{"gene":"PSMD13","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1998,"finding":"p40.5 (PSMD13) was identified as a novel subunit of the PA700/19S regulatory complex of the human 26S proteasome, with a calculated molecular mass of ~43 kDa. Its yeast ortholog Nas7p/Rpn9 is non-essential but required for growth at elevated temperatures, indicating a role in proteasome function under stress.","method":"cDNA cloning, sequence homology analysis, yeast gene disruption","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA cloning established subunit identity; yeast KO provided functional phenotype; single lab but two complementary approaches","pmids":["9714768"],"is_preprint":false},{"year":1999,"finding":"Yeast Rpn9 (ortholog of PSMD13) is required for efficient assembly of the 26S proteasome. Deletion of RPN9 results in accumulation of incomplete proteasome complexes and loss of Rpn10 incorporation into the proteasome, indicating Rpn9 is needed for incorporating Rpn10 into the 19S regulatory particle.","method":"Glycerol density gradient centrifugation, native PAGE, two-hybrid screening with Rpn10 as bait, genetic deletion (Δrpn9)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal two-hybrid, gradient fractionation, and KO phenotype with defined molecular consequence (Rpn10 exclusion), replicated across orthogonal methods in a focused study","pmids":["10490597"],"is_preprint":false},{"year":2015,"finding":"NMR solution structure of yeast Rpn9 (PSMD13 ortholog) revealed an all-helical N-terminal domain and a C-terminal PCI domain connected by a semiflexible hinge. The N-terminal domain mediates interaction with the ubiquitin receptor Rpn10, and the PCI domain mediates interaction with the neighboring PCI subunit Rpn5 via a hydrophobic center surrounded by ionic pairs on the winged helix module.","method":"NMR structure determination, protein-protein interaction mapping by NMR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR structure with domain-specific interaction mapping; single lab but high-resolution method with direct functional validation of domain interfaces","pmids":["25631053"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, rpn-9 (PSMD13 ortholog) shows synthetic lethality with ubh-4 (BAP1 ortholog): double inactivation affects body size, lifespan, and germ cell development, placing PSMD13/rpn-9 in a genetic pathway intersecting with BAP1 deubiquitinase function.","method":"CRISPR-Cas mutagenesis, RNAi screen, genetic epistasis in C. elegans","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis established by RNAi screen and CRISPR mutants with defined phenotypes; single lab, model organism","pmids":["36980270"],"is_preprint":false},{"year":2023,"finding":"In miiuy croaker, PSMD13 inhibits the NF-κB pathway by targeting TAK1: PSMD13 significantly inhibits K63-linked ubiquitination of TAK1, thereby suppressing TAK1 expression and downstream NF-κB signaling.","method":"Overexpression/knockdown assays, ubiquitination assays, NF-κB reporter assay","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, non-mammalian model organism, single set of overexpression/ubiquitination assays without mutagenesis or reconstitution","pmids":["37257570"],"is_preprint":false},{"year":2023,"finding":"Psmd13 expression in mouse hematopoietic stem cells (HSCs) is required for repopulating capacity and megakaryocytic differentiation; shRNA-mediated knockdown of Psmd13 severely compromised these functions and increased apoptosis in vivo. IL-4 stimulation in vitro inhibits Psmd13 expression, linking the IL-4 signaling pathway to proteasome function in HSCs.","method":"shRNA knockdown in HSCs, in vivo transplantation, single-cell transcriptome analysis, in vitro IL-4 stimulation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (differentiation, apoptosis, repopulation) in vivo; single lab with multiple orthogonal readouts","pmids":["37653079"],"is_preprint":false},{"year":2026,"finding":"Psmd13 co-immunoprecipitates with Dicer in mouse neural precursor cells, and ChIP-seq shows co-occupancy of Psmd13 and Dicer at the miR-29a genomic locus. RNAi-mediated Psmd13 knockdown enhances neuronal differentiation and alters miR-29a levels in a differentiation-state-dependent manner. Proteasome inhibition with MG132 reduces both Psmd13 and Dicer levels and suppresses miR-29a.","method":"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, pharmacological proteasome inhibition (MG132), QTL mapping","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP shows association but not direct binding; ChIP-seq co-occupancy is correlative; RNAi phenotype not rescued; mechanistic link between Psmd13-Dicer interaction and miR-29a regulation remains indirect","pmids":["41734180"],"is_preprint":false}],"current_model":"PSMD13 (p40.5/Rpn9) is a non-ATPase subunit of the 19S regulatory particle lid complex of the 26S proteasome, whose PCI domain interacts with neighboring PCI subunit Rpn5 and whose N-terminal domain binds the ubiquitin receptor Rpn10, with the yeast ortholog required for efficient 26S proteasome assembly, Rpn10 incorporation, and proteasome activity under stress; in mammalian/vertebrate contexts, PSMD13 has also been implicated in HSC megakaryocytic differentiation and stress resistance downstream of IL-4 signaling, a synthetic lethal interaction with BAP1/ubh-4 in C. elegans, and a possible role in miR-29a regulation through association with Dicer during neuronal differentiation."},"narrative":{"mechanistic_narrative":"PSMD13 (p40.5; yeast ortholog Nas7p/Rpn9) is a non-ATPase subunit of the PA700/19S regulatory particle of the 26S proteasome [PMID:9714768]. Structurally it comprises an all-helical N-terminal domain joined by a semiflexible hinge to a C-terminal PCI domain; the N-terminal domain binds the ubiquitin receptor Rpn10, while the PCI domain engages the neighboring PCI subunit Rpn5 through a hydrophobic interface flanked by ionic pairs on its winged-helix module [PMID:25631053]. Through these contacts PSMD13 is required for efficient 26S proteasome assembly and specifically for incorporation of Rpn10 into the regulatory particle, with its loss producing incomplete proteasome complexes [PMID:10490597]; the yeast ortholog is dispensable for viability but needed for growth under elevated-temperature stress [PMID:9714768]. Beyond its core assembly role, PSMD13 supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation, functions that are downregulated by IL-4 signaling [PMID:37653079], and it genetically intersects the BAP1 deubiquitinase pathway, showing synthetic lethality with the C. elegans BAP1 ortholog ubh-4 [PMID:36980270].","teleology":[{"year":1998,"claim":"Established PSMD13 as a bona fide subunit of the human proteasome and gave it a first functional context, answering whether p40.5 was proteasome-associated and whether it mattered.","evidence":"cDNA cloning and sequence homology with yeast gene disruption of the ortholog Nas7p/Rpn9","pmids":["9714768"],"confidence":"Medium","gaps":["No structural or interaction detail for the human subunit","Stress-sensitivity phenotype defined only in yeast","Molecular function within the particle not yet defined"]},{"year":1999,"claim":"Defined a concrete molecular role for the subunit by showing it is needed for 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, explaining why its loss impairs proteasome function.","evidence":"Glycerol gradient fractionation, native PAGE, two-hybrid with Rpn10, and Δrpn9 deletion in yeast","pmids":["10490597"],"confidence":"High","gaps":["Did not resolve the structural basis of Rpn10 recruitment","Mammalian assembly role inferred from yeast only"]},{"year":2015,"claim":"Provided the atomic basis for the subunit's two interaction surfaces, mapping the N-terminal domain to Rpn10 and the PCI domain to the neighboring Rpn5 subunit.","evidence":"NMR solution structure of yeast Rpn9 with NMR-based interaction mapping","pmids":["25631053"],"confidence":"High","gaps":["Structure determined for yeast ortholog, not the human protein","Interfaces not validated by mutation in the assembled proteasome","Does not address regulation of these contacts in vivo"]},{"year":2023,"claim":"Connected the subunit to organismal phenotypes and a deubiquitinase pathway, showing synthetic lethality with the BAP1 ortholog ubh-4.","evidence":"CRISPR mutagenesis, RNAi screen, and genetic epistasis in C. elegans","pmids":["36980270"],"confidence":"Medium","gaps":["Molecular basis of the genetic interaction with BAP1 unknown","Whether the interaction reflects proteasome function specifically is unresolved"]},{"year":2023,"claim":"Linked PSMD13 to a specific physiological output by showing it is required for HSC repopulation and megakaryocytic differentiation and is suppressed by IL-4.","evidence":"shRNA knockdown in mouse HSCs, in vivo transplantation, single-cell transcriptomics, IL-4 stimulation","pmids":["37653079"],"confidence":"Medium","gaps":["Mechanism linking IL-4 to Psmd13 transcription not defined","Whether phenotypes stem from proteasome assembly defects is untested"]},{"year":2023,"claim":"Proposed a non-proteasomal regulatory role in which PSMD13 dampens NF-κB signaling by reducing K63-linked ubiquitination of TAK1.","evidence":"Overexpression/knockdown, ubiquitination assays, and NF-κB reporter assays in miiuy croaker","pmids":["37257570"],"confidence":"Low","gaps":["Single set of overexpression assays without mutagenesis or reconstitution","Direct action on TAK1 ubiquitination not demonstrated mechanistically","Non-mammalian model, not independently confirmed"]},{"year":2026,"claim":"Associated PSMD13 with Dicer and miR-29a regulation during neuronal differentiation, hinting at a role coupling proteasome subunit levels to microRNA output.","evidence":"Co-IP, ChIP-seq co-occupancy, RNAi knockdown, and MG132 proteasome inhibition in mouse neural precursors","pmids":["41734180"],"confidence":"Low","gaps":["Co-IP shows association but not direct binding","ChIP-seq co-occupancy is correlative and RNAi phenotype not rescued","Mechanistic link between Psmd13-Dicer and miR-29a remains indirect"]},{"year":null,"claim":"It remains unresolved whether the reported non-proteasomal activities of PSMD13 (NF-κB/TAK1 modulation, Dicer/miR-29a regulation, HSC and BAP1-pathway phenotypes) are separable from its core role in 19S lid assembly or are downstream consequences of altered proteasome function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experiment separates assembly-dependent from assembly-independent roles","Human protein structure and interfaces not directly determined","No reconstitution of proposed moonlighting activities"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["26S proteasome 19S regulatory particle (lid)"],"partners":["PSMD4/RPN10","PSMD12/RPN5","DICER1"],"other_free_text":[]}},"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 analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9714768","citation_count":80,"is_preprint":false},{"pmid":"17059877","id":"PMC_17059877","title":"Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13.","date":"2006","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17059877","citation_count":70,"is_preprint":false},{"pmid":"10490597","id":"PMC_10490597","title":"Rpn9 is required for efficient assembly of the yeast 26S proteasome.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10490597","citation_count":62,"is_preprint":false},{"pmid":"16905670","id":"PMC_16905670","title":"Down-regulation of the 26S proteasome subunit RPN9 inhibits viral systemic transport and alters plant vascular development.","date":"2006","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16905670","citation_count":48,"is_preprint":false},{"pmid":"25631053","id":"PMC_25631053","title":"Solution structure of yeast Rpn9: insights into proteasome lid assembly.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25631053","citation_count":12,"is_preprint":false},{"pmid":"37257570","id":"PMC_37257570","title":"PSMD13 inhibits NF-κB pathway by targeting TAK1 for K63-linked ubiquitination in miiuy croaker (Miichthys miiuy).","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37257570","citation_count":6,"is_preprint":false},{"pmid":"36731897","id":"PMC_36731897","title":"Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk.","date":"2023","source":"Journal of gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36731897","citation_count":6,"is_preprint":false},{"pmid":"36980270","id":"PMC_36980270","title":"BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36980270","citation_count":5,"is_preprint":false},{"pmid":"37653079","id":"PMC_37653079","title":"Interlukin-4 weakens resistance to stress injury and megakaryocytic differentiation of hematopoietic stem cells by inhibiting Psmd13 expression.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37653079","citation_count":4,"is_preprint":false},{"pmid":"41734180","id":"PMC_41734180","title":"Psmd13, a proteasome regulatory subunit identified in miR-29a regulation during neuronal differentiation.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41734180","citation_count":1,"is_preprint":false},{"pmid":"23832675","id":"PMC_23832675","title":"¹H, ¹³C and ¹⁵N resonance assignments of Rpn9, a regulatory subunit of 26S proteasome from Saccharomyces cerevisiae.","date":"2013","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/23832675","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.14.648858","title":"Psmd13, a proteosome regulatory subunit identified in miR-29a regulation during neurogenesis","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.14.648858","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7518,"output_tokens":1917,"usd":0.025655,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8838,"output_tokens":2636,"usd":0.055045,"stage2_stop_reason":"end_turn"},"total_usd":0.0807,"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\": 1998,\n      \"finding\": \"p40.5 (PSMD13) was identified as a novel subunit of the PA700/19S regulatory complex of the human 26S proteasome, with a calculated molecular mass of ~43 kDa. Its yeast ortholog Nas7p/Rpn9 is non-essential but required for growth at elevated temperatures, indicating a role in proteasome function under stress.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, yeast gene disruption\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA cloning established subunit identity; yeast KO provided functional phenotype; single lab but two complementary approaches\",\n      \"pmids\": [\"9714768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Yeast Rpn9 (ortholog of PSMD13) is required for efficient assembly of the 26S proteasome. Deletion of RPN9 results in accumulation of incomplete proteasome complexes and loss of Rpn10 incorporation into the proteasome, indicating Rpn9 is needed for incorporating Rpn10 into the 19S regulatory particle.\",\n      \"method\": \"Glycerol density gradient centrifugation, native PAGE, two-hybrid screening with Rpn10 as bait, genetic deletion (Δrpn9)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal two-hybrid, gradient fractionation, and KO phenotype with defined molecular consequence (Rpn10 exclusion), replicated across orthogonal methods in a focused study\",\n      \"pmids\": [\"10490597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NMR solution structure of yeast Rpn9 (PSMD13 ortholog) revealed an all-helical N-terminal domain and a C-terminal PCI domain connected by a semiflexible hinge. The N-terminal domain mediates interaction with the ubiquitin receptor Rpn10, and the PCI domain mediates interaction with the neighboring PCI subunit Rpn5 via a hydrophobic center surrounded by ionic pairs on the winged helix module.\",\n      \"method\": \"NMR structure determination, protein-protein interaction mapping by NMR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR structure with domain-specific interaction mapping; single lab but high-resolution method with direct functional validation of domain interfaces\",\n      \"pmids\": [\"25631053\"],\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): double inactivation affects body size, lifespan, and germ cell development, placing PSMD13/rpn-9 in a genetic pathway intersecting with BAP1 deubiquitinase function.\",\n      \"method\": \"CRISPR-Cas mutagenesis, RNAi screen, genetic epistasis in C. elegans\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis established by RNAi screen and CRISPR mutants with defined phenotypes; single lab, model organism\",\n      \"pmids\": [\"36980270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In miiuy croaker, PSMD13 inhibits the NF-κB pathway by targeting TAK1: PSMD13 significantly inhibits K63-linked ubiquitination of TAK1, thereby suppressing TAK1 expression and downstream NF-κB signaling.\",\n      \"method\": \"Overexpression/knockdown assays, ubiquitination assays, NF-κB reporter assay\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, non-mammalian model organism, single set of overexpression/ubiquitination assays without mutagenesis or reconstitution\",\n      \"pmids\": [\"37257570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Psmd13 expression in mouse hematopoietic stem cells (HSCs) is required for repopulating capacity and megakaryocytic differentiation; shRNA-mediated knockdown of Psmd13 severely compromised these functions and increased apoptosis in vivo. IL-4 stimulation in vitro inhibits Psmd13 expression, linking the IL-4 signaling pathway to proteasome function in HSCs.\",\n      \"method\": \"shRNA knockdown in HSCs, in vivo transplantation, single-cell transcriptome analysis, in vitro IL-4 stimulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (differentiation, apoptosis, repopulation) in vivo; single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"37653079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Psmd13 co-immunoprecipitates with Dicer in mouse neural precursor cells, and ChIP-seq shows co-occupancy of Psmd13 and Dicer at the miR-29a genomic locus. RNAi-mediated Psmd13 knockdown enhances neuronal differentiation and alters miR-29a levels in a differentiation-state-dependent manner. Proteasome inhibition with MG132 reduces both Psmd13 and Dicer levels and suppresses miR-29a.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNAi knockdown, pharmacological proteasome inhibition (MG132), QTL mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP shows association but not direct binding; ChIP-seq co-occupancy is correlative; RNAi phenotype not rescued; mechanistic link between Psmd13-Dicer interaction and miR-29a regulation remains indirect\",\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, whose PCI domain interacts with neighboring PCI subunit Rpn5 and whose N-terminal domain binds the ubiquitin receptor Rpn10, with the yeast ortholog required for efficient 26S proteasome assembly, Rpn10 incorporation, and proteasome activity under stress; in mammalian/vertebrate contexts, PSMD13 has also been implicated in HSC megakaryocytic differentiation and stress resistance downstream of IL-4 signaling, a synthetic lethal interaction with BAP1/ubh-4 in C. elegans, and a possible role in miR-29a regulation through association with Dicer during neuronal differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD13 (p40.5; yeast ortholog Nas7p/Rpn9) is a non-ATPase subunit of the PA700/19S regulatory particle of the 26S proteasome [#0]. Structurally it comprises an all-helical N-terminal domain joined by a semiflexible hinge to a C-terminal PCI domain; the N-terminal domain binds the ubiquitin receptor Rpn10, while the PCI domain engages the neighboring PCI subunit Rpn5 through a hydrophobic interface flanked by ionic pairs on its winged-helix module [#2]. Through these contacts PSMD13 is required for efficient 26S proteasome assembly and specifically for incorporation of Rpn10 into the regulatory particle, with its loss producing incomplete proteasome complexes [#1]; the yeast ortholog is dispensable for viability but needed for growth under elevated-temperature stress [#0]. Beyond its core assembly role, PSMD13 supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation, functions that are downregulated by IL-4 signaling [#5], and it genetically intersects the BAP1 deubiquitinase pathway, showing synthetic lethality with the C. elegans BAP1 ortholog ubh-4 [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established PSMD13 as a bona fide subunit of the human proteasome and gave it a first functional context, answering whether p40.5 was proteasome-associated and whether it mattered.\",\n      \"evidence\": \"cDNA cloning and sequence homology with yeast gene disruption of the ortholog Nas7p/Rpn9\",\n      \"pmids\": [\"9714768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or interaction detail for the human subunit\",\n        \"Stress-sensitivity phenotype defined only in yeast\",\n        \"Molecular function within the particle not yet defined\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined a concrete molecular role for the subunit by showing it is needed for 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, explaining why its loss impairs proteasome function.\",\n      \"evidence\": \"Glycerol gradient fractionation, native PAGE, two-hybrid with Rpn10, and \\u0394rpn9 deletion in yeast\",\n      \"pmids\": [\"10490597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the structural basis of Rpn10 recruitment\",\n        \"Mammalian assembly role inferred from yeast only\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the atomic basis for the subunit's two interaction surfaces, mapping the N-terminal domain to Rpn10 and the PCI domain to the neighboring Rpn5 subunit.\",\n      \"evidence\": \"NMR solution structure of yeast Rpn9 with NMR-based interaction mapping\",\n      \"pmids\": [\"25631053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure determined for yeast ortholog, not the human protein\",\n        \"Interfaces not validated by mutation in the assembled proteasome\",\n        \"Does not address regulation of these contacts in vivo\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected the subunit to organismal phenotypes and a deubiquitinase pathway, showing synthetic lethality with the BAP1 ortholog ubh-4.\",\n      \"evidence\": \"CRISPR mutagenesis, RNAi screen, and genetic epistasis in C. elegans\",\n      \"pmids\": [\"36980270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of the genetic interaction with BAP1 unknown\",\n        \"Whether the interaction reflects proteasome function specifically is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PSMD13 to a specific physiological output by showing it is required for HSC repopulation and megakaryocytic differentiation and is suppressed by IL-4.\",\n      \"evidence\": \"shRNA knockdown in mouse HSCs, in vivo transplantation, single-cell transcriptomics, IL-4 stimulation\",\n      \"pmids\": [\"37653079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking IL-4 to Psmd13 transcription not defined\",\n        \"Whether phenotypes stem from proteasome assembly defects is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed a non-proteasomal regulatory role in which PSMD13 dampens NF-\\u03baB signaling by reducing K63-linked ubiquitination of TAK1.\",\n      \"evidence\": \"Overexpression/knockdown, ubiquitination assays, and NF-\\u03baB reporter assays in miiuy croaker\",\n      \"pmids\": [\"37257570\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single set of overexpression assays without mutagenesis or reconstitution\",\n        \"Direct action on TAK1 ubiquitination not demonstrated mechanistically\",\n        \"Non-mammalian model, not independently confirmed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Associated PSMD13 with Dicer and miR-29a regulation during neuronal differentiation, hinting at a role coupling proteasome subunit levels to microRNA output.\",\n      \"evidence\": \"Co-IP, ChIP-seq co-occupancy, RNAi knockdown, and MG132 proteasome inhibition in mouse neural precursors\",\n      \"pmids\": [\"41734180\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Co-IP shows association but not direct binding\",\n        \"ChIP-seq co-occupancy is correlative and RNAi phenotype not rescued\",\n        \"Mechanistic link between Psmd13-Dicer and miR-29a remains indirect\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the reported non-proteasomal activities of PSMD13 (NF-\\u03baB/TAK1 modulation, Dicer/miR-29a regulation, HSC and BAP1-pathway phenotypes) are separable from its core role in 19S lid assembly or are downstream consequences of altered proteasome function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No experiment separates assembly-dependent from assembly-independent roles\",\n        \"Human protein structure and interfaces not directly determined\",\n        \"No reconstitution of proposed moonlighting activities\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"26S proteasome 19S regulatory particle (lid)\"],\n    \"partners\": [\"PSMD4/Rpn10\", \"PSMD12/Rpn5\", \"DICER1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}