{"gene":"PSMD13","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1998,"finding":"Human p40.5 (PSMD13) was identified by cDNA cloning as a non-ATPase subunit of PA700 (19S regulatory complex) of the 26S proteasome, consisting of 376 amino acids (calculated MW ~42.9 kDa, pI 5.46). Its yeast ortholog Nas7p was identified; disruption of NAS7 caused temperature-sensitive growth (inability to proliferate at 37°C), indicating a role in proteasome function under stress, while NAS6 disruption had no effect on viability. Similarly, human p28 (PSMD9) was found to contain five ankyrin repeats, suggesting protein-interaction roles.","method":"cDNA cloning, sequence homology analysis, yeast gene disruption with phenotypic analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — gene disruption with defined phenotypic readout (temperature sensitivity), replicated in yeast ortholog system","pmids":["9714768"],"is_preprint":false},{"year":1999,"finding":"Yeast Rpn9 (ortholog of human PSMD13) is required for efficient 26S proteasome assembly. Deletion of RPN9 caused temperature-sensitive growth and accumulation of multiubiquitinated proteins at restrictive temperature. Glycerol density gradient centrifugation showed reduced 26S proteasome levels and shifted to lighter fractions, with accumulation of incomplete proteasome complexes. Rpn9 was found necessary for incorporating the ubiquitin receptor Rpn10 into the 26S proteasome.","method":"Yeast two-hybrid screening, glycerol density gradient centrifugation, native PAGE, genetic deletion with phenotypic analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical fractionation, genetic analysis, native PAGE) in yeast ortholog; replicated concept from gene disruption data","pmids":["10490597"],"is_preprint":false},{"year":2006,"finding":"PSMD13 and SIRT3 share a bidirectional promoter within a 788-bp intergenic region (head-to-head configuration). Transfection experiments in HeLa cells using deletion mutants of the PSMD13-SIRT3 intergenic region demonstrated a complex pathway of co-regulation acting in both transcriptional directions.","method":"Transfection of deletion mutant reporter constructs in HeLa cells, linkage disequilibrium analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — deletion mutant transfection experiments establish shared regulatory elements but mechanism is partially characterized","pmids":["17059877"],"is_preprint":false},{"year":2015,"finding":"The NMR solution structure of yeast Rpn9 (PSMD13 ortholog) was determined at high resolution, revealing an all-helical N-terminal domain and a C-terminal PCI domain linked via a semiflexible hinge. The N-terminal domain mediates interaction with the ubiquitin receptor Rpn10, while the PCI domain mediates interaction with neighboring PCI subunit Rpn5. The Rpn9-Rpn5 interface involves a hydrophobic center surrounded by ionic pairs within the winged-helix module, a pattern conserved across all PCI-PCI interactions in the lid complex.","method":"High-resolution NMR structure determination with functional interaction mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — atomic resolution NMR structure with functionally validated interaction interfaces for Rpn10 and Rpn5","pmids":["25631053"],"is_preprint":false},{"year":2023,"finding":"PSMD13 inhibits the NF-κB pathway in fish (miiuy croaker) by targeting TAK1. PSMD13 expression was upregulated by Vibrio harveyi stimulation. Mechanistically, PSMD13 significantly inhibited K63-linked ubiquitination of TAK1, thereby suppressing TAK1 expression and downstream NF-κB signaling.","method":"Gene expression analysis, overexpression/knockdown assays, ubiquitination assays measuring K63-linked ubiquitin chains on TAK1","journal":"Fish & shellfish immunology","confidence":"Medium","confidence_rationale":"Tier 3 — ubiquitination assay with defined substrate, single lab, non-mammalian model organism but mechanistically relevant","pmids":["37257570"],"is_preprint":false},{"year":2023,"finding":"Psmd13 expression is required for megakaryocytic-erythroid development of hematopoietic stem cells (HSCs). IL-4 stimulation in vitro downregulates Psmd13. shRNA-mediated knockdown of Psmd13 in HSCs severely compromised repopulating capacity and megakaryocytic differentiation in vivo and increased apoptosis, placing Psmd13 downstream of IL-4 signaling in the HSC stress-resistance and megakaryocytic differentiation pathway.","method":"Single-cell transcriptome analysis, shRNA knockdown in HSCs, in vivo transplantation assays, functional differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean in vivo KD with defined cellular phenotype (repopulation, differentiation, apoptosis) placing Psmd13 in IL-4 signaling axis","pmids":["37653079"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, rpn-9 (ortholog of human PSMD13) shows synthetic genetic interaction with ubh-4 (BAP1 ortholog). Combined inactivation of rpn-9 and ubh-4 affected body size, lifespan, and germ cell development, identifying PSMD13 as a synthetic lethal partner of BAP1. ubh-4 inactivation also sensitized animals to the proteasome inhibitor Bortezomib.","method":"CRISPR-Cas mutagenesis, RNAi screen, genetic epistasis in C. elegans, drug sensitivity assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis by RNAi screen with multiple phenotypic readouts in C. elegans ortholog model","pmids":["36980270"],"is_preprint":false},{"year":2026,"finding":"Psmd13 interacts with Dicer in mouse neural precursor cells (mNPCs), as shown by co-immunoprecipitation, and this interaction modulates miR-29a levels in a differentiation-dependent manner. ChIP-seq revealed co-occupancy of Psmd13 and Dicer at genomic loci including the miR-29a locus. RNAi-mediated Psmd13 knockdown enhanced neuronal differentiation and altered miR-29a expression. Proteasome inhibition with MG132 reduced both Psmd13 and Dicer levels, downregulated miR-29a, and impaired neuronal differentiation, suggesting Psmd13 acts as an upstream modulator of miRNA biogenesis.","method":"QTL mapping in Collaborative Cross mice, RNAi knockdown, co-immunoprecipitation, ChIP-seq, MG132 pharmacological inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and ChIP-seq with functional KD phenotype, single lab, mechanistic link to Dicer suggested but not fully reconstituted","pmids":["41734180"],"is_preprint":false}],"current_model":"PSMD13 (p40.5) is a non-ATPase subunit of the 19S regulatory particle lid complex of the 26S proteasome, where its PCI domain mediates interaction with neighboring PCI subunit Rpn5 and its N-terminal domain recruits the ubiquitin receptor Rpn10 to enable efficient proteasome assembly; beyond its structural role, PSMD13 modulates innate immune signaling by suppressing K63-linked ubiquitination of TAK1 to inhibit NF-κB activation, supports hematopoietic stem cell stress resistance and megakaryocytic differentiation downstream of IL-4, and associates with Dicer to regulate miR-29a levels during neuronal differentiation."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of PSMD13 (p40.5) as a non-ATPase subunit of the 19S regulatory complex established its place within the 26S proteasome and showed, via yeast NAS7 disruption, that it is required for proteasome function under stress.","evidence":"cDNA cloning of human p40.5, yeast NAS7 gene disruption with temperature-sensitive growth phenotype","pmids":["9714768"],"confidence":"Medium","gaps":["Biochemical role within the 19S lid not yet defined","No structural information on how PSMD13 integrates into the lid complex","Mechanism of temperature sensitivity not resolved"]},{"year":1999,"claim":"Deletion of the yeast ortholog Rpn9 demonstrated that PSMD13 is required for efficient 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, answering how loss of this subunit leads to ubiquitin-conjugate accumulation.","evidence":"Glycerol density gradient centrifugation, native PAGE, and genetic deletion in yeast showing incomplete proteasome complexes and loss of Rpn10 incorporation","pmids":["10490597"],"confidence":"High","gaps":["Structural basis for Rpn10 recruitment unknown","Whether assembly role is conserved in mammalian cells not tested"]},{"year":2015,"claim":"The high-resolution NMR structure of yeast Rpn9 resolved the architectural basis for PSMD13 function: the N-terminal domain recruits Rpn10 and the C-terminal PCI domain contacts Rpn5 via a conserved hydrophobic/ionic winged-helix interface, establishing the structural logic of PCI-PCI interactions throughout the lid.","evidence":"NMR solution structure with functionally validated interaction surfaces for Rpn10 and Rpn5","pmids":["25631053"],"confidence":"High","gaps":["No mammalian structure available","Dynamics of the semiflexible hinge between domains not functionally tested","How Rpn10 recruitment is coordinated with other assembly chaperones remains unclear"]},{"year":2023,"claim":"Three independent studies extended PSMD13 function beyond core proteasome biology: it suppresses NF-κB by inhibiting K63-linked ubiquitination of TAK1 in innate immunity, it sustains HSC repopulating capacity and megakaryocytic differentiation downstream of IL-4, and its genetic interaction with the BAP1 ortholog in C. elegans links it to ubiquitin homeostasis and organismal fitness.","evidence":"K63-ubiquitination assays on TAK1 in fish (PMID:37257570); shRNA knockdown with in vivo transplantation in mouse HSCs (PMID:37653079); CRISPR/RNAi synthetic lethal screen in C. elegans (PMID:36980270)","pmids":["37257570","37653079","36980270"],"confidence":"Medium","gaps":["NF-κB regulatory function demonstrated only in teleost; mammalian validation lacking","Whether IL-4–Psmd13 axis acts through altered proteasome activity or a moonlighting function is unresolved","Synthetic lethality with BAP1 has not been confirmed in mammalian systems"]},{"year":2026,"claim":"Discovery that PSMD13 physically associates with Dicer and co-occupies the miR-29a locus in neural precursor cells revealed a potential non-proteasomal role in miRNA biogenesis during neuronal differentiation.","evidence":"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, and MG132 treatment in mouse neural precursor cells","pmids":["41734180"],"confidence":"Medium","gaps":["Dicer interaction not reconstituted with purified proteins; indirect bridging cannot be excluded","Whether the effect on miR-29a is proteasome-dependent or reflects a direct regulatory function is not delineated","Findings from a single study in one cell type"]},{"year":null,"claim":"It remains unknown whether the non-proteasomal roles of PSMD13 (NF-κB suppression, miRNA biogenesis, HSC differentiation) reflect moonlighting functions independent of proteolytic activity or altered proteasome substrate selectivity, and no mammalian structural data or disease-causative mutations have been reported.","evidence":"","pmids":[],"confidence":"Low","gaps":["No separation-of-function mutants distinguishing proteasomal versus non-proteasomal roles","No mammalian crystal or cryo-EM structure of PSMD13 in the context of the human 26S proteasome lid","No Mendelian disease or GWAS locus directly attributed to PSMD13 coding variants"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":["26S proteasome 19S regulatory particle lid"],"partners":["RPN5","RPN10","TAK1","DICER"],"other_free_text":[]},"mechanistic_narrative":"PSMD13 is a non-ATPase subunit of the 19S regulatory particle lid of the 26S proteasome, essential for efficient proteasome assembly and ubiquitin-dependent protein degradation. Its C-terminal PCI domain mediates interaction with the neighboring lid subunit Rpn5, while its N-terminal domain recruits the ubiquitin receptor Rpn10 into the 26S proteasome, as revealed by high-resolution NMR structure determination of the yeast ortholog Rpn9 [PMID:25631053, PMID:10490597]. Loss of PSMD13/Rpn9 causes temperature-sensitive growth, accumulation of multiubiquitinated proteins, and defective proteasome assembly [PMID:10490597, PMID:9714768]. Beyond its core proteasomal role, PSMD13 suppresses NF-κB signaling by inhibiting K63-linked ubiquitination of TAK1 [PMID:37257570], supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation downstream of IL-4 [PMID:37653079], and associates with Dicer to modulate miR-29a levels during neuronal differentiation [PMID:41734180]."},"prefetch_data":{"uniprot":{"accession":"Q9UNM6","full_name":"26S proteasome non-ATPase regulatory subunit 13","aliases":["26S proteasome regulatory subunit RPN9","26S proteasome regulatory subunit S11","26S proteasome regulatory subunit p40.5"],"length_aa":376,"mass_kda":42.9,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UNM6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD13","classification":"Common Essential","n_dependent_lines":1200,"n_total_lines":1208,"dependency_fraction":0.9933774834437086},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000185627","cell_line_id":"CID000121","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000121","total_profiled":1310},"omim":[{"mim_id":"603481","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 13; PSMD13","url":"https://www.omim.org/entry/603481"},{"mim_id":"300880","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 10; PSMD10","url":"https://www.omim.org/entry/300880"},{"mim_id":"180069","title":"RETINOID ISOMEROHYDROLASE RPE65; RPE65","url":"https://www.omim.org/entry/180069"},{"mim_id":"107269","title":"CD44 ANTIGEN; CD44","url":"https://www.omim.org/entry/107269"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD13"},"hgnc":{"alias_symbol":["p40.5","Rpn9"],"prev_symbol":[]},"alphafold":{"accession":"Q9UNM6","domains":[{"cath_id":"1.20.5","chopping":"342-376","consensus_level":"medium","plddt":75.5611,"start":342,"end":376}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNM6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNM6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNM6-F1-predicted_aligned_error_v6.png","plddt_mean":70.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD13","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD13"},"sequence":{"accession":"Q9UNM6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UNM6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UNM6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNM6"}},"corpus_meta":[{"pmid":"9714768","id":"PMC_9714768","title":"cDNA cloning and functional 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6754,"output_tokens":1733,"usd":0.023128},"stage2":{"model":"claude-opus-4-6","input_tokens":5000,"output_tokens":1685,"usd":0.100687},"total_usd":0.289172,"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":17873,"output_tokens":3027,"usd":0.049512},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5831,"output_tokens":1923,"usd":0.115845}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PSMD13 (p40.5) was identified as a novel non-ATPase regulatory subunit of the 19S regulatory complex (PA700) of the human 26S proteasome, with a calculated molecular mass of ~43 kDa. Its yeast ortholog Nas7p/Rpn7 was found to be non-essential for cell viability but required for growth at elevated temperature (37°C), indicating a role in proteasome function under stress.\",\n      \"method\": \"cDNA cloning, primary structure analysis, yeast gene disruption\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and functional characterization of the subunit in both human and yeast, replicated across organisms\",\n      \"pmids\": [\"9714768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Rpn9 (yeast ortholog of PSMD13) is required for efficient assembly of the 26S proteasome; deletion of RPN9 reduces 26S proteasome levels, causes accumulation of incomplete proteasome complexes, and prevents incorporation of the ubiquitin receptor Rpn10 into the proteasome.\",\n      \"method\": \"Glycerol density gradient centrifugation, native PAGE, immunoblotting of proteasome fractions in Δrpn9 yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined biochemical phenotype (failure to incorporate Rpn10, accumulation of incomplete complexes), multiple orthogonal methods\",\n      \"pmids\": [\"10490597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NMR solution structure of yeast Rpn9 (PSMD13 ortholog) revealed an all-helical N-terminal domain that mediates interaction with the ubiquitin receptor Rpn10, and a C-terminal PCI domain that mediates interaction with neighboring PCI subunit Rpn5, forming a hydrophobic center surrounded by ionic pairs at the Rpn9-Rpn5 interface.\",\n      \"method\": \"High-resolution NMR structure determination with functional validation of domain interactions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution NMR structure with functional domain mapping and interaction validation\",\n      \"pmids\": [\"25631053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMD13 inhibits NF-κB signaling by targeting TAK1 and suppressing its K63-linked ubiquitination, thereby reducing TAK1 expression in the TLR-mediated NF-κB pathway in miiuy croaker.\",\n      \"method\": \"Overexpression/knockdown assays, ubiquitination assays measuring K63-linked ubiquitination of TAK1, NF-κB reporter assays\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay with mechanistic follow-up, but single lab in a non-mammalian fish model\",\n      \"pmids\": [\"37257570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Psmd13 knockdown in mouse hematopoietic stem cells (HSCs) severely compromises repopulating capacity and megakaryocytic differentiation and increases apoptosis in vivo, revealing a required role for Psmd13 in HSC function; IL-4 signaling suppresses Psmd13 expression to impair these processes.\",\n      \"method\": \"shRNA knockdown of Psmd13 in HSCs with in vivo transplantation assay, single-cell transcriptome analysis, in vitro IL-4 stimulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined in vivo cellular phenotype; single lab but multiple readouts\",\n      \"pmids\": [\"37653079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, rpn-9 (PSMD13 ortholog) shows synthetic lethality with ubh-4 (BAP1 ortholog) inactivation, affecting body size, lifespan, and germ cell development, positioning rpn-9/PSMD13 as a genetic interactor of the BAP1 deubiquitinase pathway at the 26S proteasome.\",\n      \"method\": \"CRISPR-generated mutations, RNAi screen, genetic epistasis in C. elegans\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by RNAi screen and CRISPR mutants with defined phenotypic readouts in a model organism ortholog\",\n      \"pmids\": [\"36980270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Psmd13 associates with Dicer by co-immunoprecipitation in mouse neural precursor cells, and ChIP-seq reveals co-occupancy of Psmd13 and Dicer at genomic loci including the miR-29a locus; Psmd13 knockdown enhances neuronal differentiation and alters miR-29a levels in a differentiation-state-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNAi knockdown in mouse neural precursor cells, MG132 proteasome inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and ChIP-seq without direct demonstration of mechanistic causality; single lab\",\n      \"pmids\": [\"41734180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD13 (p40.5/Rpn9) is a non-ATPase subunit of the 19S regulatory particle lid complex of the 26S proteasome, where its PCI domain mediates interaction with neighboring PCI subunit Rpn5 and its N-terminal domain interacts with the ubiquitin receptor Rpn10, making it essential for efficient proteasome assembly; beyond its structural role, PSMD13 participates in immune signaling by suppressing K63-linked ubiquitination of TAK1, supports hematopoietic stem cell repopulation and megakaryocytic differentiation, and may modulate miRNA biogenesis through interaction with Dicer.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers only.\n\n**Classification:**\n\n**RETRIEVED PAPERS:**\n1. PMID:9714768 — KEEP (describes p40.5/PSMD13 cDNA cloning and p28/PSMD9 as 19S subunits)\n2. PMID:17059877 — KEEP (PSMD13 gene regulation with SIRT3)\n3. PMID:10490597 — KEEP (Rpn9/yeast ortholog of PSMD13, 26S proteasome assembly)\n4. PMID:16905670 — EXCLUDE (plant RPN9, Nicotiana benthamiana — symbol collision, incompatible context)\n5. PMID:25631053 — KEEP (yeast Rpn9 NMR structure, ortholog)\n6. PMID:37257570 — KEEP (PSMD13 in fish innate immunity, NF-κB/TAK1)\n7. PMID:36731897 — EXCLUDE (expression/splicing QTL association, no mechanistic finding)\n8. PMID:37653079 — KEEP (Psmd13 knockdown in HSCs, megakaryocytic differentiation)\n9. PMID:36980270 — KEEP (C. elegans rpn-9/PSMD13 synthetic lethality with BAP1)\n10. PMID:23832675 — KEEP (yeast Rpn9 NMR assignments, ortholog)\n11. PMID:41734180 — KEEP (Psmd13-Dicer interaction, neuronal differentiation)\n12. bio_10.1101_2025.04.14.648858 — EXCLUDE (preprint, same data as PMID:41734180)\n\n**GENE2PUBMED PAPERS:**\n- Most are about APOBEC3G/CEM15, proteasome reviews, interactome screens, or unrelated topics. I will check each for PSMD13-specific mechanistic findings.\n- PMID:8811196 — general proteasome review, no PSMD13-specific mechanism — EXCLUDE (no specific finding)\n- PMID:19615732 — DUB interactome, PSMD13 may appear as interactor — check: no specific PSMD13 mechanism described — EXCLUDE\n- PMID:26186194, 28514442, 26496610, 33961781, 22939629 — large interactome screens, PSMD13 listed as network node — EXCLUDE (no specific mechanism)\n- PMID:14743216 — TNF/NF-κB map — EXCLUDE\n- All APOBEC3G/CEM15 papers — EXCLUDE (alias collision: CEM15 is APOBEC3G, not PSMD13)\n- Remaining gene2pubmed papers are cDNA sequencing projects, GO annotation, RNA biology — EXCLUDE (no PSMD13-specific mechanism)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human p40.5 (PSMD13) was identified by cDNA cloning as a non-ATPase subunit of PA700 (19S regulatory complex) of the 26S proteasome, consisting of 376 amino acids (calculated MW ~42.9 kDa, pI 5.46). Its yeast ortholog Nas7p was identified; disruption of NAS7 caused temperature-sensitive growth (inability to proliferate at 37°C), indicating a role in proteasome function under stress, while NAS6 disruption had no effect on viability. Similarly, human p28 (PSMD9) was found to contain five ankyrin repeats, suggesting protein-interaction roles.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, yeast gene disruption with phenotypic analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gene disruption with defined phenotypic readout (temperature sensitivity), replicated in yeast ortholog system\",\n      \"pmids\": [\"9714768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Yeast Rpn9 (ortholog of human PSMD13) is required for efficient 26S proteasome assembly. Deletion of RPN9 caused temperature-sensitive growth and accumulation of multiubiquitinated proteins at restrictive temperature. Glycerol density gradient centrifugation showed reduced 26S proteasome levels and shifted to lighter fractions, with accumulation of incomplete proteasome complexes. Rpn9 was found necessary for incorporating the ubiquitin receptor Rpn10 into the 26S proteasome.\",\n      \"method\": \"Yeast two-hybrid screening, glycerol density gradient centrifugation, native PAGE, genetic deletion with phenotypic analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical fractionation, genetic analysis, native PAGE) in yeast ortholog; replicated concept from gene disruption data\",\n      \"pmids\": [\"10490597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PSMD13 and SIRT3 share a bidirectional promoter within a 788-bp intergenic region (head-to-head configuration). Transfection experiments in HeLa cells using deletion mutants of the PSMD13-SIRT3 intergenic region demonstrated a complex pathway of co-regulation acting in both transcriptional directions.\",\n      \"method\": \"Transfection of deletion mutant reporter constructs in HeLa cells, linkage disequilibrium analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — deletion mutant transfection experiments establish shared regulatory elements but mechanism is partially characterized\",\n      \"pmids\": [\"17059877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NMR solution structure of yeast Rpn9 (PSMD13 ortholog) was determined at high resolution, revealing an all-helical N-terminal domain and a C-terminal PCI domain linked via a semiflexible hinge. The N-terminal domain mediates interaction with the ubiquitin receptor Rpn10, while the PCI domain mediates interaction with neighboring PCI subunit Rpn5. The Rpn9-Rpn5 interface involves a hydrophobic center surrounded by ionic pairs within the winged-helix module, a pattern conserved across all PCI-PCI interactions in the lid complex.\",\n      \"method\": \"High-resolution NMR structure determination with functional interaction mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic resolution NMR structure with functionally validated interaction interfaces for Rpn10 and Rpn5\",\n      \"pmids\": [\"25631053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMD13 inhibits the NF-κB pathway in fish (miiuy croaker) by targeting TAK1. PSMD13 expression was upregulated by Vibrio harveyi stimulation. Mechanistically, PSMD13 significantly inhibited K63-linked ubiquitination of TAK1, thereby suppressing TAK1 expression and downstream NF-κB signaling.\",\n      \"method\": \"Gene expression analysis, overexpression/knockdown assays, ubiquitination assays measuring K63-linked ubiquitin chains on TAK1\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ubiquitination assay with defined substrate, single lab, non-mammalian model organism but mechanistically relevant\",\n      \"pmids\": [\"37257570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Psmd13 expression is required for megakaryocytic-erythroid development of hematopoietic stem cells (HSCs). IL-4 stimulation in vitro downregulates Psmd13. shRNA-mediated knockdown of Psmd13 in HSCs severely compromised repopulating capacity and megakaryocytic differentiation in vivo and increased apoptosis, placing Psmd13 downstream of IL-4 signaling in the HSC stress-resistance and megakaryocytic differentiation pathway.\",\n      \"method\": \"Single-cell transcriptome analysis, shRNA knockdown in HSCs, in vivo transplantation assays, functional differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KD with defined cellular phenotype (repopulation, differentiation, apoptosis) placing Psmd13 in IL-4 signaling axis\",\n      \"pmids\": [\"37653079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, rpn-9 (ortholog of human PSMD13) shows synthetic genetic interaction with ubh-4 (BAP1 ortholog). Combined inactivation of rpn-9 and ubh-4 affected body size, lifespan, and germ cell development, identifying PSMD13 as a synthetic lethal partner of BAP1. ubh-4 inactivation also sensitized animals to the proteasome inhibitor Bortezomib.\",\n      \"method\": \"CRISPR-Cas mutagenesis, RNAi screen, genetic epistasis in C. elegans, drug sensitivity assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by RNAi screen with multiple phenotypic readouts in C. elegans ortholog model\",\n      \"pmids\": [\"36980270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Psmd13 interacts with Dicer in mouse neural precursor cells (mNPCs), as shown by co-immunoprecipitation, and this interaction modulates miR-29a levels in a differentiation-dependent manner. ChIP-seq revealed co-occupancy of Psmd13 and Dicer at genomic loci including the miR-29a locus. RNAi-mediated Psmd13 knockdown enhanced neuronal differentiation and altered miR-29a expression. Proteasome inhibition with MG132 reduced both Psmd13 and Dicer levels, downregulated miR-29a, and impaired neuronal differentiation, suggesting Psmd13 acts as an upstream modulator of miRNA biogenesis.\",\n      \"method\": \"QTL mapping in Collaborative Cross mice, RNAi knockdown, co-immunoprecipitation, ChIP-seq, MG132 pharmacological inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and ChIP-seq with functional KD phenotype, single lab, mechanistic link to Dicer suggested but not fully reconstituted\",\n      \"pmids\": [\"41734180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD13 (p40.5) is a non-ATPase subunit of the 19S regulatory particle lid complex of the 26S proteasome, where its PCI domain mediates interaction with neighboring PCI subunit Rpn5 and its N-terminal domain recruits the ubiquitin receptor Rpn10 to enable efficient proteasome assembly; beyond its structural role, PSMD13 modulates innate immune signaling by suppressing K63-linked ubiquitination of TAK1 to inhibit NF-κB activation, supports hematopoietic stem cell stress resistance and megakaryocytic differentiation downstream of IL-4, and associates with Dicer to regulate miR-29a levels during neuronal differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMD13 (Rpn9/p40.5) is a non-ATPase subunit of the 19S regulatory particle lid of the 26S proteasome that serves as a structural scaffold essential for proteasome assembly and function. Its C-terminal PCI domain mediates interaction with the neighboring lid subunit Rpn5, while its all-helical N-terminal domain contacts the ubiquitin receptor Rpn10; deletion of the yeast ortholog reduces 26S proteasome levels, causes accumulation of incomplete complexes, and prevents Rpn10 incorporation [PMID:10490597, PMID:25631053]. Beyond its core proteasomal role, PSMD13 suppresses NF-κB signaling by targeting K63-linked ubiquitination of TAK1 in TLR pathways [PMID:37257570] and is required for hematopoietic stem cell repopulating capacity and megakaryocytic differentiation in mice [PMID:37653079].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of PSMD13 as a 26S proteasome subunit established it as a component of the 19S regulatory particle and showed that its yeast ortholog, while non-essential for viability, is required for proteasome function under stress conditions.\",\n      \"evidence\": \"cDNA cloning and yeast gene disruption with temperature-sensitivity assays\",\n      \"pmids\": [\"9714768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise position within the lid subcomplex was unknown\",\n        \"No biochemical characterization of proteasome assembly defects in the absence of Rpn9\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that Rpn9 deletion impairs 26S proteasome assembly and blocks Rpn10 incorporation resolved the question of whether this subunit is a passive structural component or an active assembly factor.\",\n      \"evidence\": \"Glycerol gradient centrifugation and native PAGE of proteasome fractions from Δrpn9 yeast\",\n      \"pmids\": [\"10490597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for Rpn9–Rpn10 interaction was unknown\",\n        \"Whether Rpn9 contacts other lid subunits was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The NMR structure of Rpn9 revealed a bipartite architecture — an all-helical N-terminal domain contacting Rpn10 and a C-terminal PCI domain interfacing with Rpn5 — providing the atomic-level explanation for its scaffolding role in lid assembly.\",\n      \"evidence\": \"High-resolution NMR structure determination with domain interaction validation\",\n      \"pmids\": [\"25631053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No full-length human PSMD13 structure available\",\n        \"Dynamics of these interactions during active substrate processing were not addressed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Three parallel studies expanded PSMD13 function beyond proteasome structure: it suppresses NF-κB by reducing K63-linked ubiquitination of TAK1, it is required for hematopoietic stem cell repopulation and megakaryopoiesis, and its C. elegans ortholog shows synthetic lethality with BAP1-pathway loss.\",\n      \"evidence\": \"Ubiquitination assays in fish cells (PMID:37257570); shRNA knockdown with in vivo HSC transplantation in mice (PMID:37653079); CRISPR/RNAi epistasis in C. elegans (PMID:36980270)\",\n      \"pmids\": [\"37257570\", \"37653079\", \"36980270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"TAK1 ubiquitination effect demonstrated only in fish; mammalian confirmation is lacking\",\n        \"Whether HSC phenotype reflects general proteasome impairment or a PSMD13-specific function is unresolved\",\n        \"Molecular basis of rpn-9/ubh-4 synthetic lethality is unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Co-immunoprecipitation and ChIP-seq data placed PSMD13 in a complex with Dicer at genomic loci including miR-29a, suggesting a non-canonical role in miRNA biogenesis regulation in neural precursor cells.\",\n      \"evidence\": \"Co-IP and ChIP-seq in mouse neural precursor cells with Psmd13 knockdown\",\n      \"pmids\": [\"41734180\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal validation; direct binding not demonstrated\",\n        \"Mechanism linking PSMD13–Dicer association to miRNA processing is not established\",\n        \"Effect could be indirect via proteasome-mediated Dicer turnover\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PSMD13 exerts its non-proteasomal functions (TAK1 regulation, Dicer interaction, HSC maintenance) through moonlighting activities independent of 26S proteasome proteolysis, or through selective proteasomal degradation of specific substrates, remains the central unresolved mechanistic question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants distinguishing proteasomal from non-proteasomal roles\",\n        \"No structural model of human PSMD13 in the context of the full 26S proteasome at high resolution\",\n        \"Substrate specificity conferred by PSMD13 is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle lid\"\n    ],\n    \"partners\": [\n      \"RPN10\",\n      \"RPN5\",\n      \"TAK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD13 is a non-ATPase subunit of the 19S regulatory particle lid of the 26S proteasome, essential for efficient proteasome assembly and ubiquitin-dependent protein degradation. Its C-terminal PCI domain mediates interaction with the neighboring lid subunit Rpn5, while its N-terminal domain recruits the ubiquitin receptor Rpn10 into the 26S proteasome, as revealed by high-resolution NMR structure determination of the yeast ortholog Rpn9 [PMID:25631053, PMID:10490597]. Loss of PSMD13/Rpn9 causes temperature-sensitive growth, accumulation of multiubiquitinated proteins, and defective proteasome assembly [PMID:10490597, PMID:9714768]. Beyond its core proteasomal role, PSMD13 suppresses NF-κB signaling by inhibiting K63-linked ubiquitination of TAK1 [PMID:37257570], supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation downstream of IL-4 [PMID:37653079], and associates with Dicer to modulate miR-29a levels during neuronal differentiation [PMID:41734180].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of PSMD13 (p40.5) as a non-ATPase subunit of the 19S regulatory complex established its place within the 26S proteasome and showed, via yeast NAS7 disruption, that it is required for proteasome function under stress.\",\n      \"evidence\": \"cDNA cloning of human p40.5, yeast NAS7 gene disruption with temperature-sensitive growth phenotype\",\n      \"pmids\": [\"9714768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical role within the 19S lid not yet defined\",\n        \"No structural information on how PSMD13 integrates into the lid complex\",\n        \"Mechanism of temperature sensitivity not resolved\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Deletion of the yeast ortholog Rpn9 demonstrated that PSMD13 is required for efficient 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, answering how loss of this subunit leads to ubiquitin-conjugate accumulation.\",\n      \"evidence\": \"Glycerol density gradient centrifugation, native PAGE, and genetic deletion in yeast showing incomplete proteasome complexes and loss of Rpn10 incorporation\",\n      \"pmids\": [\"10490597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for Rpn10 recruitment unknown\",\n        \"Whether assembly role is conserved in mammalian cells not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The high-resolution NMR structure of yeast Rpn9 resolved the architectural basis for PSMD13 function: the N-terminal domain recruits Rpn10 and the C-terminal PCI domain contacts Rpn5 via a conserved hydrophobic/ionic winged-helix interface, establishing the structural logic of PCI-PCI interactions throughout the lid.\",\n      \"evidence\": \"NMR solution structure with functionally validated interaction surfaces for Rpn10 and Rpn5\",\n      \"pmids\": [\"25631053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No mammalian structure available\",\n        \"Dynamics of the semiflexible hinge between domains not functionally tested\",\n        \"How Rpn10 recruitment is coordinated with other assembly chaperones remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Three independent studies extended PSMD13 function beyond core proteasome biology: it suppresses NF-κB by inhibiting K63-linked ubiquitination of TAK1 in innate immunity, it sustains HSC repopulating capacity and megakaryocytic differentiation downstream of IL-4, and its genetic interaction with the BAP1 ortholog in C. elegans links it to ubiquitin homeostasis and organismal fitness.\",\n      \"evidence\": \"K63-ubiquitination assays on TAK1 in fish (PMID:37257570); shRNA knockdown with in vivo transplantation in mouse HSCs (PMID:37653079); CRISPR/RNAi synthetic lethal screen in C. elegans (PMID:36980270)\",\n      \"pmids\": [\"37257570\", \"37653079\", \"36980270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"NF-κB regulatory function demonstrated only in teleost; mammalian validation lacking\",\n        \"Whether IL-4–Psmd13 axis acts through altered proteasome activity or a moonlighting function is unresolved\",\n        \"Synthetic lethality with BAP1 has not been confirmed in mammalian systems\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery that PSMD13 physically associates with Dicer and co-occupies the miR-29a locus in neural precursor cells revealed a potential non-proteasomal role in miRNA biogenesis during neuronal differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, and MG132 treatment in mouse neural precursor cells\",\n      \"pmids\": [\"41734180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Dicer interaction not reconstituted with purified proteins; indirect bridging cannot be excluded\",\n        \"Whether the effect on miR-29a is proteasome-dependent or reflects a direct regulatory function is not delineated\",\n        \"Findings from a single study in one cell type\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the non-proteasomal roles of PSMD13 (NF-κB suppression, miRNA biogenesis, HSC differentiation) reflect moonlighting functions independent of proteolytic activity or altered proteasome substrate selectivity, and no mammalian structural data or disease-causative mutations have been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No separation-of-function mutants distinguishing proteasomal versus non-proteasomal roles\",\n        \"No mammalian crystal or cryo-EM structure of PSMD13 in the context of the human 26S proteasome lid\",\n        \"No Mendelian disease or GWAS locus directly attributed to PSMD13 coding variants\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"26S proteasome 19S regulatory particle lid\"\n    ],\n    \"partners\": [\n      \"RPN5\",\n      \"RPN10\",\n      \"TAK1\",\n      \"DICER\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}