{"gene":"PSMD1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"PSMD1 (human p112) was identified as the largest regulatory subunit of the 26S proteasome 19S regulatory particle. cDNA cloning revealed a 953-amino acid polypeptide (MW ~105,865 Da) mapped to chromosome 2q37.1–q37.2. Functional complementation showed p112 is the human orthologue of yeast Sen3p; disruption of SEN3 caused defects in ubiquitin-dependent proteolysis, the N-end rule pathway, stress response, and nuclear protein transport, demonstrating PSMD1/Sen3p is essential for multiple 26S proteasome-mediated cellular processes.","method":"cDNA cloning, yeast complementation assay, temperature-sensitive growth phenotype analysis, ubiquitin pathway functional assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — original cloning with functional complementation across species and multiple orthogonal phenotypic assays","pmids":["8816993"],"is_preprint":false},{"year":2002,"finding":"Computational modeling predicted that the proteasome/cyclosome (PC) repeat-containing domain of Rpn2/PSMD1 (and Rpn1) forms a novel alpha-helical toroid structure with a central pore, proposed to function as an 'antechamber' that assists ATPases in unfolding protein substrates prior to proteolysis by the 20S core.","method":"Sequence pattern analysis, molecular modeling of PC repeat domains","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no direct structural validation at this stage","pmids":["12270919"],"is_preprint":false},{"year":2004,"finding":"Rpn2/PSMD1 harbors a functional bipartite nuclear localization sequence (NLS). Deletion of the Rpn2 NLS resulted in improper nuclear proteasome localization and impaired proteasome function in yeast, demonstrating that Rpn2 is required for karyopherin αβ-mediated nuclear import of the 19S base complex.","method":"NLS deletion mutagenesis, immunofluorescence localization, yeast genetics, karyopherin pathway analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct mutagenesis with clear localization and functional phenotype in vivo","pmids":["15210724"],"is_preprint":false},{"year":2008,"finding":"Rpn13 (proteasomal ubiquitin receptor) is anchored to the proteasome through direct interaction with Rpn2/PSMD1, establishing PSMD1 as the docking site for this ubiquitin receptor within the 19S regulatory particle.","method":"Biochemical interaction studies, identification of Rpn13 as proteasome subunit","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal biochemical interaction with functional follow-up; highly cited foundational paper","pmids":["18497817"],"is_preprint":false},{"year":2012,"finding":"The crystal structure of the 26S proteasome subunit Rpn2/PSMD1 was determined, revealing that the eleven PC repeats form a closed toroidal structure of two concentric rings of α-helices encircling two axial α-helices. A rod-like N-terminal domain of 17 stacked α-helices and a globular C-terminal domain emerge from one face of the toroid. Rpn13 (ubiquitin receptor) binds to the C-terminal 20 residues of Rpn2.","method":"X-ray crystallography, structural analysis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with domain-level functional assignment of Rpn13 binding site","pmids":["22405010"],"is_preprint":false},{"year":2012,"finding":"Rpn2/PSMD1 serves as a central hub in the 19S regulatory particle: it docks ubiquitin shuttle proteins Rad23 and Dsk2 (via Rpn1 in the same study context), and directly anchors the ubiquitin receptor Rpn13, which binds exclusively to the C-terminal domain of Rpn2. The presence of Rpn2 also stabilizes the association of Rpn10 with Rpn1, coordinating multiple ubiquitin-processing factors simultaneously at the proteasome base.","method":"Binding affinity measurements, yeast two-hybrid, pulldown assays, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods identifying distinct binding sites and affinities","pmids":["22318722"],"is_preprint":false},{"year":2014,"finding":"PSMD1 (Psmd1) undergoes SUMOylation via the SUMO E3 ligase PIASy. The SUMO deconjugating enzyme xSENP1 specifically interacts with Psmd1. SUMOylation of a critical lysine immediately adjacent to the Adrm1(Rpn13)-binding domain of Psmd1 regulates the association of Adrm1 with the proteasome. Disruption of xSENP1 targeting delays mitotic exit, suggesting that SUMO-regulated Psmd1–Adrm1 interaction modulates proteasome composition and function during cell division.","method":"Co-immunoprecipitation, SUMO site mapping, PIASy E3 ligase assay, xSENP1 interaction studies, mitotic exit phenotype assay in Xenopus","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — identified writer (PIASy) and eraser (xSENP1) of SUMO modification, mapped site, demonstrated functional consequence on proteasome composition and mitosis","pmids":["24910440"],"is_preprint":false},{"year":2017,"finding":"The crystal structure of hRpn13 (Adrm1) bound to a segment of hRpn2/PSMD1 was determined, showing that a proline-rich C-terminal extension of Rpn2 stretches across the ubiquitin-binding Pru domain of Rpn13, blocking an RA190-binding surface. Biophysical and cell-based analyses showed hRpn13 binds preferentially to hRpn2/proteasomes over the drug RA190; RA190 instead directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abolishes RA190-induced substrate accumulation at proteasomes.","method":"NMR/crystal structure, surface plasmon resonance, cell-based ubiquitin substrate accumulation assay, hRpn13 deletion cell line","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biophysical quantification and cell-based functional validation","pmids":["28598414"],"is_preprint":false},{"year":2017,"finding":"The RPN2/PSMD1–RPN13 interaction was mapped to the C-terminal 14 residues of RPN2, which bind the N-terminal PRU domain of RPN13. Crystal structures of the RPN13 PRU domain in complex with RPN2 C-terminal peptides and ubiquitin were solved. Mutational analysis validated the RPN2-binding interface; RPN2, ubiquitin, and UCH37 bind RPN13 with independent energetics, clarifying the substrate recruitment mechanism at the proteasome.","method":"Crystal structure, surface plasmon resonance, fluorescence polarization, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures combined with quantitative binding measurements and mutagenesis validation","pmids":["28442575"],"is_preprint":false},{"year":2018,"finding":"PSMD1 knockdown in breast cancer cells caused cell cycle arrest and accumulation of p53 protein by inhibiting p53 protein degradation. p53 target genes p21 and SFN were upregulated upon PSMD1 silencing, identifying PSMD1 as a component of the ubiquitin-proteasome pathway required for p53 turnover and linking PSMD1 function to tamoxifen resistance.","method":"siRNA knockdown, immunoblotting, cell cycle analysis, p53 protein stability assay","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, KD with defined phenotype (p53 accumulation, cell cycle arrest) but no direct biochemical reconstitution of p53 degradation","pmids":["28992264"],"is_preprint":false},{"year":2018,"finding":"PSMD1 and PSMD2 (19S regulatory particle components) directly interact with ATG16, a core autophagosomal protein in Dictyostelium discoideum. The N-terminal half of ATG16 interacts with PSMD1 alone, while the C-terminal half interacts with both PSMD1 and PSMD2. RFP-tagged PSMD1 and PSMD2 co-localize with ATG16-GFP and GFP-ATG8a(LC3) in autophagosomes; lysotracker labeling and proteolytic cleavage assays confirmed their presence in lysosomes. ATG16 is required for autophagic degradation of PSMD1 and PSMD2, establishing a direct link between the ubiquitin-proteasome system and autophagy.","method":"Co-immunoprecipitation, deletion analysis, fluorescence co-localization, LysoTracker labeling, proteolytic cleavage assay","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple methods (Co-IP, colocalization, lysosomal assay) in Dictyostelium model; direct interaction mapped","pmids":["30269947"],"is_preprint":false},{"year":2019,"finding":"Knockdown of PSMD1 and/or PSMD2 in HepG2 hepatocellular carcinoma cells decreased formation of cellular lipid droplets and reduced cell proliferation. Mechanistically, PSMD1 and PSMD2 regulate expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.","method":"siRNA knockdown, lipid droplet quantification, gene expression analysis, pathway inhibitor studies","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, KD with defined metabolic phenotype and pathway placement via signaling inhibitors","pmids":["31703613"],"is_preprint":false},{"year":2021,"finding":"PSMD1 and PSMD3 (19S regulatory complex subunits) promote NF-κB protein expression in chronic myeloid leukemia (CML) cells. Knockdown of PSMD1 or PSMD3 reduced NF-κB activity (confirmed by luciferase reporter and immunoblot), reduced survival, and increased apoptosis in CML cells but not normal cord blood CD34+ progenitors. STAT3 further activates NF-κB in TKI-resistant scenarios, placing PSMD1 upstream of NF-κB in kinase-independent TKI resistance.","method":"shRNA knockdown, luciferase NF-κB reporter assay, nucleocytoplasmic fractionation, apoptosis assay, immunoblotting","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional assays placing PSMD1 upstream of NF-κB, but mechanism of NF-κB stabilization not directly biochemically resolved","pmids":["33712704"],"is_preprint":false}],"current_model":"PSMD1 (human p112/Rpn2) is the largest non-ATPase scaffolding subunit of the 26S proteasome 19S regulatory particle, forming a closed toroidal PC-repeat domain that anchors the ubiquitin receptor RPN13/Adrm1 through its C-terminal residues; its NLS drives karyopherin αβ-dependent nuclear import of the base complex; its interaction with RPN13 is dynamically regulated by PIASy-mediated SUMOylation and xSENP1-mediated deSUMOylation; and it promotes degradation of substrates including p53, regulates NF-κB stability in cancer cells, controls lipid droplet metabolism via p38-JNK/AKT signaling, and is itself subject to ATG16-dependent autophagic degradation."},"narrative":{"teleology":[{"year":1996,"claim":"Cloning of human p112 (PSMD1) and yeast complementation established it as the largest 19S regulatory subunit essential for multiple 26S proteasome-mediated processes including ubiquitin-dependent proteolysis and nuclear transport.","evidence":"cDNA cloning with yeast SEN3 complementation and phenotypic assays","pmids":["8816993"],"confidence":"High","gaps":["No structural information on PSMD1 or its domain architecture","Binding partners within the 19S particle not yet mapped"]},{"year":2002,"claim":"Computational modeling predicted that the PC-repeat domain of PSMD1 forms a novel toroidal α-helical fold, providing the first structural hypothesis for how the subunit might assist substrate unfolding.","evidence":"Sequence pattern analysis and molecular modeling","pmids":["12270919"],"confidence":"Low","gaps":["No experimental structure to validate the toroid model","Functional role of the predicted pore unresolved"]},{"year":2004,"claim":"Identification of a functional bipartite NLS in Rpn2/PSMD1 resolved how the 19S base complex enters the nucleus, showing that PSMD1 itself directs karyopherin αβ-dependent nuclear import.","evidence":"NLS deletion mutagenesis with immunofluorescence in yeast","pmids":["15210724"],"confidence":"High","gaps":["Whether PSMD1 NLS is the sole import signal for the 19S base or acts redundantly with other subunit NLSs","Mechanism by which nuclear proteasome mislocalization impairs function not fully delineated"]},{"year":2008,"claim":"Discovery that the ubiquitin receptor Rpn13 is anchored to the proteasome through direct interaction with PSMD1 defined a key substrate-recruitment axis at the 19S particle.","evidence":"Biochemical interaction mapping and Rpn13 identification as proteasome subunit","pmids":["18497817"],"confidence":"High","gaps":["Precise binding site on PSMD1 not yet mapped","Regulation of the PSMD1–Rpn13 interaction unknown"]},{"year":2012,"claim":"Crystal structure of PSMD1 confirmed the closed toroidal PC-repeat fold and located the Rpn13-binding site to the C-terminal ~20 residues, while biochemical mapping showed PSMD1 coordinates multiple ubiquitin-processing factors at the proteasome base.","evidence":"X-ray crystallography combined with binding-affinity measurements, pulldown, and yeast two-hybrid assays","pmids":["22405010","22318722"],"confidence":"High","gaps":["No high-resolution co-crystal of PSMD1 with Rpn13 at this point","Energetic independence of ubiquitin and Rpn13 binding to PSMD1 not yet resolved"]},{"year":2014,"claim":"PIASy-mediated SUMOylation of PSMD1 adjacent to the Rpn13-binding domain, and its reversal by xSENP1, was shown to regulate Rpn13 proteasome association and mitotic exit, revealing a post-translational mechanism that tunes proteasome composition during cell division.","evidence":"Co-IP, SUMO site mapping, PIASy/xSENP1 functional studies, mitotic exit assay in Xenopus egg extracts","pmids":["24910440"],"confidence":"High","gaps":["Whether SUMO-dependent regulation of PSMD1–Rpn13 operates in mammalian mitosis not directly shown","Full spectrum of PSMD1 SUMOylation sites and their functional consequences unexplored"]},{"year":2017,"claim":"Co-crystal structures of hRpn13 PRU domain bound to hRpn2 C-terminal peptides resolved the atomic interface and demonstrated that Rpn2 occupancy occludes the RA190 drug-binding surface on Rpn13, clarifying both substrate recruitment and pharmacological targeting mechanisms.","evidence":"NMR and X-ray crystallography, SPR, fluorescence polarization, mutagenesis, and cell-based RA190 assays","pmids":["28598414","28442575"],"confidence":"High","gaps":["No full-length PSMD1–Rpn13 complex structure in the context of the intact 26S proteasome","Structural basis for how SUMOylation disrupts the C-terminal interaction not determined"]},{"year":2018,"claim":"Functional studies in cancer cells revealed that PSMD1 loss stabilizes p53 protein and causes cell-cycle arrest, while in Dictyostelium PSMD1 directly interacts with ATG16 and is subject to autophagic degradation, linking proteasome turnover to the autophagy pathway.","evidence":"siRNA knockdown with p53 stability and cell-cycle assays (breast cancer); Co-IP, colocalization, lysosomal assays in Dictyostelium","pmids":["28992264","30269947"],"confidence":"Medium","gaps":["p53 stabilization upon PSMD1 knockdown likely reflects general proteasome impairment rather than a PSMD1-specific mechanism — not disambiguated","ATG16-dependent degradation of PSMD1 not confirmed in mammalian cells","Direct reconstitution of PSMD1 autophagic turnover lacking"]},{"year":2019,"claim":"PSMD1 knockdown in hepatocellular carcinoma cells reduced lipid droplet formation and cell proliferation via p38-JNK/AKT signaling, extending PSMD1's functional impact to lipid metabolism.","evidence":"siRNA knockdown, lipid droplet quantification, pathway inhibitor studies in HepG2 cells","pmids":["31703613"],"confidence":"Medium","gaps":["Whether lipid metabolic effects are PSMD1-specific or reflect general proteasome inhibition not resolved","Direct proteasomal substrates linking PSMD1 to lipid synthesis genes not identified"]},{"year":2021,"claim":"PSMD1 was placed upstream of NF-κB in chronic myeloid leukemia cells, where its depletion reduces NF-κB activity and induces apoptosis selectively in leukemia but not normal progenitor cells, connecting PSMD1 to kinase-independent TKI resistance.","evidence":"shRNA knockdown, NF-κB luciferase reporter, nucleocytoplasmic fractionation, apoptosis assays","pmids":["33712704"],"confidence":"Medium","gaps":["Biochemical mechanism by which PSMD1 promotes NF-κB stability (direct substrate identity) not determined","In vivo validation in CML models lacking"]},{"year":null,"claim":"It remains unresolved whether the cancer-context phenotypes of PSMD1 depletion (p53 stabilization, NF-κB reduction, lipid droplet loss) reflect PSMD1-specific scaffolding functions or general proteasome impairment, and no full-length cryo-EM or crystal structure of PSMD1 within the complete human 26S proteasome has been described in this timeline.","evidence":"","pmids":[],"confidence":"High","gaps":["Substrate specificity conferred by PSMD1 versus general proteasome function not disentangled","Full structural context of PSMD1 within the assembled human 26S holoenzyme not captured","Whether SUMO-mediated regulation of PSMD1–Rpn13 operates in vivo in mammals unconfirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,7,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4,5,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]}],"complexes":["26S proteasome","19S regulatory particle (base subcomplex)"],"partners":["ADRM1","PSMD2","PIASY","SENP1","ATG16","UCH37"],"other_free_text":[]},"mechanistic_narrative":"PSMD1 (Rpn2) is the largest non-ATPase scaffolding subunit of the 26S proteasome 19S regulatory particle, essential for ubiquitin-dependent proteolysis, stress responses, and nuclear protein transport [PMID:8816993]. Its eleven PC repeats fold into a closed toroidal structure of concentric α-helical rings, from which a rod-like N-terminal domain and a globular C-terminal domain emerge; the C-terminal ~14–20 residues serve as the exclusive docking site for the ubiquitin receptor Rpn13/Adrm1, coordinating substrate recognition at the proteasome [PMID:22405010, PMID:28442575]. A bipartite NLS within PSMD1 mediates karyopherin αβ-dependent nuclear import of the 19S base complex [PMID:15210724], and PIASy-mediated SUMOylation of a lysine adjacent to the Rpn13-binding site dynamically regulates Rpn13 association with the proteasome, with disruption of SUMO cycling delaying mitotic exit [PMID:24910440]. PSMD1 knockdown stabilizes p53, arrests the cell cycle in breast cancer cells [PMID:28992264], sustains NF-κB signaling in chronic myeloid leukemia [PMID:33712704], and promotes lipid droplet formation via p38-JNK/AKT pathways in hepatocellular carcinoma cells [PMID:31703613]."},"prefetch_data":{"uniprot":{"accession":"Q99460","full_name":"26S proteasome non-ATPase regulatory subunit 1","aliases":["26S proteasome regulatory subunit RPN2","26S proteasome regulatory subunit S1","26S proteasome subunit p112"],"length_aa":953,"mass_kda":105.8,"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/Q99460/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD1","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000173692","cell_line_id":"CID000127","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMA6","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000127","total_profiled":1310},"omim":[{"mim_id":"618784","title":"PITH DOMAIN-CONTAINING PROTEIN 1; PITHD1","url":"https://www.omim.org/entry/618784"},{"mim_id":"617842","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 1; PSMD1","url":"https://www.omim.org/entry/617842"},{"mim_id":"610650","title":"ADHESION-REGULATING MOLECULE 1; ADRM1","url":"https://www.omim.org/entry/610650"},{"mim_id":"606576","title":"TAF3 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 140-KD; TAF3","url":"https://www.omim.org/entry/606576"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD1"},"hgnc":{"alias_symbol":["S1","P112","Rpn2"],"prev_symbol":[]},"alphafold":{"accession":"Q99460","domains":[{"cath_id":"-","chopping":"90-212","consensus_level":"medium","plddt":81.4358,"start":90,"end":212},{"cath_id":"-","chopping":"787-814_874-934","consensus_level":"medium","plddt":78.9889,"start":787,"end":934},{"cath_id":"1.25.40","chopping":"6-89","consensus_level":"medium","plddt":84.636,"start":6,"end":89},{"cath_id":"1.10.220","chopping":"217-272_320-331","consensus_level":"medium","plddt":80.7637,"start":217,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99460","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99460-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99460-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD1","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD1"},"sequence":{"accession":"Q99460","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99460.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99460/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99460"}},"corpus_meta":[{"pmid":"27298336","id":"PMC_27298336","title":"S1-DRIP-seq 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N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14564014","citation_count":1006,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12808465","id":"PMC_12808465","title":"The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808465","citation_count":912,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23503661","id":"PMC_23503661","title":"Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23503661","citation_count":870,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14743216","id":"PMC_14743216","title":"A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14743216","citation_count":841,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528300","id":"PMC_14528300","title":"The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528300","citation_count":798,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12859895","id":"PMC_12859895","title":"Species-specific exclusion of APOBEC3G from HIV-1 virions by 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readouts in single study\",\n      \"pmids\": [\"8816993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Computational/structural modeling of the proteasome/cyclosome (PC) repeats in Rpn2/S1 (PSMD1) predicted a novel alpha-helical toroid architecture with a central pore, suggesting Rpn2 forms an antechamber that assists ATPases in unfolding substrates prior to proteolysis.\",\n      \"method\": \"Sequence pattern analysis, molecular modeling, structural bioinformatics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no direct experimental validation in this paper\",\n      \"pmids\": [\"12270919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The bipartite nuclear localization sequence (NLS) of Rpn2 (PSMD1) is required for nuclear import of the proteasomal base complex via the karyopherin alpha/beta pathway; deletion of the Rpn2 NLS results in mislocalized nuclear proteasomes and impaired proteasome function.\",\n      \"method\": \"NLS deletion mutagenesis, nuclear localization assays, karyopherin pathway analysis, functional proteasome assays in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined localization and functional consequences, clean KO phenotype\",\n      \"pmids\": [\"15210724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rpn2 (PSMD1) serves as a docking site coordinating ubiquitin-processing factors at the proteasome: Rpn10 attaches to the central solenoid of Rpn1 stabilized by Rpn2, and Rpn13 binds directly to Rpn2, enabling competition between intrinsic ubiquitin receptors and substrate shuttles to modulate substrate residency time.\",\n      \"method\": \"Reciprocal Co-IP, pulldown assays, affinity measurements, proteasome reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple binding partner characterizations in one study\",\n      \"pmids\": [\"22318722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The 11 PC repeats of Rpn2 (PSMD1) form a closed toroidal structure of two concentric rings of alpha-helices with a rod-like N-terminal domain and a globular C-terminal domain; Rpn13 (ubiquitin receptor) binds to the C-terminal 20 residues of Rpn2, defining the structural basis for ubiquitin receptor docking.\",\n      \"method\": \"X-ray crystallography / structural determination, domain mapping\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with experimental validation of Rpn13-binding domain\",\n      \"pmids\": [\"22405010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSMD1 (Psmd1) becomes SUMOylated by the SUMO E3 enzyme PIASy at a critical lysine immediately adjacent to its Adrm1/Rpn13-binding domain; this SUMOylation is removed by xSENP1, and SUMOylation at this site directly regulates the association of Adrm1 with Psmd1, thereby controlling proteasome composition and ubiquitin-mediated protein degradation.\",\n      \"method\": \"Co-IP, SUMOylation site mapping by mutagenesis, identification of writer (PIASy) and eraser (xSENP1), functional cell-based assays, mitotic exit analysis in Xenopus\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — PTM writer/eraser/reader identified with mutagenesis, functional consequence demonstrated\",\n      \"pmids\": [\"24910440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structures of the hRpn13 PRU domain in complex with a peptide from the C-terminal 14 residues of hRpn2 (PSMD1) and with ubiquitin reveal that Rpn2's C-terminus and ubiquitin bind the same surface of Rpn13 with independent energetics, clarifying the structural basis of substrate recruitment to the proteasome via Rpn2-Rpn13 interaction.\",\n      \"method\": \"Crystal structure determination, mutational analysis, surface plasmon resonance, fluorescence polarization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and quantitative binding measurements\",\n      \"pmids\": [\"28442575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A proline-rich C-terminal extension of hRpn2 (PSMD1) stretches across a canyon of the hRpn13 Pru domain, blocking the RA190-binding surface; hRpn13 binds preferentially to hRpn2 and proteasomes over RA190, and RA190 inactivates Uch37 rather than disrupting the Rpn13-Rpn2 interaction.\",\n      \"method\": \"NMR/crystal structure of hRpn13-hRpn2 segment complex, biophysical binding assays, cell-based functional assays, hRpn13 deletion in HCT116 cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure plus multiple orthogonal methods and cell-based validation\",\n      \"pmids\": [\"28598414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 promotes p53 protein degradation; knockdown of PSMD1 in breast cancer cells causes cell cycle arrest and accumulation of p53 protein with upregulation of p53 target genes p21 and SFN, identifying PSMD1 as a regulator of p53 stability through the proteasome.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, immunoblot for p53 and target genes\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with defined molecular phenotype but no direct in vitro reconstitution\",\n      \"pmids\": [\"28992264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 and PSMD2 directly interact with the autophagy protein ATG16 (Dictyostelium homolog); deletion analysis showed the N-terminal half of ATG16 interacts with PSMD1 alone, while the C-terminal half interacts with both PSMD1 and PSMD2. PSMD1 and PSMD2 localize to autophagosomes/autolysosomes in an ATG16-dependent manner, indicating ATG16-mediated autophagic degradation of these 19S proteasome subunits.\",\n      \"method\": \"Co-IP, pulldown, deletion mutagenesis, fluorescence co-localization (RFP/GFP tags), LysoTracker labeling, proteolytic cleavage assay in Dictyostelium\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction mapping with multiple readouts, but model organism (Dictyostelium) not mammalian cells\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD1 and PSMD2 regulate HepG2 hepatocellular carcinoma cell proliferation by modulating cellular lipid droplet accumulation; knockdown of PSMD1 and/or PSMD2 decreases lipid droplet formation and reduces expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.\",\n      \"method\": \"siRNA knockdown, lipid droplet quantification, gene expression analysis, signaling pathway analysis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with mechanistic pathway placement but no direct biochemical reconstitution\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD1 and PSMD3 promote NF-κB protein expression and stabilization in chronic myeloid leukemia cells; knockdown of PSMD1 reduces NF-κB activity (confirmed by luciferase reporter and immunoblot), reduces CML cell survival, and increases apoptosis, while not affecting normal CD34+ progenitors.\",\n      \"method\": \"Genome-wide expression analysis, siRNA knockdown, luciferase reporter assays, immunoblot, nucleocytoplasmic fractionation, apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple orthogonal methods in single lab with defined molecular mechanism\",\n      \"pmids\": [\"33712704\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD1 (also called Rpn2/p112) is the largest scaffolding subunit of the 19S regulatory particle of the 26S proteasome, forming a closed toroidal alpha-helical structure whose C-terminus directly docks the ubiquitin receptor Rpn13/Adrm1 (with the interaction regulated by PIASy-mediated SUMOylation removed by SENP1), whose body coordinates Rpn10 attachment and substrate shuttle binding, and whose bipartite NLS directs nuclear import of the base complex via karyopherin alpha/beta; through these scaffolding roles PSMD1 controls p53 protein degradation, NF-κB stability, and lipid droplet metabolism, and can itself be degraded via ATG16-mediated autophagy.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about PSMD1 (the human 26S proteasome 19S regulatory particle non-ATPase subunit 1, also known as Rpn2/S1 in yeast/mammalian contexts).\n\nKey aliases: PSMD1 = human p112 = Rpn2 (NOT Rpn1) = S2 subunit of 19S = the largest non-ATPase subunit of the 26S proteasome 19S regulatory particle.\n\nCRITICAL DISAMBIGUATION:\n- Many papers about \"S1\" refer to bacterial ribosomal protein S1, viral S1 proteins, nuclease S1, casein αS1, KIR3DL1/S1, etc. → EXCLUDE (alias collision)\n- RPN2 papers: In some nomenclature, Rpn2 = PSMD1. BUT many \"RPN2\" papers in this corpus are about Ribophorin II (RPN2), an N-oligosaccharyltransferase complex subunit — this is a COMPLETELY DIFFERENT protein from PSMD1/Rpn2. → EXCLUDE (alias collision)\n- Papers about yeast Rpn2/Sen3p and human p112 proteasome subunit → KEEP\n\nLet me carefully identify KEEP papers:\n- PMID:8816993 (Yokota 1996): cDNA cloning of p112, largest regulatory subunit of human 26S proteasome, yeast homologue Sen3p → KEEP\n- PMID:22405010 (He 2012): Structure of 26S proteasome subunit Rpn2 → KEEP\n- PMID:12270919 (Kajava 2002): Structural model of Rpn1/S2 and Rpn2/S1 proteins of 26S proteasome → KEEP (Rpn2/S1 = PSMD1)\n- PMID:15210724 (Wendler 2004): Bipartite NLS of Rpn2 for nuclear import → KEEP\n- PMID:22318722 (Rosenzweig 2012): Rpn1 and Rpn2 coordinate ubiquitin processing at proteasome → KEEP\n- PMID:28598414 (Lu 2017): Structure of Rpn13-Rpn2 complex → KEEP\n- PMID:28442575 (VanderLinden 2017): Structure and energetics of RPN2-RPN13-ubiquitin interactions → KEEP\n- PMID:24910440 (Ryu 2014): SUMOylation of Psmd1 → KEEP\n- PMID:31703613 (Tan 2019): PSMD1 and PSMD2 regulate HepG2 cell proliferation via lipid metabolism → KEEP\n- PMID:28992264 (Okumura 2018): PSMD1 regulates breast cancer via p53 degradation → KEEP\n- PMID:33712704 (Bencomo-Alvarez 2021): PSMD1 and PSMD3 stabilize NF-κB in CML → KEEP\n- PMID:30269947 (Xiong 2018): ATG16 mediates autophagic degradation of PSMD1 and PSMD2 → KEEP\n\nFrom additional papers:\n- PMID:8811196 (Coux 1996): Review of 20S and 26S proteasomes → general review, no specific PSMD1 mechanism\n- PMID:19489727 (Finley 2009): Review mentioning Rpn2 as scaffold → general\n- PMID:18497817 (Husnjak 2008): Rpn13 binds Rpn2... → KEEP (mentions Rpn13 is proteasomal receptor anchored via Rpn2)\n\nNow extracting discoveries:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PSMD1 (human p112) was identified as the largest regulatory subunit of the 26S proteasome 19S regulatory particle. cDNA cloning revealed a 953-amino acid polypeptide (MW ~105,865 Da) mapped to chromosome 2q37.1–q37.2. Functional complementation showed p112 is the human orthologue of yeast Sen3p; disruption of SEN3 caused defects in ubiquitin-dependent proteolysis, the N-end rule pathway, stress response, and nuclear protein transport, demonstrating PSMD1/Sen3p is essential for multiple 26S proteasome-mediated cellular processes.\",\n      \"method\": \"cDNA cloning, yeast complementation assay, temperature-sensitive growth phenotype analysis, ubiquitin pathway functional assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original cloning with functional complementation across species and multiple orthogonal phenotypic assays\",\n      \"pmids\": [\"8816993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Computational modeling predicted that the proteasome/cyclosome (PC) repeat-containing domain of Rpn2/PSMD1 (and Rpn1) forms a novel alpha-helical toroid structure with a central pore, proposed to function as an 'antechamber' that assists ATPases in unfolding protein substrates prior to proteolysis by the 20S core.\",\n      \"method\": \"Sequence pattern analysis, molecular modeling of PC repeat domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no direct structural validation at this stage\",\n      \"pmids\": [\"12270919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rpn2/PSMD1 harbors a functional bipartite nuclear localization sequence (NLS). Deletion of the Rpn2 NLS resulted in improper nuclear proteasome localization and impaired proteasome function in yeast, demonstrating that Rpn2 is required for karyopherin αβ-mediated nuclear import of the 19S base complex.\",\n      \"method\": \"NLS deletion mutagenesis, immunofluorescence localization, yeast genetics, karyopherin pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mutagenesis with clear localization and functional phenotype in vivo\",\n      \"pmids\": [\"15210724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rpn13 (proteasomal ubiquitin receptor) is anchored to the proteasome through direct interaction with Rpn2/PSMD1, establishing PSMD1 as the docking site for this ubiquitin receptor within the 19S regulatory particle.\",\n      \"method\": \"Biochemical interaction studies, identification of Rpn13 as proteasome subunit\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical interaction with functional follow-up; highly cited foundational paper\",\n      \"pmids\": [\"18497817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The crystal structure of the 26S proteasome subunit Rpn2/PSMD1 was determined, revealing that the eleven PC repeats form a closed toroidal structure of two concentric rings of α-helices encircling two axial α-helices. A rod-like N-terminal domain of 17 stacked α-helices and a globular C-terminal domain emerge from one face of the toroid. Rpn13 (ubiquitin receptor) binds to the C-terminal 20 residues of Rpn2.\",\n      \"method\": \"X-ray crystallography, structural analysis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with domain-level functional assignment of Rpn13 binding site\",\n      \"pmids\": [\"22405010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rpn2/PSMD1 serves as a central hub in the 19S regulatory particle: it docks ubiquitin shuttle proteins Rad23 and Dsk2 (via Rpn1 in the same study context), and directly anchors the ubiquitin receptor Rpn13, which binds exclusively to the C-terminal domain of Rpn2. The presence of Rpn2 also stabilizes the association of Rpn10 with Rpn1, coordinating multiple ubiquitin-processing factors simultaneously at the proteasome base.\",\n      \"method\": \"Binding affinity measurements, yeast two-hybrid, pulldown assays, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods identifying distinct binding sites and affinities\",\n      \"pmids\": [\"22318722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSMD1 (Psmd1) undergoes SUMOylation via the SUMO E3 ligase PIASy. The SUMO deconjugating enzyme xSENP1 specifically interacts with Psmd1. SUMOylation of a critical lysine immediately adjacent to the Adrm1(Rpn13)-binding domain of Psmd1 regulates the association of Adrm1 with the proteasome. Disruption of xSENP1 targeting delays mitotic exit, suggesting that SUMO-regulated Psmd1–Adrm1 interaction modulates proteasome composition and function during cell division.\",\n      \"method\": \"Co-immunoprecipitation, SUMO site mapping, PIASy E3 ligase assay, xSENP1 interaction studies, mitotic exit phenotype assay in Xenopus\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identified writer (PIASy) and eraser (xSENP1) of SUMO modification, mapped site, demonstrated functional consequence on proteasome composition and mitosis\",\n      \"pmids\": [\"24910440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The crystal structure of hRpn13 (Adrm1) bound to a segment of hRpn2/PSMD1 was determined, showing that a proline-rich C-terminal extension of Rpn2 stretches across the ubiquitin-binding Pru domain of Rpn13, blocking an RA190-binding surface. Biophysical and cell-based analyses showed hRpn13 binds preferentially to hRpn2/proteasomes over the drug RA190; RA190 instead directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abolishes RA190-induced substrate accumulation at proteasomes.\",\n      \"method\": \"NMR/crystal structure, surface plasmon resonance, cell-based ubiquitin substrate accumulation assay, hRpn13 deletion cell line\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biophysical quantification and cell-based functional validation\",\n      \"pmids\": [\"28598414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The RPN2/PSMD1–RPN13 interaction was mapped to the C-terminal 14 residues of RPN2, which bind the N-terminal PRU domain of RPN13. Crystal structures of the RPN13 PRU domain in complex with RPN2 C-terminal peptides and ubiquitin were solved. Mutational analysis validated the RPN2-binding interface; RPN2, ubiquitin, and UCH37 bind RPN13 with independent energetics, clarifying the substrate recruitment mechanism at the proteasome.\",\n      \"method\": \"Crystal structure, surface plasmon resonance, fluorescence polarization, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures combined with quantitative binding measurements and mutagenesis validation\",\n      \"pmids\": [\"28442575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 knockdown in breast cancer cells caused cell cycle arrest and accumulation of p53 protein by inhibiting p53 protein degradation. p53 target genes p21 and SFN were upregulated upon PSMD1 silencing, identifying PSMD1 as a component of the ubiquitin-proteasome pathway required for p53 turnover and linking PSMD1 function to tamoxifen resistance.\",\n      \"method\": \"siRNA knockdown, immunoblotting, cell cycle analysis, p53 protein stability assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with defined phenotype (p53 accumulation, cell cycle arrest) but no direct biochemical reconstitution of p53 degradation\",\n      \"pmids\": [\"28992264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 and PSMD2 (19S regulatory particle components) directly interact with ATG16, a core autophagosomal protein in Dictyostelium discoideum. The N-terminal half of ATG16 interacts with PSMD1 alone, while the C-terminal half interacts with both PSMD1 and PSMD2. RFP-tagged PSMD1 and PSMD2 co-localize with ATG16-GFP and GFP-ATG8a(LC3) in autophagosomes; lysotracker labeling and proteolytic cleavage assays confirmed their presence in lysosomes. ATG16 is required for autophagic degradation of PSMD1 and PSMD2, establishing a direct link between the ubiquitin-proteasome system and autophagy.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, fluorescence co-localization, LysoTracker labeling, proteolytic cleavage assay\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple methods (Co-IP, colocalization, lysosomal assay) in Dictyostelium model; direct interaction mapped\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of PSMD1 and/or PSMD2 in HepG2 hepatocellular carcinoma cells decreased formation of cellular lipid droplets and reduced cell proliferation. Mechanistically, PSMD1 and PSMD2 regulate expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.\",\n      \"method\": \"siRNA knockdown, lipid droplet quantification, gene expression analysis, pathway inhibitor studies\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with defined metabolic phenotype and pathway placement via signaling inhibitors\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD1 and PSMD3 (19S regulatory complex subunits) promote NF-κB protein expression in chronic myeloid leukemia (CML) cells. Knockdown of PSMD1 or PSMD3 reduced NF-κB activity (confirmed by luciferase reporter and immunoblot), reduced survival, and increased apoptosis in CML cells but not normal cord blood CD34+ progenitors. STAT3 further activates NF-κB in TKI-resistant scenarios, placing PSMD1 upstream of NF-κB in kinase-independent TKI resistance.\",\n      \"method\": \"shRNA knockdown, luciferase NF-κB reporter assay, nucleocytoplasmic fractionation, apoptosis assay, immunoblotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional assays placing PSMD1 upstream of NF-κB, but mechanism of NF-κB stabilization not directly biochemically resolved\",\n      \"pmids\": [\"33712704\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD1 (human p112/Rpn2) is the largest non-ATPase scaffolding subunit of the 26S proteasome 19S regulatory particle, forming a closed toroidal PC-repeat domain that anchors the ubiquitin receptor RPN13/Adrm1 through its C-terminal residues; its NLS drives karyopherin αβ-dependent nuclear import of the base complex; its interaction with RPN13 is dynamically regulated by PIASy-mediated SUMOylation and xSENP1-mediated deSUMOylation; and it promotes degradation of substrates including p53, regulates NF-κB stability in cancer cells, controls lipid droplet metabolism via p38-JNK/AKT signaling, and is itself subject to ATG16-dependent autophagic degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMD1 (Rpn2/p112) is the largest scaffolding subunit of the 19S regulatory particle of the 26S proteasome, coordinating ubiquitin receptor docking, substrate recruitment, and nuclear import of the proteasome complex. Its 11 PC repeats fold into a closed toroidal alpha-helical structure whose C-terminal residues directly dock the ubiquitin receptor Rpn13/ADRM1, an interaction regulated by PIASy-mediated SUMOylation and reversed by SENP1, while its body coordinates attachment of Rpn10 and substrate shuttle factors [PMID:22405010, PMID:22318722, PMID:24910440]. A bipartite nuclear localization signal in PSMD1 is required for karyopherin alpha/beta–dependent nuclear import of the proteasomal base complex, and its deletion causes proteasome mislocalization and functional impairment [PMID:15210724]. Through its role in proteasome integrity, PSMD1 controls degradation of key substrates including p53 and NF-κB pathway components, and PSMD1 itself can be targeted for ATG16-dependent autophagic degradation [PMID:28992264, PMID:33712704, PMID:30269947].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing PSMD1 as a core functional scaffold of the 19S proteasome: cross-species complementation showed that human p112 rescues yeast SEN3 disruption phenotypes affecting ubiquitin-pathway proteolysis, the N-end rule, and nuclear protein transport, defining PSMD1 as essential for proteasome function.\",\n      \"evidence\": \"cDNA cloning and yeast SEN3 disruption with complementation by human p112 cDNA, genetic and phenotypic analysis\",\n      \"pmids\": [\"8816993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PSMD1 scaffolding unknown\", \"Direct binding partners within the 19S particle uncharacterized\", \"Mammalian loss-of-function phenotype not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Determining how the proteasome reaches the nucleus: the bipartite NLS of PSMD1 was shown to be required for nuclear import of the proteasomal base complex via the karyopherin alpha/beta pathway, with NLS deletion causing proteasome mislocalization and functional impairment.\",\n      \"evidence\": \"NLS deletion mutagenesis with localization assays and functional proteasome readouts in yeast\",\n      \"pmids\": [\"15210724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this NLS is the sole import signal for the base complex\", \"Regulation of NLS accessibility not examined\", \"Mammalian validation not performed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolving the atomic architecture of PSMD1 and how it docks ubiquitin receptors: crystallography revealed the toroidal alpha-helical structure of Rpn2's PC repeats, and biochemical studies showed the C-terminal 20 residues of Rpn2 directly bind Rpn13 while the solenoid coordinates Rpn10 attachment and substrate shuttle binding, establishing PSMD1 as the central organizer of substrate recognition at the proteasome.\",\n      \"evidence\": \"X-ray crystallography, domain mapping, reciprocal Co-IP, pulldown assays, affinity measurements, proteasome reconstitution\",\n      \"pmids\": [\"22405010\", \"22318722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full proteasome-context structure of Rpn2 interactions not resolved at atomic detail\", \"Dynamics of Rpn10 versus shuttle factor competition not measured in real time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a regulatory switch on the PSMD1–Rpn13 interaction: PIASy SUMOylates PSMD1 at a lysine adjacent to the Rpn13-binding domain, and SENP1 removes this modification; SUMOylation directly regulates Rpn13 association with PSMD1, thereby controlling proteasome composition and function during mitotic exit.\",\n      \"evidence\": \"SUMOylation site mapping by mutagenesis, identification of writer (PIASy) and eraser (xSENP1), functional assays in Xenopus\",\n      \"pmids\": [\"24910440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional PTMs regulate the same interface\", \"Conservation of this regulatory mechanism across mammalian cell types not established\", \"Impact on global proteasome substrate selectivity not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining at atomic resolution how Rpn13 simultaneously engages PSMD1 and ubiquitin: crystal and NMR structures showed that Rpn2's C-terminal proline-rich extension occupies a canyon on the Rpn13 Pru domain with independent energetics from ubiquitin binding, and that Rpn13 preferentially binds Rpn2 over the drug RA190, clarifying substrate recruitment and pharmacological targeting.\",\n      \"evidence\": \"Crystal and NMR structures of hRpn13–hRpn2 peptide complexes, SPR, fluorescence polarization, cell-based assays\",\n      \"pmids\": [\"28442575\", \"28598414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformational changes in full-length Rpn2 within the intact proteasome affect Rpn13 binding dynamics\", \"Whether the Rpn2–Rpn13 interface is druggable independently of Uch37\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking PSMD1 to specific substrate degradation pathways: PSMD1 knockdown in breast cancer cells caused p53 accumulation and cell cycle arrest, placing PSMD1 as a regulator of p53 stability; separately, ATG16 was shown to directly interact with PSMD1 and target it for autophagic degradation, revealing a reciprocal proteolytic control of the proteasome scaffold.\",\n      \"evidence\": \"siRNA knockdown with immunoblot/cell cycle analysis in breast cancer cells; Co-IP, pulldown, and fluorescence co-localization in Dictyostelium\",\n      \"pmids\": [\"28992264\", \"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of p53 by PSMD1-containing proteasomes not reconstituted in vitro\", \"ATG16-PSMD1 interaction not validated in mammalian cells\", \"Selectivity of autophagic degradation of PSMD1 versus whole 26S proteasome unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending PSMD1 function to lipid metabolism: PSMD1 knockdown reduced lipid droplet accumulation and de novo lipogenesis gene expression via p38-JNK and AKT signaling in hepatocellular carcinoma cells, revealing non-canonical roles of proteasome scaffolding in metabolic regulation.\",\n      \"evidence\": \"siRNA knockdown, lipid droplet quantification, gene expression and signaling pathway analysis in HepG2 cells\",\n      \"pmids\": [\"31703613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteasome substrate(s) mediating lipid droplet phenotype unknown\", \"Whether effect is PSMD1-specific or reflects general proteasome impairment not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connecting PSMD1 to NF-κB signaling in leukemia: PSMD1 knockdown reduced NF-κB protein levels and activity, decreased CML cell survival, and increased apoptosis without affecting normal CD34+ progenitors, establishing PSMD1 as a regulator of NF-κB stability with potential therapeutic specificity.\",\n      \"evidence\": \"siRNA knockdown, luciferase reporter, immunoblot, nucleocytoplasmic fractionation, apoptosis assays in CML cells\",\n      \"pmids\": [\"33712704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NF-κB stabilization reflects direct IκB degradation via PSMD1-containing proteasomes\", \"In vivo validation in animal models not performed\", \"Mechanism of differential sensitivity between CML and normal progenitors not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include how PSMD1 SUMOylation is dynamically regulated across cell cycle stages in mammalian cells, which specific ubiquitinated substrates require PSMD1-mediated Rpn13 docking for degradation, and whether autophagic turnover of PSMD1 serves as a physiological mechanism for proteasome remodeling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No systematic identification of substrates dependent on PSMD1–Rpn13 axis\", \"SUMOylation dynamics not characterized in mammalian somatic cells\", \"Physiological role of ATG16-mediated PSMD1 degradation in mammalian proteostasis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"26S proteasome\", \"19S regulatory particle\"],\n    \"partners\": [\"ADRM1\", \"PSMD2\", \"PSMD3\", \"PSMD4\", \"PIAS4\", \"SENP1\", \"ATG16\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD1 (Rpn2) is the largest non-ATPase scaffolding subunit of the 26S proteasome 19S regulatory particle, essential for ubiquitin-dependent proteolysis, stress responses, and nuclear protein transport [PMID:8816993]. Its eleven PC repeats fold into a closed toroidal structure of concentric α-helical rings, from which a rod-like N-terminal domain and a globular C-terminal domain emerge; the C-terminal ~14–20 residues serve as the exclusive docking site for the ubiquitin receptor Rpn13/Adrm1, coordinating substrate recognition at the proteasome [PMID:22405010, PMID:28442575]. A bipartite NLS within PSMD1 mediates karyopherin αβ-dependent nuclear import of the 19S base complex [PMID:15210724], and PIASy-mediated SUMOylation of a lysine adjacent to the Rpn13-binding site dynamically regulates Rpn13 association with the proteasome, with disruption of SUMO cycling delaying mitotic exit [PMID:24910440]. PSMD1 knockdown stabilizes p53, arrests the cell cycle in breast cancer cells [PMID:28992264], sustains NF-κB signaling in chronic myeloid leukemia [PMID:33712704], and promotes lipid droplet formation via p38-JNK/AKT pathways in hepatocellular carcinoma cells [PMID:31703613].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning of human p112 (PSMD1) and yeast complementation established it as the largest 19S regulatory subunit essential for multiple 26S proteasome-mediated processes including ubiquitin-dependent proteolysis and nuclear transport.\",\n      \"evidence\": \"cDNA cloning with yeast SEN3 complementation and phenotypic assays\",\n      \"pmids\": [\"8816993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information on PSMD1 or its domain architecture\",\n        \"Binding partners within the 19S particle not yet mapped\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Computational modeling predicted that the PC-repeat domain of PSMD1 forms a novel toroidal α-helical fold, providing the first structural hypothesis for how the subunit might assist substrate unfolding.\",\n      \"evidence\": \"Sequence pattern analysis and molecular modeling\",\n      \"pmids\": [\"12270919\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No experimental structure to validate the toroid model\",\n        \"Functional role of the predicted pore unresolved\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of a functional bipartite NLS in Rpn2/PSMD1 resolved how the 19S base complex enters the nucleus, showing that PSMD1 itself directs karyopherin αβ-dependent nuclear import.\",\n      \"evidence\": \"NLS deletion mutagenesis with immunofluorescence in yeast\",\n      \"pmids\": [\"15210724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PSMD1 NLS is the sole import signal for the 19S base or acts redundantly with other subunit NLSs\",\n        \"Mechanism by which nuclear proteasome mislocalization impairs function not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that the ubiquitin receptor Rpn13 is anchored to the proteasome through direct interaction with PSMD1 defined a key substrate-recruitment axis at the 19S particle.\",\n      \"evidence\": \"Biochemical interaction mapping and Rpn13 identification as proteasome subunit\",\n      \"pmids\": [\"18497817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise binding site on PSMD1 not yet mapped\",\n        \"Regulation of the PSMD1–Rpn13 interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystal structure of PSMD1 confirmed the closed toroidal PC-repeat fold and located the Rpn13-binding site to the C-terminal ~20 residues, while biochemical mapping showed PSMD1 coordinates multiple ubiquitin-processing factors at the proteasome base.\",\n      \"evidence\": \"X-ray crystallography combined with binding-affinity measurements, pulldown, and yeast two-hybrid assays\",\n      \"pmids\": [\"22405010\", \"22318722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution co-crystal of PSMD1 with Rpn13 at this point\",\n        \"Energetic independence of ubiquitin and Rpn13 binding to PSMD1 not yet resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PIASy-mediated SUMOylation of PSMD1 adjacent to the Rpn13-binding domain, and its reversal by xSENP1, was shown to regulate Rpn13 proteasome association and mitotic exit, revealing a post-translational mechanism that tunes proteasome composition during cell division.\",\n      \"evidence\": \"Co-IP, SUMO site mapping, PIASy/xSENP1 functional studies, mitotic exit assay in Xenopus egg extracts\",\n      \"pmids\": [\"24910440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SUMO-dependent regulation of PSMD1–Rpn13 operates in mammalian mitosis not directly shown\",\n        \"Full spectrum of PSMD1 SUMOylation sites and their functional consequences unexplored\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Co-crystal structures of hRpn13 PRU domain bound to hRpn2 C-terminal peptides resolved the atomic interface and demonstrated that Rpn2 occupancy occludes the RA190 drug-binding surface on Rpn13, clarifying both substrate recruitment and pharmacological targeting mechanisms.\",\n      \"evidence\": \"NMR and X-ray crystallography, SPR, fluorescence polarization, mutagenesis, and cell-based RA190 assays\",\n      \"pmids\": [\"28598414\", \"28442575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No full-length PSMD1–Rpn13 complex structure in the context of the intact 26S proteasome\",\n        \"Structural basis for how SUMOylation disrupts the C-terminal interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Functional studies in cancer cells revealed that PSMD1 loss stabilizes p53 protein and causes cell-cycle arrest, while in Dictyostelium PSMD1 directly interacts with ATG16 and is subject to autophagic degradation, linking proteasome turnover to the autophagy pathway.\",\n      \"evidence\": \"siRNA knockdown with p53 stability and cell-cycle assays (breast cancer); Co-IP, colocalization, lysosomal assays in Dictyostelium\",\n      \"pmids\": [\"28992264\", \"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"p53 stabilization upon PSMD1 knockdown likely reflects general proteasome impairment rather than a PSMD1-specific mechanism — not disambiguated\",\n        \"ATG16-dependent degradation of PSMD1 not confirmed in mammalian cells\",\n        \"Direct reconstitution of PSMD1 autophagic turnover lacking\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PSMD1 knockdown in hepatocellular carcinoma cells reduced lipid droplet formation and cell proliferation via p38-JNK/AKT signaling, extending PSMD1's functional impact to lipid metabolism.\",\n      \"evidence\": \"siRNA knockdown, lipid droplet quantification, pathway inhibitor studies in HepG2 cells\",\n      \"pmids\": [\"31703613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether lipid metabolic effects are PSMD1-specific or reflect general proteasome inhibition not resolved\",\n        \"Direct proteasomal substrates linking PSMD1 to lipid synthesis genes not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PSMD1 was placed upstream of NF-κB in chronic myeloid leukemia cells, where its depletion reduces NF-κB activity and induces apoptosis selectively in leukemia but not normal progenitor cells, connecting PSMD1 to kinase-independent TKI resistance.\",\n      \"evidence\": \"shRNA knockdown, NF-κB luciferase reporter, nucleocytoplasmic fractionation, apoptosis assays\",\n      \"pmids\": [\"33712704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical mechanism by which PSMD1 promotes NF-κB stability (direct substrate identity) not determined\",\n        \"In vivo validation in CML models lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the cancer-context phenotypes of PSMD1 depletion (p53 stabilization, NF-κB reduction, lipid droplet loss) reflect PSMD1-specific scaffolding functions or general proteasome impairment, and no full-length cryo-EM or crystal structure of PSMD1 within the complete human 26S proteasome has been described in this timeline.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Substrate specificity conferred by PSMD1 versus general proteasome function not disentangled\",\n        \"Full structural context of PSMD1 within the assembled human 26S holoenzyme not captured\",\n        \"Whether SUMO-mediated regulation of PSMD1–Rpn13 operates in vivo in mammals unconfirmed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4, 5, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle (base subcomplex)\"\n    ],\n    \"partners\": [\n      \"ADRM1\",\n      \"PSMD2\",\n      \"PIASy\",\n      \"SENP1\",\n      \"ATG16\",\n      \"UCH37\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}