antigen presentation, and linked it to ATP-dependent (hybrid) proteasome activity.","evidence":"PA28alpha/PA28beta double-knockout mice with proteolytic activity and CTL antigen presentation assays","pmids":["11689430"],"confidence":"High","gaps":["Why only certain antigens depend on PA28 unresolved","Contribution of hybrid versus capped proteasomes not quantified"]},{"year":2001,"claim":"Determined when PA28alpha/beta engages the proteasome, showing association from precursor assembly through maturation rather than only with mature particles.","evidence":"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor and mature complexes in dendritic cells","pmids":["11745344"],"confidence":"Medium","gaps":["Single method (co-IP) without reciprocal or structural confirmation","Functional significance of precursor association untested"]},{"year":2016,"claim":"Extended PA28 function to diabetic microvascular pathology, showing PA28-20S activity drives inflammatory gene expression under high glucose.","evidence":"PA28alpha/beta double-knockout mice in STZ-diabetes model plus peptide inhibitors of PA28-20S binding and OPN/MCP-1 readouts","pmids":["27830089"],"confidence":"Medium","gaps":["Direct substrates linking PA28 activity to OPN/MCP-1 expression unidentified","Single lab"]},{"year":2019,"claim":"Identified CDK15 as a downstream target whose PA28-dependent down-regulation promotes tumor invasion, connecting PA28 activity to a defined oncogenic phenotype.","evidence":"siRNA knockdown of PA28alpha, PA28beta and beta5i in breast cancer cells with invasion assays and CDK15 protein measurement","pmids":["31824858"],"confidence":"Medium","gaps":["Whether CDK15 is a direct proteasome substrate not established","Single lab"]},{"year":2020,"claim":"Demonstrated a proliferation and drug-resistance role in multiple myeloma, where PA28alpha sets proteasomal load and dependence.","evidence":"PA28alpha knockdown in myeloma cell lines with proteasome activity, growth, and proteasome-inhibitor sensitivity assays","pmids":["33318477"],"confidence":"Medium","gaps":["Molecular basis of the homeostatic shift away from proteasome dependence unclear","Single lab, cell-line based"]},{"year":2021,"claim":"Linked PSME1/2 proteasome activity to bone homeostasis through control of beta-catenin levels and Wnt signaling.","evidence":"Recombinant PSME1/2 treatment of osteoblast/osteoclast cultures, beta-catenin level/localization assays, carfilzomib, and OVX mouse micro-CT","pmids":["34838695"],"confidence":"Medium","gaps":["Whether beta-catenin is a direct PA28-proteasome substrate not shown","Single lab"]},{"year":2021,"claim":"Probed PA28alpha's role in proteostasis and aging, showing it can sustain anti-aggregation capacity yet paradoxically lower PA28-dependent proteasome capacity in some tissues.","evidence":"Transgenic PA28alpha-overexpressing mice with aggregation assays, proteasome activity, and behavioral testing across ages","pmids":["33720528"],"confidence":"Medium","gaps":["Mechanism behind tissue-specific and paradoxical proteasome effects unresolved","Sex-specific findings not generalized"]},{"year":2023,"claim":"Revealed a substrate-stabilizing function in viral infection, where PSME1 binds HBV core protein and protects it from 26S degradation.","evidence":"APEX2 proximity labeling and co-IP of PSME1 with HBc, plus PSME1 knockdown measuring HBc stability and HBV transcription","pmids":["39281837"],"confidence":"Medium","gaps":["How a 20S activator shields a substrate from 26S degradation mechanistically unclear","Single lab"]},{"year":2024,"claim":"Defined a PA28alpha/ABCA1/cholesterol efflux axis in podocytes regulated by CCDC92, connecting PA28-mediated degradation to lipid handling in diabetic kidney disease.","evidence":"Podocyte-specific Ccdc92 knockout mice with ABCA1 degradation, cholesterol efflux, and PA28alpha activity assays","pmids":["38228909"],"confidence":"Medium","gaps":["Direct physical/biochemical link between PA28alpha and ABCA1 degradation not fully defined","Single lab"]},{"year":null,"claim":"How PA28alpha switches between activating proteasomal degradation of some targets and stabilizing others, and what dictates its substrate/epitope selectivity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the PA28-20S or PA28-substrate complex in the corpus","No unifying rule for substrate/epitope selection across the diverse disease contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7]}],"complexes":["PA28alpha/beta (11S/REG) proteasome activator","20S proteasome (PA28-capped/hybrid proteasome)"],"partners":["PSME2","HBC"],"other_free_text":[]}},"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 presentation.","date":"1996","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8610016","citation_count":294,"is_preprint":false},{"pmid":"9403698","id":"PMC_9403698","title":"Structure of the proteasome activator REGalpha (PA28alpha).","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9403698","citation_count":150,"is_preprint":false},{"pmid":"11689430","id":"PMC_11689430","title":"Immunoproteasome assembly and antigen presentation in mice lacking both PA28alpha and PA28beta.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11689430","citation_count":133,"is_preprint":false},{"pmid":"11169410","id":"PMC_11169410","title":"The proteasome regulator PA28alpha/beta can enhance antigen presentation without affecting 20S proteasome subunit composition.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11169410","citation_count":56,"is_preprint":false},{"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},{"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},{"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 oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31824858","citation_count":16,"is_preprint":false},{"pmid":"34838695","id":"PMC_34838695","title":"Carfilzomib alleviated osteoporosis by targeting PSME1/2 to activate Wnt/β-catenin signaling.","date":"2021","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34838695","citation_count":12,"is_preprint":false},{"pmid":"27830089","id":"PMC_27830089","title":"Proteasome Activators, PA28α and PA28β, Govern Development of Microvascular Injury in Diabetic Nephropathy and Retinopathy.","date":"2016","source":"International journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/27830089","citation_count":11,"is_preprint":false},{"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":10,"is_preprint":false},{"pmid":"33318477","id":"PMC_33318477","title":"Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma.","date":"2020","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/33318477","citation_count":10,"is_preprint":false},{"pmid":"15373739","id":"PMC_15373739","title":"Sequence characterization, polymorphism and chromosomal localizations of the porcine PSME1 and PSME2 genes.","date":"2004","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15373739","citation_count":9,"is_preprint":false},{"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},{"pmid":"39281837","id":"PMC_39281837","title":"The proteasome activator subunit PSME1 promotes HBV replication by inhibiting the degradation of HBV core protein.","date":"2023","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39281837","citation_count":5,"is_preprint":false},{"pmid":"23916540","id":"PMC_23916540","title":"Genomic structural characterization and transcriptional expression analysis of proteasome activator PA28α and PA28β subunits from Oplegnathus fasciatus.","date":"2013","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23916540","citation_count":4,"is_preprint":false},{"pmid":"41035633","id":"PMC_41035633","title":"Immunoproteasome components LMP2, PSME1, and PSME2 as novel tissue biomarkers 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},{"pmid":"42052091","id":"PMC_42052091","title":"Altered expression of ADAR1, N4BP1, and PSME1 in PBMCs correlated with therapeutic outcomes in HBeAg-negative chronic hepatitis B patients treated with Peg-IFN-α.","date":"2026","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/42052091","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10363,"output_tokens":3005,"usd":0.038082,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10505,"output_tokens":3627,"usd":0.0716,"stage2_stop_reason":"end_turn"},"total_usd":0.109682,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PA28alpha (PSME1) overexpression at IFN-gamma-inducible levels markedly enhanced MHC class I-restricted presentation of viral antigens (MCMV pp89 and influenza nucleoprotein) in mouse fibroblasts, establishing an in vivo function for PA28alpha in antigen processing. PA28alpha alone is sufficient to activate the peptide-hydrolysing activity of the 20S proteasome in vitro.\",\n      \"method\": \"Transfection of PA28alpha into fibroblasts expressing viral antigen; cytotoxic T cell recognition assay; in vitro peptide-hydrolysis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional cellular assay with defined readout (CTL recognition), in vitro biochemical activity confirmed, replicated across two viral antigens\",\n      \"pmids\": [\"8610016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of human REGalpha (PA28alpha/PSME1) determined at 2.8 Å resolution, revealing 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 induces conformational changes that open a pore in proteasome alpha-subunits to allow substrate/product passage.\",\n      \"method\": \"X-ray crystallography of recombinant human REGalpha heptamer\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.8 Å resolution, heptameric assembly directly visualized with functional inference from structure\",\n      \"pmids\": [\"9403698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2 heteromer) enhances MHC class I antigen presentation independently of changes in 20S proteasome subunit composition; fibroblasts overexpressing both subunits showed enhanced pp89 epitope presentation with identical 20S subunit composition to control cells.\",\n      \"method\": \"Stable transfection of PA28alpha and PA28beta; proteasome subunit composition analysis; CTL recognition assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular functional assay with biochemical subunit analysis, single lab but two orthogonal methods\",\n      \"pmids\": [\"11169410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In PA28alpha/beta double-knockout mice, ATP-dependent proteolytic activities were decreased, implicating hybrid proteasomes (containing both 19S and PA28 caps) in protein degradation. PA28alpha/beta is essential for processing the melanoma antigen TRP2 but not required for general antigen presentation (e.g., ovalbumin processing was unaffected).\",\n      \"method\": \"Genetic knockout (double PA28alpha/PA28beta KO mice); proteolytic activity assays; CTL antigen presentation assays; influenza virus infection model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in vivo with multiple defined phenotypic readouts across independent antigens, replicated in different assay contexts\",\n      \"pmids\": [\"11689430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PA28alpha/beta co-precipitated with 13S/16S proteasome precursor complexes (assembling proteasomes) and with mature constitutive and immunoproteasomes to the same extent, indicating PA28alpha/beta associates with proteasomes throughout their assembly and maturation.\",\n      \"method\": \"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor complexes in dendritic cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-precipitation in a relevant cell type, single lab, single method but consistent result across multiple proteasome forms\",\n      \"pmids\": [\"11745344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic deletion of PA28alpha/beta (PSME1/PSME2) protected diabetic mice from renal and retinal microvascular injury; PA28-mediated proteasome activity in mesangial cells and retinal pericytes under high-glucose conditions drove expression of OPN and MCP-1, and this was suppressed by peptides that inhibit PA28 binding to the 20S proteasome.\",\n      \"method\": \"PA28alpha/beta double-knockout mice in STZ-induced diabetes model; primary cell cultures under high glucose; peptide inhibitors of PA28–20S binding; OPN/MCP-1 expression analysis\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype plus peptide inhibitor mechanistic follow-up, single lab\",\n      \"pmids\": [\"27830089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PA28alpha/beta (PSME1/PSME2) promotes breast cancer cell invasion and metastasis by down-regulating CDK15 protein levels; knockdown of PA28alpha/beta or immunoproteasome subunit beta5i up-regulated CDK15, and loss of CDK15 was shown to be important for tumor cell invasion.\",\n      \"method\": \"siRNA knockdown of PA28alpha, PA28beta, and beta5i in breast cancer cells; migration/invasion assays; CDK15 protein expression analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, two orthogonal knockdown targets\",\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 proteasomal load and activity, shifts protein homeostasis to be less proteasome-dependent, and confers resistance to proteasome inhibitors.\",\n      \"method\": \"PA28alpha knockdown in MM cell lines; proteasome activity assays; cell growth/proliferation assays; proteasome inhibitor sensitivity assays\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KD phenotype with biochemical (proteasome activity) and cellular (growth, drug resistance) readouts, single lab\",\n      \"pmids\": [\"33318477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation in vitro, and inhibited β-catenin protein levels, limiting Wnt/β-catenin signaling. Carfilzomib (CFZ) inhibited PSME1/2 proteasome activities, increased β-catenin protein levels, and promoted its nuclear translocation to activate Wnt/β-catenin signaling.\",\n      \"method\": \"Recombinant PSME1/2 protein treatment of osteoblast/osteoclast cultures; β-catenin protein level and localization assays; CFZ treatment; OVX mouse model with micro-CT\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with recombinant protein plus in vivo model, single lab, multiple readouts\",\n      \"pmids\": [\"34838695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of PA28alpha (PSME1) in female mice maintained hippocampal anti-aggregation capacity through aging; protein extracts from PA28alpha-overexpressing hippocampi prevented protein aggregation more efficiently than wild type, though PA28alpha overexpression paradoxically lowered PA28-dependent proteasome capacity in heart and hippocampus without reducing protein damage load.\",\n      \"method\": \"Transgenic PA28alpha overexpressing mice (C57BL/6N×BALB/c); protein aggregation assays with hippocampal extracts; proteasome activity assays; behavioral testing across age groups\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression with biochemical (aggregation, proteasome activity) and behavioral phenotypes, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"33720528\"],\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; PSME1 knockdown decreased HBc protein levels and inhibited HBV transcription in an HBV infection system.\",\n      \"method\": \"APEX2-proximity labeling to identify HBc-interacting proteins; Co-immunoprecipitation of PSME1 with HBc; PSME1 knockdown with measurement of HBc stability and HBV transcription\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling plus co-IP plus functional KD, single lab, mechanistic follow-up with multiple methods\",\n      \"pmids\": [\"39281837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC92 promotes degradation of ABCA1 by regulating PA28alpha-mediated proteasome activity, thereby reducing cholesterol efflux and causing lipid accumulation in podocytes; this PA28alpha/ABCA1/cholesterol efflux axis contributes to podocyte injury in diabetic kidney disease.\",\n      \"method\": \"Podocyte-specific Ccdc92 knockout mice; ABCA1 degradation assays; cholesterol efflux assays; PA28alpha activity measurements in podocytes\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined substrate (ABCA1) and functional (cholesterol efflux) readouts, single lab\",\n      \"pmids\": [\"38228909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSME1 (PA28alpha) is an IFN-gamma-inducible heptameric activator of the 20S proteasome that binds to the proteasome's alpha-ring face (as revealed by its crystal structure) to stimulate peptide-hydrolysing activity and alter cleavage patterns, thereby enhancing MHC class I antigen presentation for specific epitopes; beyond antigen processing, PSME1/PA28alpha regulates protein homeostasis in diverse contexts including myeloma cell survival, viral core protein stability, Wnt/β-catenin signaling via β-catenin levels, CDK15-mediated tumor invasion, and podocyte cholesterol efflux through ABCA1 degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSME1 (PA28alpha/REGalpha) is an IFN-gamma-inducible proteasome regulator that assembles into a heptameric, barrel-shaped activator which docks onto the alpha-ring face of the 20S proteasome to stimulate peptide hydrolysis and reshape cleavage patterns [#0, #1]. Its crystal structure reveals a central channel that widens toward the proteasome-binding surface, providing a structural basis for opening the alpha-subunit gate to permit substrate and product passage [#1]. The principal characterized cellular role is enhancement of MHC class I antigen presentation: PA28alpha alone activates 20S peptide hydrolysis in vitro and, at IFN-gamma-inducible levels, boosts presentation of viral epitopes, while the PA28alpha/beta (PSME1/PSME2) heteromer augments epitope presentation without altering 20S subunit composition and is selectively required for processing particular antigens such as the melanoma antigen TRP2 [#0, #2, #3]. PA28alpha/beta associates with proteasomes throughout assembly and maturation and contributes to ATP-dependent proteolysis via hybrid proteasomes [#3, #4]. Beyond antigen processing, PSME1-dependent proteasome activity controls protein homeostasis and the stability of specific factors in disease contexts: it supports myeloma cell proliferation and proteasome-inhibitor sensitivity [#7], drives breast cancer invasion by lowering CDK15 [#6], stabilizes HBV core protein to sustain viral transcription [#10], limits Wnt/beta-catenin signaling by reducing beta-catenin levels [#8], and promotes ABCA1 degradation to impair podocyte cholesterol efflux in diabetic kidney disease [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that PA28alpha is not merely an in vitro proteasome activator but functions in cells to enhance antigen processing, answering whether its biochemical activity has an immunological consequence.\",\n      \"evidence\": \"Transfection of PA28alpha into antigen-expressing fibroblasts with CTL recognition readout and in vitro peptide-hydrolysis assay\",\n      \"pmids\": [\"8610016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural mechanism of 20S activation\", \"Limited to two viral epitopes; generality across the epitope repertoire unaddressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the heptameric architecture and central channel of PA28alpha, providing a structural model for how REG binding opens the proteasome alpha-ring gate.\",\n      \"evidence\": \"X-ray crystallography of recombinant human REGalpha heptamer at 2.8 Å\",\n      \"pmids\": [\"9403698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the PA28-20S complex not determined\", \"Conformational change in alpha-subunits inferred rather than directly visualized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that the PA28alpha/beta heteromer enhances presentation without changing 20S subunit composition, distinguishing a gating/processing effect from a change in catalytic subunit makeup.\",\n      \"evidence\": \"Stable co-transfection of PA28alpha and PA28beta with subunit composition analysis and CTL recognition assay\",\n      \"pmids\": [\"11169410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which cleavage specificity is altered not defined\", \"Tested for a single epitope\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic loss-of-function established that PA28alpha/beta is required for processing specific antigens but dispensable for general antigen presentation, and linked it to ATP-dependent (hybrid) proteasome activity.\",\n      \"evidence\": \"PA28alpha/PA28beta double-knockout mice with proteolytic activity and CTL antigen presentation assays\",\n      \"pmids\": [\"11689430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only certain antigens depend on PA28 unresolved\", \"Contribution of hybrid versus capped proteasomes not quantified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Determined when PA28alpha/beta engages the proteasome, showing association from precursor assembly through maturation rather than only with mature particles.\",\n      \"evidence\": \"Co-immunoprecipitation of PA28alpha/beta with proteasome precursor and mature complexes in dendritic cells\",\n      \"pmids\": [\"11745344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (co-IP) without reciprocal or structural confirmation\", \"Functional significance of precursor association untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended PA28 function to diabetic microvascular pathology, showing PA28-20S activity drives inflammatory gene expression under high glucose.\",\n      \"evidence\": \"PA28alpha/beta double-knockout mice in STZ-diabetes model plus peptide inhibitors of PA28-20S binding and OPN/MCP-1 readouts\",\n      \"pmids\": [\"27830089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates linking PA28 activity to OPN/MCP-1 expression unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CDK15 as a downstream target whose PA28-dependent down-regulation promotes tumor invasion, connecting PA28 activity to a defined oncogenic phenotype.\",\n      \"evidence\": \"siRNA knockdown of PA28alpha, PA28beta and beta5i in breast cancer cells with invasion assays and CDK15 protein measurement\",\n      \"pmids\": [\"31824858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDK15 is a direct proteasome substrate not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a proliferation and drug-resistance role in multiple myeloma, where PA28alpha sets proteasomal load and dependence.\",\n      \"evidence\": \"PA28alpha knockdown in myeloma cell lines with proteasome activity, growth, and proteasome-inhibitor sensitivity assays\",\n      \"pmids\": [\"33318477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the homeostatic shift away from proteasome dependence unclear\", \"Single lab, cell-line based\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PSME1/2 proteasome activity to bone homeostasis through control of beta-catenin levels and Wnt signaling.\",\n      \"evidence\": \"Recombinant PSME1/2 treatment of osteoblast/osteoclast cultures, beta-catenin level/localization assays, carfilzomib, and OVX mouse micro-CT\",\n      \"pmids\": [\"34838695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether beta-catenin is a direct PA28-proteasome substrate not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Probed PA28alpha's role in proteostasis and aging, showing it can sustain anti-aggregation capacity yet paradoxically lower PA28-dependent proteasome capacity in some tissues.\",\n      \"evidence\": \"Transgenic PA28alpha-overexpressing mice with aggregation assays, proteasome activity, and behavioral testing across ages\",\n      \"pmids\": [\"33720528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism behind tissue-specific and paradoxical proteasome effects unresolved\", \"Sex-specific findings not generalized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a substrate-stabilizing function in viral infection, where PSME1 binds HBV core protein and protects it from 26S degradation.\",\n      \"evidence\": \"APEX2 proximity labeling and co-IP of PSME1 with HBc, plus PSME1 knockdown measuring HBc stability and HBV transcription\",\n      \"pmids\": [\"39281837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a 20S activator shields a substrate from 26S degradation mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a PA28alpha/ABCA1/cholesterol efflux axis in podocytes regulated by CCDC92, connecting PA28-mediated degradation to lipid handling in diabetic kidney disease.\",\n      \"evidence\": \"Podocyte-specific Ccdc92 knockout mice with ABCA1 degradation, cholesterol efflux, and PA28alpha activity assays\",\n      \"pmids\": [\"38228909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical/biochemical link between PA28alpha and ABCA1 degradation not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PA28alpha switches between activating proteasomal degradation of some targets and stabilizing others, and what dictates its substrate/epitope selectivity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the PA28-20S or PA28-substrate complex in the corpus\", \"No unifying rule for substrate/epitope selection across the diverse disease contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"PA28alpha/beta (11S/REG) proteasome activator\", \"20S proteasome (PA28-capped/hybrid proteasome)\"],\n    \"partners\": [\"PSME2\", \"HBc\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}