{"gene":"PSMC6","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"The 26S proteasome (of which PSMC6/Rpt4 is one of six AAA-ATPase subunits in the 19S regulatory particle) was established as the ATP-dependent protease responsible for degrading ubiquitinated proteins. The six ATPases form a ring that drives substrate unfolding and translocation into the 20S core particle.","method":"Biochemical reconstitution, subunit purification, peptidase activity assays, structural analysis of 20S and 19S particles","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — foundational biochemical reconstitution and structural characterization, replicated across multiple labs and organisms","pmids":["8811196"],"is_preprint":false},{"year":2009,"finding":"PSMC6, as part of the six-ATPase ring of the 19S regulatory particle, participates in ATP-dependent substrate unfolding and translocation into the 20S core for degradation. Deubiquitinating enzymes (DUBs) associated with the regulatory particle can remove ubiquitin either to allow substrate degradation or to permit substrate escape before degradation initiates.","method":"Biochemical reconstitution, mutant analysis, structural studies of proteasome ATPase ring function","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — mechanistic reconstitution with mutagenesis, replicated","pmids":["19489727"],"is_preprint":false},{"year":2009,"finding":"Affinity-purification mass spectrometry of 75 human deubiquitinating enzymes identified PSMC6 (as a 19S proteasome ATPase subunit) as part of proteasome-associated protein complexes linked to protein turnover, providing a protein-interaction landscape for the proteasome regulatory particle.","method":"Affinity-purification mass spectrometry (CompPASS platform), reciprocal interaction proteomics","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale AP-MS with confidence scoring, single study but systematic","pmids":["19615732"],"is_preprint":false},{"year":2013,"finding":"PARKIN-dependent ubiquitylation of mitochondrial outer membrane proteins upon depolarization was found to direct substrates to the proteasome (including the PSMC6-containing 19S regulatory particle), with depolarization-dependent PARKIN association detected with the proteasome by interaction proteomics.","method":"Quantitative diGly capture proteomics, affinity-purification mass spectrometry","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative proteomics with orthogonal validation, but PSMC6 role inferred as part of proteasome complex rather than individually dissected","pmids":["23503661"],"is_preprint":false},{"year":2015,"finding":"BioPlex AP-MS network identified interaction partners of PSMC6 in HEK293T cells, placing it within the 19S proteasome regulatory particle complex and revealing its co-complex associations with other proteasome subunits at proteome scale.","method":"High-throughput affinity-purification mass spectrometry (BioPlex)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale AP-MS with 86% novel interactions, systematic but not individually validated for PSMC6","pmids":["26186194"],"is_preprint":false},{"year":2017,"finding":"Genome-wide CRISPR screening in multiple myeloma cells identified PSMC6 as the sole validated gene whose loss reproducibly confers resistance to bortezomib (a proteasome inhibitor). Loss of PSMC6 significantly reduced inhibition of chymotrypsin-like proteasome activity by bortezomib, demonstrating that PSMC6 is required for bortezomib's mechanism of action. Individual knockout of each PSMC1–PSMC5 subunit also conferred bortezomib resistance, indicating a shared requirement for 19S ATPase subunits in drug sensitivity.","method":"Genome-wide CRISPR sgRNA library screen, secondary targeted CRISPR screen with 4 sgRNAs/gene, individual gene validation, proteasome chymotrypsin-like activity assay","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 — two independent whole-genome screens plus individual validation with functional proteasome activity assay","pmids":["28958990"],"is_preprint":false},{"year":2020,"finding":"PSMC6 promotes osteoblast apoptosis by inhibiting the PI3K/AKT signaling pathway. In an ovariectomy-induced osteoporosis mouse model, PSMC6 knockout elevated bone mineral density and increased PI3K phosphorylation, while PSMC6 overexpression promoted apoptosis (increased cleaved caspase-3/-9) and inhibited cell cycle progression and proliferation. PI3K activation significantly decreased PSMC6-induced osteoblast apoptosis, acting via p53, cyclinD1, and cleaved caspase-3/9 protein levels.","method":"Knockout mouse model (OVX osteoporosis), siRNA knockdown, overexpression, MTT assay, BrdU assay, flow cytometry, Western blot for PI3K/AKT pathway components and apoptosis markers","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple in vitro and in vivo methods but mechanistic pathway placement relies on inhibitor/overexpression rather than direct biochemical reconstitution","pmids":["32017075"],"is_preprint":false},{"year":2021,"finding":"Silencing of PSMC6 by siRNA in lung adenocarcinoma cell lines inhibited cell growth, migration, and invasion. Bioinformatic analysis suggested PSMC6 overexpression may activate WNT signaling by promoting proteasomal degradation of AXIN protein, and PSMC6 expression was positively correlated with other proteasome subunits (PSMD10, PSMD6, PSMD9, PSMD13, PSMB3, PSMB1, PSMA4, PSMC1, PSMC2, PSMD7, PSMD14).","method":"siRNA knockdown, cell proliferation/migration/invasion assays, gene set enrichment analysis, correlation analysis of proteasome subunit co-expression","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 — siRNA phenotype with no direct biochemical validation of AXIN degradation by PSMC6; pathway placement is bioinformatic inference","pmids":["34239933"],"is_preprint":false}],"current_model":"PSMC6 (Rpt4) is one of six AAA-ATPase subunits forming the ring of the 19S regulatory particle of the 26S proteasome, where it drives ATP-dependent substrate unfolding and translocation into the 20S catalytic core for degradation of ubiquitinated proteins; it is specifically required for bortezomib sensitivity in multiple myeloma cells, and in osteoblasts it promotes apoptosis by suppressing PI3K/AKT signaling, while its loss in lung adenocarcinoma cells reduces proliferation, migration, and invasion."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that the 26S proteasome — including its six AAA-ATPase ring subunits such as PSMC6 — is the principal ATP-dependent protease for ubiquitin-conjugated substrates resolved the long-standing question of how cells selectively degrade marked proteins.","evidence":"Biochemical reconstitution, subunit purification, peptidase assays, and structural analysis of 19S and 20S particles","pmids":["8811196"],"confidence":"High","gaps":["Individual contributions of each ATPase subunit to the unfolding cycle were not resolved","No structural model at atomic resolution for the mammalian 19S ring at this time"]},{"year":2009,"claim":"Detailed mechanistic analysis showed how the six-ATPase ring (including PSMC6) couples ATP hydrolysis to substrate unfolding and threading, and revealed that proteasome-associated deubiquitinases gate substrate commitment versus escape, clarifying the decision point before irreversible degradation.","evidence":"Biochemical reconstitution with mutant ATPase subunits and structural studies of proteasome ATPase ring; complemented by large-scale AP-MS mapping proteasome–DUB interactions","pmids":["19489727","19615732"],"confidence":"High","gaps":["PSMC6-specific catalytic contribution within the ATPase ring not individually dissected","Structural basis for ordered ATP hydrolysis around the ring not yet available"]},{"year":2013,"claim":"PARKIN-dependent ubiquitylation of mitochondrial outer membrane substrates upon depolarization was shown to funnel substrates to the proteasome, linking the PSMC6-containing 19S particle to mitophagy-associated protein turnover and broadening the physiological contexts of proteasomal degradation.","evidence":"Quantitative diGly-capture proteomics and AP-MS detecting PARKIN–proteasome association","pmids":["23503661"],"confidence":"Medium","gaps":["PSMC6 role inferred as part of intact proteasome; no subunit-specific perturbation performed","Whether PARKIN substrates are preferentially handled by a PSMC6-dependent sub-pathway is unknown"]},{"year":2015,"claim":"Systematic proteome-scale interaction mapping confirmed PSMC6's co-complex associations with other 19S regulatory particle subunits, providing an unbiased human interaction network for the proteasome.","evidence":"BioPlex high-throughput AP-MS in HEK293T cells","pmids":["26186194"],"confidence":"Medium","gaps":["Interactions not individually validated for PSMC6 beyond co-complex membership","Dynamic or cell-type-specific interaction partners not explored"]},{"year":2017,"claim":"CRISPR screening revealed that PSMC6 loss is sufficient to confer bortezomib resistance in myeloma cells by reducing proteasome inhibition, answering the question of which genetic determinants govern clinical proteasome-inhibitor sensitivity.","evidence":"Two independent genome-wide CRISPR screens with secondary targeted validation and chymotrypsin-like activity assays in multiple myeloma cells","pmids":["28958990"],"confidence":"High","gaps":["Mechanism by which 19S ATPase loss alters 20S active-site accessibility to bortezomib not biochemically resolved","Whether PSMC6 loss affects drug sensitivity in other cancer types remains untested"]},{"year":2020,"claim":"Discovery that PSMC6 promotes osteoblast apoptosis via PI3K/AKT pathway suppression — and that its knockout in vivo improves bone density in osteoporosis — established a non-canonical, cell-type-specific role for PSMC6 beyond bulk proteolysis.","evidence":"Ovariectomy-induced osteoporosis mouse model with PSMC6 knockout, siRNA knockdown, overexpression, and PI3K/AKT pathway analysis by Western blot and flow cytometry","pmids":["32017075"],"confidence":"Medium","gaps":["Whether apoptosis promotion is a direct effect of PSMC6 or secondary to altered proteasomal degradation of PI3K/AKT pathway components is unresolved","Pathway placement relies on inhibitor and overexpression studies rather than direct biochemical reconstitution"]},{"year":2021,"claim":"siRNA-mediated silencing of PSMC6 in lung adenocarcinoma cells reduced proliferation, migration, and invasion, with bioinformatic inference suggesting WNT pathway activation via proteasomal AXIN degradation as a potential mechanism.","evidence":"siRNA knockdown with proliferation/migration/invasion assays and gene set enrichment analysis in lung adenocarcinoma cell lines","pmids":["34239933"],"confidence":"Low","gaps":["No direct biochemical evidence that PSMC6 specifically promotes AXIN degradation","WNT pathway link is inferred computationally, not validated experimentally","Single study without independent replication"]},{"year":null,"claim":"The specific mechanistic contribution of PSMC6 versus the other five 19S ATPase subunits to the ordered ATP hydrolysis cycle, substrate engagement selectivity, and proteasome assembly remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No subunit-specific reconstitution distinguishing PSMC6 from other ATPases in the ring","Structural basis for PSMC6's unique role in bortezomib sensitivity not determined","Whether PSMC6-dependent apoptotic signaling in osteoblasts is proteasome-dependent or reflects a moonlighting function is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]}],"complexes":["26S proteasome","19S regulatory particle"],"partners":["PSMC1","PSMC2","PSMC3","PSMC4","PSMC5","PSMD14","PRKN"],"other_free_text":[]},"mechanistic_narrative":"PSMC6 (Rpt4/S10b) is one of six AAA-ATPase subunits that form the heterohexameric ring of the 19S regulatory particle of the 26S proteasome, where it powers ATP-dependent unfolding and translocation of ubiquitinated substrates into the 20S catalytic core for degradation [PMID:8811196, PMID:19489727]. Genome-wide CRISPR screening in multiple myeloma cells established that loss of PSMC6 confers resistance to the proteasome inhibitor bortezomib by reducing inhibition of chymotrypsin-like proteasome activity, a property shared by all six 19S ATPase subunits [PMID:28958990]. In osteoblasts, PSMC6 promotes apoptosis through suppression of PI3K/AKT signaling, and its knockout in an ovariectomy-induced osteoporosis mouse model elevates bone mineral density [PMID:32017075]."},"prefetch_data":{"uniprot":{"accession":"P62333","full_name":"26S proteasome regulatory subunit 10B","aliases":["26S proteasome AAA-ATPase subunit RPT4","Proteasome 26S subunit ATPase 6","Proteasome subunit p42"],"length_aa":389,"mass_kda":44.2,"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. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62333/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC6","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100519","cell_line_id":"CID000128","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMD4","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMC1","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"UCHL5","stoichiometry":10.0},{"gene":"PSMD13","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000128","total_profiled":1310},"omim":[{"mim_id":"606223","title":"PROTEASOME 26S SUBUNIT, NON-ATPASE, 2; PSMD2","url":"https://www.omim.org/entry/606223"},{"mim_id":"603146","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 9; PSMD9","url":"https://www.omim.org/entry/603146"},{"mim_id":"602708","title":"PROTEASOME 26S SUBUNIT, ATPase, 6; PSMC6","url":"https://www.omim.org/entry/602708"},{"mim_id":"602706","title":"PROTEASOME 26S SUBUNIT, ATPase, 1; PSMC1","url":"https://www.omim.org/entry/602706"},{"mim_id":"186852","title":"PROTEASOME 26S SUBUNIT, ATPase, 3; PSMC3","url":"https://www.omim.org/entry/186852"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMC6"},"hgnc":{"alias_symbol":["p42","RPT5"],"prev_symbol":[]},"alphafold":{"accession":"P62333","domains":[{"cath_id":"2.40.50.140","chopping":"54-109","consensus_level":"high","plddt":89.7339,"start":54,"end":109},{"cath_id":"3.40.50.300","chopping":"117-299","consensus_level":"high","plddt":85.4098,"start":117,"end":299},{"cath_id":"1.10.8.60","chopping":"305-379","consensus_level":"high","plddt":90.2547,"start":305,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62333","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62333-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62333-F1-predicted_aligned_error_v6.png","plddt_mean":86.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC6","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC6"},"sequence":{"accession":"P62333","fasta_url":"https://rest.uniprot.org/uniprotkb/P62333.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62333/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62333"}},"corpus_meta":[{"pmid":"10551817","id":"PMC_10551817","title":"p42/p44 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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 Vif.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859895","citation_count":763,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14527406","id":"PMC_14527406","title":"HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14527406","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12750511","id":"PMC_12750511","title":"Hypermutation of HIV-1 DNA in the absence of the Vif protein.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12750511","citation_count":570,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23535732","id":"PMC_23535732","title":"Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23535732","citation_count":463,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16239144","id":"PMC_16239144","title":"Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16239144","citation_count":443,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57741,"output_tokens":837,"usd":0.092889},"stage2":{"model":"claude-opus-4-6","input_tokens":4018,"output_tokens":1215,"usd":0.075698},"total_usd":0.41636,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":68912,"output_tokens":2973,"usd":0.125666},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5576,"output_tokens":2141,"usd":0.122107}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMC6 promotes osteoblast apoptosis by inhibiting the PI3K/AKT signaling pathway; PSMC6 knockout elevated PI3K phosphorylation and reduced cleaved caspase-3/-9, while PSMC6 overexpression promoted apoptosis and inhibited cell cycle progression in vitro. PI3K activation rescued PSMC6-induced apoptosis.\",\n      \"method\": \"Gene knockout mouse model (OVX), siRNA knockdown and overexpression in osteoblasts, MTT/BrdU/flow cytometry assays, Western blotting for PI3K/AKT/caspase pathway components\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular phenotype and pathway rescue, single lab\",\n      \"pmids\": [\"32017075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSMC6 is required for bortezomib sensitivity in multiple myeloma; loss of PSMC6 (and other PSMC1-5 subunits) significantly reduced bortezomib-mediated inhibition of chymotrypsin-like proteasome activity, conferring drug resistance. PSMC6 was the single gene reproducibly validated from genome-wide CRISPR screens.\",\n      \"method\": \"Genome-wide CRISPR screen, secondary sgRNA library validation, individual gene knockout validation, proteasome activity assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two independent genome-wide CRISPR screens plus functional proteasome activity assay, strong mechanistic validation\",\n      \"pmids\": [\"28958990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing PSMC6 inhibits cell growth, migration, and invasion in lung adenocarcinoma cell lines; PSMC6 overexpression correlates with activation of WNT signaling, proposed to occur via proteasomal degradation of AXIN protein.\",\n      \"method\": \"siRNA knockdown, cell proliferation/migration/invasion assays, gene set enrichment analysis, correlation analysis of proteasome subunit co-expression\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — siRNA KD with cellular phenotype but WNT/AXIN mechanism is bioinformatic inference without direct experimental validation\",\n      \"pmids\": [\"34239933\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC6 is an AAA-ATPase subunit of the 19S proteasome regulatory particle whose proteasome activity is essential for bortezomib sensitivity in multiple myeloma (loss of PSMC6 reduces chymotrypsin-like proteasome inhibition by bortezomib), and which promotes osteoblast apoptosis by suppressing PI3K/AKT signaling, while its overexpression in cancer contexts may enhance WNT signaling through proteasomal degradation of pathway regulators such as AXIN.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe corpus is overwhelmingly about p42/p44 MAPK (ERK1/2) signaling — these are ALIAS COLLISION papers (EXCLUDE). PSMC6 is the 26S proteasome regulatory particle AAA-ATPase subunit 6.\n\nPapers to KEEP (about canonical PSMC6 protein):\n- PMID:32017075 — directly about PSMC6 in osteoblasts/osteoporosis\n- PMID:28958990 — CRISPR screen identifying PSMC6 for bortezomib sensitivity\n- PMID:34239933 — PSMC6 silencing in lung adenocarcinoma\n- PMID:8811196 — 26S proteasome structure/function (foundational)\n- PMID:19489727 — Proteasome recognition of ubiquitin conjugates (includes AAA-ATPase ring)\n- PMID:19615732 — DUB interaction landscape (proteasome complex context)\n- PMID:26186194 — BioPlex (PSMC6 interactions identified)\n- PMID:28514442 — BioPlex 2.0\n- PMID:33961781 — BioPlex 3.0\n- PMID:16189514 — Human interactome (may include PSMC6)\n- PMID:25416956 — HuRI\n- PMID:32296183 — HuRI reference\n- PMID:17353931 — Large-scale MS interactions\n- PMID:26496610 — Quantitative interactome\n- PMID:22939629 — Census of human complexes\n- PMID:23503661 — PARKIN ubiquitylome (proteasome substrates)\n\nPapers about other \"p42\" entities (EXCLUDE as alias collisions):\n- All the p42/p44 MAPK papers (majority of corpus)\n- PMID:19223514 — Arabidopsis RPT5 (SYMBOL COLLISION, plant)\n- PMID:10097131 — p42 ETS1 variant\n- PMID:8003962 — p42/p51 ETS1\n- PMID:14597612 — p42 CAK (different gene)\n- PMID:10796018 — Beet necrotic yellow vein virus P42 (viral protein)\n- PMID:9847305 — Influenza C virus P42\n- PMID:20716519 — AUF1 p42 isoform\n- PMID:25091984 — P42 peptide Huntington's\n- PMID:26984770 — P42 peptide HD therapy\n- PMID:24998263 — p42 Ebp1\n- PMID:38290838 — MOG antibody P42 epitope\n- All APOBEC3G/CEM15 papers (EXCLUDE — different gene)\n- PMID:12167863, 12808466, 12809610, 14564014, 14528300, 12808465, 14527406, 14528301, 12750511, 12859895 — APOBEC3G\n- PMID:12477932 — MGC cDNA (general)\n- PMID:21873635 — GO phylogenetic annotation\n- PMID:23535732 — Prostate cancer GWAS\n- PMID:16239144 — Integrator complex\n- PMID:28302793 — RBM39/indisulam\n- PMID:19056867 — Urinary exosomes\n- PMID:29507755 — VIRMA/m6A\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The 26S proteasome (of which PSMC6/Rpt4 is one of six AAA-ATPase subunits in the 19S regulatory particle) was established as the ATP-dependent protease responsible for degrading ubiquitinated proteins. The six ATPases form a ring that drives substrate unfolding and translocation into the 20S core particle.\",\n      \"method\": \"Biochemical reconstitution, subunit purification, peptidase activity assays, structural analysis of 20S and 19S particles\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational biochemical reconstitution and structural characterization, replicated across multiple labs and organisms\",\n      \"pmids\": [\"8811196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMC6, as part of the six-ATPase ring of the 19S regulatory particle, participates in ATP-dependent substrate unfolding and translocation into the 20S core for degradation. Deubiquitinating enzymes (DUBs) associated with the regulatory particle can remove ubiquitin either to allow substrate degradation or to permit substrate escape before degradation initiates.\",\n      \"method\": \"Biochemical reconstitution, mutant analysis, structural studies of proteasome ATPase ring function\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic reconstitution with mutagenesis, replicated\",\n      \"pmids\": [\"19489727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Affinity-purification mass spectrometry of 75 human deubiquitinating enzymes identified PSMC6 (as a 19S proteasome ATPase subunit) as part of proteasome-associated protein complexes linked to protein turnover, providing a protein-interaction landscape for the proteasome regulatory particle.\",\n      \"method\": \"Affinity-purification mass spectrometry (CompPASS platform), reciprocal interaction proteomics\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale AP-MS with confidence scoring, single study but systematic\",\n      \"pmids\": [\"19615732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARKIN-dependent ubiquitylation of mitochondrial outer membrane proteins upon depolarization was found to direct substrates to the proteasome (including the PSMC6-containing 19S regulatory particle), with depolarization-dependent PARKIN association detected with the proteasome by interaction proteomics.\",\n      \"method\": \"Quantitative diGly capture proteomics, affinity-purification mass spectrometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative proteomics with orthogonal validation, but PSMC6 role inferred as part of proteasome complex rather than individually dissected\",\n      \"pmids\": [\"23503661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BioPlex AP-MS network identified interaction partners of PSMC6 in HEK293T cells, placing it within the 19S proteasome regulatory particle complex and revealing its co-complex associations with other proteasome subunits at proteome scale.\",\n      \"method\": \"High-throughput affinity-purification mass spectrometry (BioPlex)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale AP-MS with 86% novel interactions, systematic but not individually validated for PSMC6\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genome-wide CRISPR screening in multiple myeloma cells identified PSMC6 as the sole validated gene whose loss reproducibly confers resistance to bortezomib (a proteasome inhibitor). Loss of PSMC6 significantly reduced inhibition of chymotrypsin-like proteasome activity by bortezomib, demonstrating that PSMC6 is required for bortezomib's mechanism of action. Individual knockout of each PSMC1–PSMC5 subunit also conferred bortezomib resistance, indicating a shared requirement for 19S ATPase subunits in drug sensitivity.\",\n      \"method\": \"Genome-wide CRISPR sgRNA library screen, secondary targeted CRISPR screen with 4 sgRNAs/gene, individual gene validation, proteasome chymotrypsin-like activity assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent whole-genome screens plus individual validation with functional proteasome activity assay\",\n      \"pmids\": [\"28958990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMC6 promotes osteoblast apoptosis by inhibiting the PI3K/AKT signaling pathway. In an ovariectomy-induced osteoporosis mouse model, PSMC6 knockout elevated bone mineral density and increased PI3K phosphorylation, while PSMC6 overexpression promoted apoptosis (increased cleaved caspase-3/-9) and inhibited cell cycle progression and proliferation. PI3K activation significantly decreased PSMC6-induced osteoblast apoptosis, acting via p53, cyclinD1, and cleaved caspase-3/9 protein levels.\",\n      \"method\": \"Knockout mouse model (OVX osteoporosis), siRNA knockdown, overexpression, MTT assay, BrdU assay, flow cytometry, Western blot for PI3K/AKT pathway components and apoptosis markers\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple in vitro and in vivo methods but mechanistic pathway placement relies on inhibitor/overexpression rather than direct biochemical reconstitution\",\n      \"pmids\": [\"32017075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing of PSMC6 by siRNA in lung adenocarcinoma cell lines inhibited cell growth, migration, and invasion. Bioinformatic analysis suggested PSMC6 overexpression may activate WNT signaling by promoting proteasomal degradation of AXIN protein, and PSMC6 expression was positively correlated with other proteasome subunits (PSMD10, PSMD6, PSMD9, PSMD13, PSMB3, PSMB1, PSMA4, PSMC1, PSMC2, PSMD7, PSMD14).\",\n      \"method\": \"siRNA knockdown, cell proliferation/migration/invasion assays, gene set enrichment analysis, correlation analysis of proteasome subunit co-expression\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — siRNA phenotype with no direct biochemical validation of AXIN degradation by PSMC6; pathway placement is bioinformatic inference\",\n      \"pmids\": [\"34239933\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC6 (Rpt4) is one of six AAA-ATPase subunits forming the ring of the 19S regulatory particle of the 26S proteasome, where it drives ATP-dependent substrate unfolding and translocation into the 20S catalytic core for degradation of ubiquitinated proteins; it is specifically required for bortezomib sensitivity in multiple myeloma cells, and in osteoblasts it promotes apoptosis by suppressing PI3K/AKT signaling, while its loss in lung adenocarcinoma cells reduces proliferation, migration, and invasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMC6 is an AAA-ATPase subunit of the 19S proteasome regulatory particle that is required for chymotrypsin-like proteasome activity; loss of PSMC6 in multiple myeloma cells reduces bortezomib-mediated proteasome inhibition, conferring drug resistance [PMID:28958990]. Beyond its core proteasomal role, PSMC6 promotes osteoblast apoptosis by suppressing PI3K/AKT signaling, and PI3K activation rescues PSMC6-induced apoptosis [PMID:32017075]. Silencing PSMC6 inhibits proliferation, migration, and invasion in lung adenocarcinoma cells [PMID:34239933].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that PSMC6 is functionally required for proteasome activity and bortezomib sensitivity resolved how loss of a single 19S regulatory subunit can confer drug resistance in multiple myeloma.\",\n      \"evidence\": \"Genome-wide CRISPR screens in multiple myeloma cells with secondary validation and proteasome activity assays\",\n      \"pmids\": [\"28958990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PSMC6 loss affects proteasome assembly or substrate engagement specifically is not resolved\",\n        \"Clinical relevance of PSMC6 loss in patient-derived bortezomib-resistant myeloma not tested\",\n        \"No structural or biochemical reconstitution of the defective 19S particle\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that PSMC6 promotes osteoblast apoptosis through PI3K/AKT suppression revealed a non-canonical, proteasome-independent-appearing role for this subunit in bone biology.\",\n      \"evidence\": \"PSMC6 knockout mouse model (ovariectomy), siRNA/overexpression in osteoblasts, pathway rescue with PI3K activator, Western blotting for caspase and AKT phosphorylation\",\n      \"pmids\": [\"32017075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PI3K/AKT suppression is a direct effect of PSMC6 or secondary to altered proteasome function is unclear\",\n        \"Single-lab study without independent replication\",\n        \"Mechanism linking PSMC6 to PI3K phosphorylation not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking PSMC6 silencing to reduced lung adenocarcinoma cell growth and WNT pathway activation broadened the oncogenic contexts in which PSMC6 functions, though the proposed AXIN degradation mechanism lacked direct experimental support.\",\n      \"evidence\": \"siRNA knockdown in lung adenocarcinoma lines, proliferation/migration/invasion assays, gene set enrichment and co-expression analysis\",\n      \"pmids\": [\"34239933\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"WNT/AXIN degradation mechanism is bioinformatic inference without biochemical validation\",\n        \"No demonstration that PSMC6 directly interacts with or promotes AXIN ubiquitination/degradation\",\n        \"Phenotypic effects not confirmed with orthogonal knockdown approaches or rescue\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the apoptotic and oncogenic functions attributed to PSMC6 are mechanistically separable from its core proteasomal role, and no structural or biochemical studies have defined PSMC6-specific contributions to 26S proteasome assembly or substrate translocation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model distinguishing PSMC6 from other PSMC subunits in the 19S ring\",\n        \"No direct substrates of PSMC6-dependent proteasomal degradation identified\",\n        \"Whether PSMC6 has extra-proteasomal 'moonlighting' functions is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"26S proteasome (19S regulatory particle)\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMC6 (Rpt4/S10b) is one of six AAA-ATPase subunits that form the heterohexameric ring of the 19S regulatory particle of the 26S proteasome, where it powers ATP-dependent unfolding and translocation of ubiquitinated substrates into the 20S catalytic core for degradation [PMID:8811196, PMID:19489727]. Genome-wide CRISPR screening in multiple myeloma cells established that loss of PSMC6 confers resistance to the proteasome inhibitor bortezomib by reducing inhibition of chymotrypsin-like proteasome activity, a property shared by all six 19S ATPase subunits [PMID:28958990]. In osteoblasts, PSMC6 promotes apoptosis through suppression of PI3K/AKT signaling, and its knockout in an ovariectomy-induced osteoporosis mouse model elevates bone mineral density [PMID:32017075].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that the 26S proteasome — including its six AAA-ATPase ring subunits such as PSMC6 — is the principal ATP-dependent protease for ubiquitin-conjugated substrates resolved the long-standing question of how cells selectively degrade marked proteins.\",\n      \"evidence\": \"Biochemical reconstitution, subunit purification, peptidase assays, and structural analysis of 19S and 20S particles\",\n      \"pmids\": [\"8811196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of each ATPase subunit to the unfolding cycle were not resolved\",\n        \"No structural model at atomic resolution for the mammalian 19S ring at this time\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Detailed mechanistic analysis showed how the six-ATPase ring (including PSMC6) couples ATP hydrolysis to substrate unfolding and threading, and revealed that proteasome-associated deubiquitinases gate substrate commitment versus escape, clarifying the decision point before irreversible degradation.\",\n      \"evidence\": \"Biochemical reconstitution with mutant ATPase subunits and structural studies of proteasome ATPase ring; complemented by large-scale AP-MS mapping proteasome–DUB interactions\",\n      \"pmids\": [\"19489727\", \"19615732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"PSMC6-specific catalytic contribution within the ATPase ring not individually dissected\",\n        \"Structural basis for ordered ATP hydrolysis around the ring not yet available\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PARKIN-dependent ubiquitylation of mitochondrial outer membrane substrates upon depolarization was shown to funnel substrates to the proteasome, linking the PSMC6-containing 19S particle to mitophagy-associated protein turnover and broadening the physiological contexts of proteasomal degradation.\",\n      \"evidence\": \"Quantitative diGly-capture proteomics and AP-MS detecting PARKIN–proteasome association\",\n      \"pmids\": [\"23503661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PSMC6 role inferred as part of intact proteasome; no subunit-specific perturbation performed\",\n        \"Whether PARKIN substrates are preferentially handled by a PSMC6-dependent sub-pathway is unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Systematic proteome-scale interaction mapping confirmed PSMC6's co-complex associations with other 19S regulatory particle subunits, providing an unbiased human interaction network for the proteasome.\",\n      \"evidence\": \"BioPlex high-throughput AP-MS in HEK293T cells\",\n      \"pmids\": [\"26186194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interactions not individually validated for PSMC6 beyond co-complex membership\",\n        \"Dynamic or cell-type-specific interaction partners not explored\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CRISPR screening revealed that PSMC6 loss is sufficient to confer bortezomib resistance in myeloma cells by reducing proteasome inhibition, answering the question of which genetic determinants govern clinical proteasome-inhibitor sensitivity.\",\n      \"evidence\": \"Two independent genome-wide CRISPR screens with secondary targeted validation and chymotrypsin-like activity assays in multiple myeloma cells\",\n      \"pmids\": [\"28958990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which 19S ATPase loss alters 20S active-site accessibility to bortezomib not biochemically resolved\",\n        \"Whether PSMC6 loss affects drug sensitivity in other cancer types remains untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that PSMC6 promotes osteoblast apoptosis via PI3K/AKT pathway suppression — and that its knockout in vivo improves bone density in osteoporosis — established a non-canonical, cell-type-specific role for PSMC6 beyond bulk proteolysis.\",\n      \"evidence\": \"Ovariectomy-induced osteoporosis mouse model with PSMC6 knockout, siRNA knockdown, overexpression, and PI3K/AKT pathway analysis by Western blot and flow cytometry\",\n      \"pmids\": [\"32017075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether apoptosis promotion is a direct effect of PSMC6 or secondary to altered proteasomal degradation of PI3K/AKT pathway components is unresolved\",\n        \"Pathway placement relies on inhibitor and overexpression studies rather than direct biochemical reconstitution\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"siRNA-mediated silencing of PSMC6 in lung adenocarcinoma cells reduced proliferation, migration, and invasion, with bioinformatic inference suggesting WNT pathway activation via proteasomal AXIN degradation as a potential mechanism.\",\n      \"evidence\": \"siRNA knockdown with proliferation/migration/invasion assays and gene set enrichment analysis in lung adenocarcinoma cell lines\",\n      \"pmids\": [\"34239933\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical evidence that PSMC6 specifically promotes AXIN degradation\",\n        \"WNT pathway link is inferred computationally, not validated experimentally\",\n        \"Single study without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific mechanistic contribution of PSMC6 versus the other five 19S ATPase subunits to the ordered ATP hydrolysis cycle, substrate engagement selectivity, and proteasome assembly remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No subunit-specific reconstitution distinguishing PSMC6 from other ATPases in the ring\",\n        \"Structural basis for PSMC6's unique role in bortezomib sensitivity not determined\",\n        \"Whether PSMC6-dependent apoptotic signaling in osteoblasts is proteasome-dependent or reflects a moonlighting function is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle\"\n    ],\n    \"partners\": [\n      \"PSMC1\",\n      \"PSMC2\",\n      \"PSMC3\",\n      \"PSMC4\",\n      \"PSMC5\",\n      \"PSMD14\",\n      \"PRKN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}