{"gene":"PSMA3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2011,"finding":"PSMA3 (alpha 7 subunit of the 20S proteasome) interacts with splicing factors both in the cytoplasm and nucleus, and the 20S proteasome is involved in the regulation of SMN2 pre-mRNA splicing in vitro, revealing a functional link between the proteasome and mRNA metabolism.","method":"Co-immunoprecipitation, 2D-GE/tandem mass spectrometry interactome, in vitro splicing assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical pulldowns plus in vitro functional splicing assay; single lab but two orthogonal methods","pmids":["22079093"],"is_preprint":false},{"year":2022,"finding":"The C-terminal 69-amino-acid region of PSMA3 functions as an 'IDP trapper': it preferentially interacts with intrinsically disordered proteins (IDPs) both in vivo and in cell-free experiments, and a recombinant C-terminal fragment blocks IDP degradation by the 20S proteasome in vitro, indicating this region mediates substrate recognition for ubiquitin-independent 20S degradation.","method":"Protein interactome dataset analysis, in vivo co-immunoprecipitation, cell-free binding assays, in vitro proteasome degradation assay with recombinant C-terminal fragment","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of IDP binding and competitive inhibition of degradation, plus in vivo confirmation, multiple orthogonal methods in single study","pmids":["36291102"],"is_preprint":false},{"year":2023,"finding":"Truncation of the PSMA3 C-terminus (the IDP trapper region) phenocopies PSMD1 (19S subunit) knockdown in disrupting 26S proteasome integrity, as shown by fluorescent live-cell imaging of CRISPR-tagged proteasome subunits; the PSMA3 C-terminal region is therefore critical for 26S assembly/stability.","method":"CRISPR-based fluorescent tagging of endogenous PSMB6 (YFP) and PSMD6 (mScarlet), live-cell imaging, colocalization analysis under PSMD1 knockdown and PSMA3 C-terminal truncation conditions","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization experiment with functional consequence (loss of 26S integrity); single lab, two fluorescent reporters as orthogonal readout","pmids":["37371572"],"is_preprint":false},{"year":2024,"finding":"The RRLIF box at the C-terminus of p21 mediates direct interaction with the PSMA3 C-terminal trapper domain in cells; deletion or mutation of this box by CRISPR editing extended p21 half-life and caused aberrant cell cycle progression and enhanced senescence signaling after DNA damage, establishing the PSMA3 trapper as the receptor for a ubiquitin-independent degron on p21.","method":"Split luciferase reporter assay, p21 mutagenesis, CRISPR genome editing (HEK293/HeLa), p21 half-life measurement, cell cycle and senescence phenotypic assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (split luciferase, mutagenesis, CRISPR editing, half-life) in single preprint lab study; not yet peer-reviewed","pmids":["bio_10.1101_2024.08.29.610237"],"is_preprint":true},{"year":2019,"finding":"PSMA3 mRNA is packaged into exosomes by mesenchymal stem cells and transferred to multiple myeloma cells, where elevated PSMA3 expression promotes resistance to proteasome inhibitors (carfilzomib/bortezomib); the antisense lncRNA PSMA3-AS1 forms an RNA duplex with pre-PSMA3 to increase its mRNA stability and thus upregulate PSMA3 protein levels.","method":"Exosome characterization (DLS, TEM, Western blot), co-culture exosome transfer experiments, siRNA knockdown, in vivo xenograft model with siPSMA3-AS1","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional rescue with siRNA in vitro and in vivo, exosome transfer demonstrated; RNA duplex model supported by RNA stability data; single lab","pmids":["30610101"],"is_preprint":false}],"current_model":"PSMA3 (alpha 7 / α7 subunit of the 20S proteasome) contributes to ubiquitin-independent protein degradation through its C-terminal 'IDP trapper' domain, which directly captures intrinsically disordered proteins (including p21 via its RRLIF degron box) and delivers them for 20S proteasomal degradation; this C-terminal region is also required for 26S proteasome integrity. Additionally, PSMA3 associates with splicing factors and participates in pre-mRNA splicing regulation in vitro."},"narrative":{"mechanistic_narrative":"PSMA3 is the alpha-7 (α7) subunit of the 20S proteasome and functions as a substrate-recognition module for ubiquitin-independent protein degradation [PMID:36291102]. Its C-terminal 69-amino-acid region acts as an 'IDP trapper' that preferentially binds intrinsically disordered proteins and, as a recombinant fragment, competitively blocks their degradation by the 20S proteasome, identifying this region as the receptor that delivers disordered substrates for proteolysis [PMID:36291102]. One such substrate is the cell-cycle inhibitor p21, whose C-terminal RRLIF box docks directly onto the PSMA3 trapper domain; disrupting this degron extends p21 half-life and produces aberrant cell-cycle progression and enhanced senescence signaling after DNA damage, establishing the trapper as the receptor for a ubiquitin-independent degron [PMID:bio_10.1101_2024.08.29.610237]. Beyond substrate capture, the same C-terminal region is required for 26S proteasome integrity, since its truncation phenocopies loss of the 19S subunit PSMD1 in disrupting 26S assembly [PMID:37371572]. PSMA3 additionally associates with splicing factors in both cytoplasm and nucleus and links proteasome function to pre-mRNA splicing regulation in vitro [PMID:22079093]. PSMA3 expression is controlled post-transcriptionally by the antisense lncRNA PSMA3-AS1, which stabilizes PSMA3 mRNA and, when delivered via mesenchymal stem cell exosomes, promotes multiple myeloma resistance to proteasome inhibitors [PMID:30610101].","teleology":[{"year":2011,"claim":"Whether the proteasome core particle has roles beyond bulk degradation was unclear; this work showed PSMA3 physically associates with splicing factors and that the 20S proteasome influences pre-mRNA splicing, linking the proteasome to mRNA metabolism.","evidence":"Co-immunoprecipitation, 2D-GE/MS interactome, and in vitro SMN2 splicing assay","pmids":["22079093"],"confidence":"Medium","gaps":["Does not define which PSMA3 region mediates splicing-factor binding","In vitro splicing effect not mapped to a direct catalytic or scaffolding role","Physiological relevance of the proteasome–splicing link not established"]},{"year":2022,"claim":"How the 20S proteasome recognizes substrates without ubiquitin was unknown; this study localized substrate recognition to the PSMA3 C-terminal 69 residues, which selectively bind intrinsically disordered proteins and gate their degradation.","evidence":"Interactome analysis, in vivo Co-IP, cell-free binding, and competitive in vitro 20S degradation assay with recombinant C-terminal fragment","pmids":["36291102"],"confidence":"High","gaps":["Identity of the full IDP substrate repertoire not enumerated","Structural basis of disordered-protein recognition not resolved","How trapped IDPs are translocated into the catalytic chamber unknown"]},{"year":2023,"claim":"Whether the IDP trapper region has a structural function beyond substrate capture was open; truncating it disrupted 26S integrity comparably to loss of the 19S subunit PSMD1, showing the C-terminus is also required for holoenzyme assembly/stability.","evidence":"CRISPR fluorescent tagging of endogenous PSMB6 and PSMD6, live-cell imaging and colocalization under PSMA3 C-terminal truncation","pmids":["37371572"],"confidence":"Medium","gaps":["Does not separate the assembly role from the substrate-trapping role at residue level","Mechanism by which the C-terminus stabilizes 19S–20S docking not defined","Single-lab imaging readout without biochemical reconstitution of 26S assembly"]},{"year":2024,"claim":"It was unknown whether the trapper recognizes a defined degron; mapping identified the p21 C-terminal RRLIF box as the docking motif, and its disruption stabilized p21 and perturbed cell-cycle and senescence responses, establishing PSMA3 as a degron receptor with physiological output.","evidence":"Split-luciferase interaction reporter, p21 mutagenesis, CRISPR editing in HEK293/HeLa, half-life measurement, and cell-cycle/senescence assays (preprint)","pmids":["bio_10.1101_2024.08.29.610237"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Consensus degron beyond p21 RRLIF not generalized","Structure of the trapper–degron interface not determined"]},{"year":2019,"claim":"How PSMA3 levels are set and contribute to drug resistance was unclear; this work showed the antisense lncRNA PSMA3-AS1 stabilizes PSMA3 mRNA and that exosomal transfer of PSMA3 from stromal cells confers proteasome-inhibitor resistance in myeloma.","evidence":"Exosome characterization, co-culture transfer, siRNA knockdown, RNA-stability analysis, and xenograft model with siPSMA3-AS1","pmids":["30610101"],"confidence":"Medium","gaps":["Molecular mechanism by which elevated PSMA3 drives inhibitor resistance not defined","RNA duplex model not validated by direct structural mapping","Generality across other tumor types not tested"]},{"year":null,"claim":"The structural basis by which the PSMA3 C-terminal trapper distinguishes disordered substrates and degrons, and how this is coupled to translocation and 26S assembly, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the trapper–IDP or trapper–degron complex","Full substrate repertoire of ubiquitin-independent 20S degradation via PSMA3 unknown","Mechanistic separation of substrate-trapping versus 26S-assembly functions of the C-terminus not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["20S proteasome","26S proteasome"],"partners":["P21/CDKN1A","PSMD1","PSMA3-AS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25788","full_name":"Proteasome subunit alpha type-3","aliases":["Macropain subunit C8","Multicatalytic endopeptidase complex subunit C8","Proteasome component C8","Proteasome subunit alpha-7","alpha-7"],"length_aa":255,"mass_kda":28.4,"function":"Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P25788/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA3","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100567","cell_line_id":"CID000109","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMD3","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"UCHL5","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000109","total_profiled":1310},"omim":[{"mim_id":"613386","title":"PROTEASOME MATURATION PROTEIN; POMP","url":"https://www.omim.org/entry/613386"},{"mim_id":"606607","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 7; PSMA7","url":"https://www.omim.org/entry/606607"},{"mim_id":"606223","title":"PROTEASOME 26S SUBUNIT, NON-ATPASE, 2; PSMD2","url":"https://www.omim.org/entry/606223"},{"mim_id":"256040","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 1; PRAAS1","url":"https://www.omim.org/entry/256040"},{"mim_id":"177046","title":"PROTEASOME SUBUNIT, BETA-TYPE, 8; PSMB8","url":"https://www.omim.org/entry/177046"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA3"},"hgnc":{"alias_symbol":["HC8"],"prev_symbol":[]},"alphafold":{"accession":"P25788","domains":[{"cath_id":"3.60.20.10","chopping":"21-53_64-249","consensus_level":"high","plddt":96.8672,"start":21,"end":249}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25788","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25788-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25788-F1-predicted_aligned_error_v6.png","plddt_mean":94.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA3","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA3"},"sequence":{"accession":"P25788","fasta_url":"https://rest.uniprot.org/uniprotkb/P25788.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25788/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25788"}},"corpus_meta":[{"pmid":"30610101","id":"PMC_30610101","title":"Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30610101","citation_count":110,"is_preprint":false},{"pmid":"32005028","id":"PMC_32005028","title":"Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32005028","citation_count":60,"is_preprint":false},{"pmid":"22079093","id":"PMC_22079093","title":"Proteomic analysis of the 20S proteasome (PSMA3)-interacting proteins reveals a functional link between the proteasome and mRNA metabolism.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22079093","citation_count":38,"is_preprint":false},{"pmid":"35022330","id":"PMC_35022330","title":"PSMA3-AS1 induced by transcription factor PAX5 promotes cholangiocarcinoma proliferation, migration and invasion by sponging miR-376a-3p to up-regulate LAMC1.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/35022330","citation_count":24,"is_preprint":false},{"pmid":"33275226","id":"PMC_33275226","title":"LncRNA PSMA3-AS1 promotes colorectal cancer cell migration and invasion via regulating miR-4429.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33275226","citation_count":22,"is_preprint":false},{"pmid":"34520102","id":"PMC_34520102","title":"LncRNA PSMA3-AS1 promotes cell proliferation, migration, and invasion in ovarian cancer by activating the PI3K/Akt pathway via the miR-378a-3p/GALNT3 axis.","date":"2021","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34520102","citation_count":20,"is_preprint":false},{"pmid":"34294084","id":"PMC_34294084","title":"Long non-coding RNA PSMA3-AS1 promotes glioma progression through modulating the miR-411-3p/HOXA10 pathway.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34294084","citation_count":19,"is_preprint":false},{"pmid":"34720049","id":"PMC_34720049","title":"YY1-induced long non-coding RNA PSMA3 antisense RNA 1 functions as a competing endogenous RNA for microRNA 214-5p to expedite the viability and restrict the apoptosis of bladder cancer cells via regulating programmed cell death-ligand 1.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34720049","citation_count":17,"is_preprint":false},{"pmid":"34610219","id":"PMC_34610219","title":"lncRNA PSMA3-AS1 promotes the progression of non-small cell lung cancer through targeting miR-17-5p/PD-L1.","date":"2021","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/34610219","citation_count":17,"is_preprint":false},{"pmid":"32669876","id":"PMC_32669876","title":"LncRNA PSMA3-AS1 Promotes Lung Cancer Growth and Invasion via Sponging MiR-4504.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32669876","citation_count":15,"is_preprint":false},{"pmid":"37403106","id":"PMC_37403106","title":"Long noncoding RNA PSMA3-AS1 functions as a competing endogenous RNA to promote gastric cancer progression by regulating the miR-329-3p/ALDOA axis.","date":"2023","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/37403106","citation_count":14,"is_preprint":false},{"pmid":"24875235","id":"PMC_24875235","title":"Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.","date":"2014","source":"Pediatrics and neonatology","url":"https://pubmed.ncbi.nlm.nih.gov/24875235","citation_count":14,"is_preprint":false},{"pmid":"32945481","id":"PMC_32945481","title":"Long noncoding RNA PSMA3‑AS1 functions as a microRNA‑409‑3p sponge to promote the progression of non‑small cell lung carcinoma by targeting spindlin 1.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32945481","citation_count":13,"is_preprint":false},{"pmid":"37088992","id":"PMC_37088992","title":"METTL3 affects FLT3-ITD+ acute myeloid leukemia by mediating autophagy by regulating PSMA3-AS1 stability.","date":"2023","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/37088992","citation_count":10,"is_preprint":false},{"pmid":"38203269","id":"PMC_38203269","title":"The Expression Patterns and Implications of MALAT1, MANCR, PSMA3-AS1 and miR-101 in Esophageal Adenocarcinoma.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38203269","citation_count":8,"is_preprint":false},{"pmid":"25606411","id":"PMC_25606411","title":"PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity in Latvians, Lithuanians and Taiwanese.","date":"2014","source":"Meta gene","url":"https://pubmed.ncbi.nlm.nih.gov/25606411","citation_count":7,"is_preprint":false},{"pmid":"28560424","id":"PMC_28560424","title":"Secretomic profiling of cells from hollow fiber bioreactor reveals PSMA3 as a potential cholangiocarcinoma biomarker.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28560424","citation_count":7,"is_preprint":false},{"pmid":"32894281","id":"PMC_32894281","title":"Long non-coding RNA PSMA3-AS1 enhances cell proliferation, migration and invasion by regulating miR-302a-3p/RAB22A in glioma.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32894281","citation_count":6,"is_preprint":false},{"pmid":"36607951","id":"PMC_36607951","title":"Long Noncoding RNA PSMA3 Antisense RNA 1 Promotes Cell Proliferation, Migration, and Invasion in Pancreatic Ductal Adenocarcinoma Via Targeting MicroRNA-154-5p to Positively Modulate Karyopherin Subunit Alpha 4.","date":"2022","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/36607951","citation_count":6,"is_preprint":false},{"pmid":"36291102","id":"PMC_36291102","title":"The C-Terminus of the PSMA3 Proteasome Subunit Preferentially Traps Intrinsically Disordered Proteins for Degradation.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36291102","citation_count":6,"is_preprint":false},{"pmid":"22894781","id":"PMC_22894781","title":"Polyclonal antibodies against human proteasome subunits PSMA3, PSMA5, and PSMB5.","date":"2012","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/22894781","citation_count":5,"is_preprint":false},{"pmid":"38158666","id":"PMC_38158666","title":"LncRNA PSMA3-AS1 promotes preterm delivery by inducing ferroptosis via miR-224-3p/Nrf2 axis.","date":"2023","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38158666","citation_count":4,"is_preprint":false},{"pmid":"38279473","id":"PMC_38279473","title":"LncRNA PSMA3-AS1 activates the progression of triple-negative breast cancer cells by blocking miR-186-5p-mediated PSME3 inhibition.","date":"2023","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38279473","citation_count":3,"is_preprint":false},{"pmid":"37371572","id":"PMC_37371572","title":"Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S 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subunit of the 20S proteasome) interacts with splicing factors both in the cytoplasm and nucleus, and the 20S proteasome is involved in the regulation of SMN2 pre-mRNA splicing in vitro, revealing a functional link between the proteasome and mRNA metabolism.\",\n      \"method\": \"Co-immunoprecipitation, 2D-GE/tandem mass spectrometry interactome, in vitro splicing assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical pulldowns plus in vitro functional splicing assay; single lab but two orthogonal methods\",\n      \"pmids\": [\"22079093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminal 69-amino-acid region of PSMA3 functions as an 'IDP trapper': it preferentially interacts with intrinsically disordered proteins (IDPs) both in vivo and in cell-free experiments, and a recombinant C-terminal fragment blocks IDP degradation by the 20S proteasome in vitro, indicating this region mediates substrate recognition for ubiquitin-independent 20S degradation.\",\n      \"method\": \"Protein interactome dataset analysis, in vivo co-immunoprecipitation, cell-free binding assays, in vitro proteasome degradation assay with recombinant C-terminal fragment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of IDP binding and competitive inhibition of degradation, plus in vivo confirmation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36291102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Truncation of the PSMA3 C-terminus (the IDP trapper region) phenocopies PSMD1 (19S subunit) knockdown in disrupting 26S proteasome integrity, as shown by fluorescent live-cell imaging of CRISPR-tagged proteasome subunits; the PSMA3 C-terminal region is therefore critical for 26S assembly/stability.\",\n      \"method\": \"CRISPR-based fluorescent tagging of endogenous PSMB6 (YFP) and PSMD6 (mScarlet), live-cell imaging, colocalization analysis under PSMD1 knockdown and PSMA3 C-terminal truncation conditions\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization experiment with functional consequence (loss of 26S integrity); single lab, two fluorescent reporters as orthogonal readout\",\n      \"pmids\": [\"37371572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The RRLIF box at the C-terminus of p21 mediates direct interaction with the PSMA3 C-terminal trapper domain in cells; deletion or mutation of this box by CRISPR editing extended p21 half-life and caused aberrant cell cycle progression and enhanced senescence signaling after DNA damage, establishing the PSMA3 trapper as the receptor for a ubiquitin-independent degron on p21.\",\n      \"method\": \"Split luciferase reporter assay, p21 mutagenesis, CRISPR genome editing (HEK293/HeLa), p21 half-life measurement, cell cycle and senescence phenotypic assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (split luciferase, mutagenesis, CRISPR editing, half-life) in single preprint lab study; not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.29.610237\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMA3 mRNA is packaged into exosomes by mesenchymal stem cells and transferred to multiple myeloma cells, where elevated PSMA3 expression promotes resistance to proteasome inhibitors (carfilzomib/bortezomib); the antisense lncRNA PSMA3-AS1 forms an RNA duplex with pre-PSMA3 to increase its mRNA stability and thus upregulate PSMA3 protein levels.\",\n      \"method\": \"Exosome characterization (DLS, TEM, Western blot), co-culture exosome transfer experiments, siRNA knockdown, in vivo xenograft model with siPSMA3-AS1\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional rescue with siRNA in vitro and in vivo, exosome transfer demonstrated; RNA duplex model supported by RNA stability data; single lab\",\n      \"pmids\": [\"30610101\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA3 (alpha 7 / α7 subunit of the 20S proteasome) contributes to ubiquitin-independent protein degradation through its C-terminal 'IDP trapper' domain, which directly captures intrinsically disordered proteins (including p21 via its RRLIF degron box) and delivers them for 20S proteasomal degradation; this C-terminal region is also required for 26S proteasome integrity. Additionally, PSMA3 associates with splicing factors and participates in pre-mRNA splicing regulation in vitro.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA3 is the alpha-7 (\\u03b17) subunit of the 20S proteasome and functions as a substrate-recognition module for ubiquitin-independent protein degradation [#1]. Its C-terminal 69-amino-acid region acts as an 'IDP trapper' that preferentially binds intrinsically disordered proteins and, as a recombinant fragment, competitively blocks their degradation by the 20S proteasome, identifying this region as the receptor that delivers disordered substrates for proteolysis [#1]. One such substrate is the cell-cycle inhibitor p21, whose C-terminal RRLIF box docks directly onto the PSMA3 trapper domain; disrupting this degron extends p21 half-life and produces aberrant cell-cycle progression and enhanced senescence signaling after DNA damage, establishing the trapper as the receptor for a ubiquitin-independent degron [#3]. Beyond substrate capture, the same C-terminal region is required for 26S proteasome integrity, since its truncation phenocopies loss of the 19S subunit PSMD1 in disrupting 26S assembly [#2]. PSMA3 additionally associates with splicing factors in both cytoplasm and nucleus and links proteasome function to pre-mRNA splicing regulation in vitro [#0]. PSMA3 expression is controlled post-transcriptionally by the antisense lncRNA PSMA3-AS1, which stabilizes PSMA3 mRNA and, when delivered via mesenchymal stem cell exosomes, promotes multiple myeloma resistance to proteasome inhibitors [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether the proteasome core particle has roles beyond bulk degradation was unclear; this work showed PSMA3 physically associates with splicing factors and that the 20S proteasome influences pre-mRNA splicing, linking the proteasome to mRNA metabolism.\",\n      \"evidence\": \"Co-immunoprecipitation, 2D-GE/MS interactome, and in vitro SMN2 splicing assay\",\n      \"pmids\": [\"22079093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define which PSMA3 region mediates splicing-factor binding\", \"In vitro splicing effect not mapped to a direct catalytic or scaffolding role\", \"Physiological relevance of the proteasome\\u2013splicing link not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How the 20S proteasome recognizes substrates without ubiquitin was unknown; this study localized substrate recognition to the PSMA3 C-terminal 69 residues, which selectively bind intrinsically disordered proteins and gate their degradation.\",\n      \"evidence\": \"Interactome analysis, in vivo Co-IP, cell-free binding, and competitive in vitro 20S degradation assay with recombinant C-terminal fragment\",\n      \"pmids\": [\"36291102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the full IDP substrate repertoire not enumerated\", \"Structural basis of disordered-protein recognition not resolved\", \"How trapped IDPs are translocated into the catalytic chamber unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether the IDP trapper region has a structural function beyond substrate capture was open; truncating it disrupted 26S integrity comparably to loss of the 19S subunit PSMD1, showing the C-terminus is also required for holoenzyme assembly/stability.\",\n      \"evidence\": \"CRISPR fluorescent tagging of endogenous PSMB6 and PSMD6, live-cell imaging and colocalization under PSMA3 C-terminal truncation\",\n      \"pmids\": [\"37371572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate the assembly role from the substrate-trapping role at residue level\", \"Mechanism by which the C-terminus stabilizes 19S\\u201320S docking not defined\", \"Single-lab imaging readout without biochemical reconstitution of 26S assembly\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"It was unknown whether the trapper recognizes a defined degron; mapping identified the p21 C-terminal RRLIF box as the docking motif, and its disruption stabilized p21 and perturbed cell-cycle and senescence responses, establishing PSMA3 as a degron receptor with physiological output.\",\n      \"evidence\": \"Split-luciferase interaction reporter, p21 mutagenesis, CRISPR editing in HEK293/HeLa, half-life measurement, and cell-cycle/senescence assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.08.29.610237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Consensus degron beyond p21 RRLIF not generalized\", \"Structure of the trapper\\u2013degron interface not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How PSMA3 levels are set and contribute to drug resistance was unclear; this work showed the antisense lncRNA PSMA3-AS1 stabilizes PSMA3 mRNA and that exosomal transfer of PSMA3 from stromal cells confers proteasome-inhibitor resistance in myeloma.\",\n      \"evidence\": \"Exosome characterization, co-culture transfer, siRNA knockdown, RNA-stability analysis, and xenograft model with siPSMA3-AS1\",\n      \"pmids\": [\"30610101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which elevated PSMA3 drives inhibitor resistance not defined\", \"RNA duplex model not validated by direct structural mapping\", \"Generality across other tumor types not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis by which the PSMA3 C-terminal trapper distinguishes disordered substrates and degrons, and how this is coupled to translocation and 26S assembly, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the trapper\\u2013IDP or trapper\\u2013degron complex\", \"Full substrate repertoire of ubiquitin-independent 20S degradation via PSMA3 unknown\", \"Mechanistic separation of substrate-trapping versus 26S-assembly functions of the C-terminus not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"20S proteasome\", \"26S proteasome\"],\n    \"partners\": [\"p21/CDKN1A\", \"PSMD1\", \"PSMA3-AS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}