{"gene":"PSMC4","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"PSMC4 (TBP7) was identified as subunit 6 (S6) of the 26S protease from human erythrocytes, establishing it as an integral ATPase component of the 26S proteasome regulatory complex.","method":"SDS-PAGE, CNBr peptide mapping, internal peptide sequencing, and sequence comparison with known proteins","journal":"Biological chemistry Hoppe-Seyler","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein sequencing of purified 26S proteasome subunit matched TBP7 sequence, replicated by subsequent biochemical and immunological studies","pmids":["8060531"],"is_preprint":false},{"year":1996,"finding":"PSMC4 (MIP224/TBP7) interacts specifically with MB67, an orphan nuclear hormone receptor, and coexpression of MIP224 inhibits transactivation by MB67 in mammalian cells. This interaction was also detected with other CAD-containing proteins (MSS1, TRIP1) in yeast.","method":"Yeast two-hybrid screen, coexpression transactivation assay in mammalian cells","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional transactivation assay in mammalian cells, single lab, two orthogonal methods","pmids":["8603043"],"is_preprint":false},{"year":1996,"finding":"The N-terminal region of PSMC4 (TBP7) contains a leucine zipper domain, and its central region contains four conserved ATPase motifs (Gx4GKT, DEID, SAT, H/QRxGRx2R) characteristic of ATP-dependent RNA/DNA helicases, with strictly conserved spacing between motifs across proteasomal ATPases.","method":"cDNA cloning and protein sequence analysis of rat TBP7 orthologue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence analysis only, but consistent across multiple orthologues; structural motifs independently confirmed in human and rat sequences","pmids":["8607789"],"is_preprint":false},{"year":1998,"finding":"PSMC4 (TBP7) gene was mapped to human chromosome 19q13.11-q13.13 by fluorescence in situ hybridization, and immunoblot analysis confirmed its association with the purified 26S proteasome. TBP7 showed heterogeneity in electrical charge.","method":"Fluorescence in situ hybridization (FISH), immunoblot analysis of purified 26S proteasome","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping and biochemical confirmation of proteasome association, single lab","pmids":["9473509"],"is_preprint":false},{"year":1999,"finding":"PSMC4 (TBP7) and other proteasomal ATPases (MSS1, TBP1, SUG1, S4) form a complex with TATA-binding protein (TBP) and a novel transcriptional activator TIP120 (~800 kDa complex), but this TBP-ATPase complex is distinct from the 26S proteasome or its 19S regulatory unit. Direct TBP binding was demonstrated for SUG1 and S4 by far-Western; the remaining ATPases including TBP7 were found in the TIP preparations by 2-D electrophoresis and microsequencing.","method":"TBP pull-down, 2-D electrophoresis, far-Western analysis, protein microsequencing, Western blotting","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods in single lab; direct TBP binding for TBP7 was inferred from pull-down rather than direct far-Western","pmids":["10526239"],"is_preprint":false},{"year":2000,"finding":"Psmc4-deficient mice die before implantation with defective blastocyst development, demonstrating that PSMC4 is essential for early embryogenesis and has non-compensatory functions in vivo (not rescued by Psmc3).","method":"Gene targeting (knockout mice), embryonic lethality analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined developmental phenotype; parallel comparison with Psmc3 knockout establishes non-redundancy","pmids":["10945464"],"is_preprint":false},{"year":2000,"finding":"PSMC4 (S6/TBP7) subunit of the 26S proteasome localizes to the heterochromatic region of nuclei in insect muscle fibres undergoing programmed cell death, as determined by immunogold electron microscopy, suggesting a nuclear role for this ATPase subunit during PCD.","method":"Immunogold electron microscopy on Manduca sexta intersegmental muscles","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by immunogold EM in single study; functional consequence of nuclear localization not fully established","pmids":["11175258"],"is_preprint":false},{"year":2002,"finding":"Gankyrin (a liver oncoprotein) interacts with the C-terminal 78 amino acids of PSMC4 (S6/TBP7) ATPase, both in its free form and when associated with the 19S regulatory complex. Overexpression of tagged gankyrin in cultured cells co-precipitates PSMC4 and endogenous CDK4, suggesting a trimeric complex.","method":"Yeast two-hybrid screen, deletional mutagenesis, co-immunoprecipitation from cultured cells, precipitation of tagged proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid identification confirmed by co-IP in mammalian cells, domain mapped by deletional mutagenesis, multiple orthogonal methods in single study","pmids":["11779854"],"is_preprint":false},{"year":2002,"finding":"PSMC4 (Tbp7), an ATPase subunit of the 26S proteasome, co-immunoprecipitates with cytokeratin-8 (CK-8), ubiquitin, UBB+1, and proteasomal subunit beta5 in a high-molecular-weight complex associated with Mallory body formation. This complex increases upon incubation with ATP, suggesting active proteasomal engagement with cytokeratin aggregates.","method":"Cytokeratin-8 immunoprecipitation, Western blot, in vitro incubation with proteasomal fractions and ATP","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and in vitro reconstitution experiment in single lab with consistent results across two studies","pmids":["12231209","11784119"],"is_preprint":false},{"year":2007,"finding":"PSMC4 (S6 ATPase/tbp7) directly interacts with synphilin-1 (an alpha-synuclein-interacting protein implicated in Parkinson's disease). Co-overexpression of PSMC4 and synphilin-1 leads to colocalization in aggresome-like inclusions, reduced proteasomal activity, and increased inclusion formation compared to synphilin-1 alone. PSMC4 was also identified as a component of Lewy bodies in PD patient brains.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, proteasome activity assay, immunohistochemistry in PD brain","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction confirmed by yeast two-hybrid and co-IP, functional consequence (reduced proteasomal activity) measured, localization in patient tissue confirmed by IHC, multiple orthogonal methods","pmids":["17327361"],"is_preprint":false},{"year":2011,"finding":"PSMC4 (TBP7), an AAA-ATPase 19S proteasomal subunit, directly interacts with TRAP1 (mitochondrial HSP90) in the endoplasmic reticulum (ER), not in mitochondria. TRAP1 and TBP7 colocalize in the ER as demonstrated by biochemical fractionation, confocal microscopy, and FRET analysis. TBP7 and/or TRAP1 silencing enhances protein ubiquitination and stress-induced cell death, and TRAP1 controls ubiquitination/degradation of specific nuclear-encoded mitochondrial proteins through this ER-localized interaction.","method":"Mass spectrometry interactome, co-immunoprecipitation, confocal microscopy, FRET, subcellular fractionation, shRNA silencing, ubiquitination assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — FRET confirms direct interaction, ER localization established by multiple orthogonal methods (fractionation, confocal, EM), functional consequences of silencing measured; replicated in subsequent TRAP1 papers","pmids":["21979464"],"is_preprint":false},{"year":2011,"finding":"Nrf1 transcription factor drives expression of PSMC4 as a target gene. siRNA-mediated silencing of β-TrCP (which degrades Nrf1 in the nucleus) markedly augments PSMC4 expression, establishing PSMC4 as a downstream target of the Nrf1/β-TrCP regulatory axis.","method":"siRNA knockdown, gene expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean siRNA knockdown with defined transcriptional readout, single lab, single method for this specific finding","pmids":["21911472"],"is_preprint":false},{"year":2014,"finding":"Muscle-specific deletion of Rpt3 (Psmc4) in mice causes profound muscle growth defects, decreased force production, dysregulated proteasomal activity, impaired autophagosome formation despite upregulated autophagy pathway, accumulation of basophilic inclusions, and sarcomere disorganization. This establishes PSMC4 as essential for maintaining myofiber integrity and muscle growth in vivo.","method":"Conditional knockout mice (muscle-specific Cre), histology, electron microscopy, proteasome activity assays, autophagy pathway analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal readouts (force production, proteasome activity, autophagy, morphology); mechanistically placed PSMC4 as required for proteasome activity in muscle and for crosstalk with autophagy","pmids":["25380823"],"is_preprint":false},{"year":2013,"finding":"The ER-localized TRAP1/TBP7 (PSMC4) complex controls ubiquitination and degradation of CDK1 (and MAD2). TRAP1 interacts with CDK1 and prevents its ubiquitination in cooperation with TBP7; this is the limiting step in TRAP1 regulation of G2-M cell cycle transition.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, gene expression profiling, immunofluorescence","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays establish the mechanistic link; pathway placement supported by rescue experiments; single lab","pmids":["24113185"],"is_preprint":false},{"year":2017,"finding":"TRAP1 prevents CDK1 ubiquitination through cooperation with the proteasome regulatory particle TBP7 (PSMC4), establishing TBP7 as a co-factor in TRAP1-dependent quality control of CDK1 during G2-M transition. TRAP1 silencing causes enhanced CDK1 ubiquitination, failure of nuclear CDK1/cyclin B1 translocation, and MAD2 degradation.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, CDK1 inhibitor rescue experiments, gene expression profiling in breast/colorectal/lung carcinoma cells and tumor specimens","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway established by co-IP, ubiquitination assays, and epistatic rescue; validated across multiple cell lines and patient specimens; independently consistent with prior TRAP1/TBP7 studies","pmids":["28678347"],"is_preprint":false},{"year":2014,"finding":"PSMC4 (26S proteasome regulatory subunit 6B) was identified by affinity pull-down and LC-MS/MS as a direct binding target of neuroprotective pyrazolone small molecules. Binding of these molecules to PSMC4 (and PSMC1) was associated with proteasome activation in PC12-SOD1(G93A) cells.","method":"Affinity probe pull-down, LC-MS/MS proteomics, competitive displacement with inhibitors, fluorogenic proteasome substrate assay","journal":"ACS chemical neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity pull-down confirmed by competition assay, functional proteasome activation measured; single lab","pmids":["25001311"],"is_preprint":false},{"year":2021,"finding":"Unassembled PSMC4 forms a complex with PSMC5 and the assembly chaperone PAAF1 (PSMC4-PSMC5-PAAF1 complex) as an intermediate during proteasome base assembly. HERC1 ubiquitin ligase recognizes this unassembled intermediate via PAAF1 (which only dissociates after complete assembly) and targets PSMC5 for degradation; a neurodegeneration-causing missense mutant of HERC1 is impaired in recognizing the PSMC5-PAAF1 complex.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, HERC1 mutant analysis in mammalian cells","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex composition defined by reciprocal co-IP and MS, functional ubiquitination assay performed, disease-relevant mutant tested; published in high-tier journal with multiple orthogonal methods","pmids":["34446601"],"is_preprint":false},{"year":2018,"finding":"PSMC4 is enriched >10-fold in membrane-penetrating cell extensions compared to cell bodies in 3T3 fibroblasts. siRNA knockdown of PSMC4 reduces formation of cell extensions (~42%), collagen compaction (~1.5-fold), and pericellular collagen degradation (~1.7-fold). Recruitment of PSMC4 to extensions depends on Smad3 and ROCK-II signaling pathways.","method":"Tandem mass tagged mass spectrometry, immunostaining, immunoblotting, siRNA knockdown, collagen gel compaction assay, pathway inhibitor experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization confirmed by MS and immunostaining; functional knockdown phenotype measured with multiple readouts; pathway placement by inhibitor experiments; single lab","pmids":["29476834"],"is_preprint":false},{"year":2023,"finding":"PSMC4 promotes prostate carcinoma cell proliferation, cell cycle progression, and migration through regulation of CBX3 levels and downstream EGFR-PI3K-AKT-mTOR signaling. PSMC4 knockdown reduces CBX3 and EGFR levels and inhibits PI3K-AKT-mTOR; CBX3 overexpression rescues EGFR levels. PSMC4 and CBX3 interact as shown by co-IP.","method":"siRNA knockdown, co-immunoprecipitation, RNA-seq, Western blotting, xenograft tumor model, cell proliferation/apoptosis/migration assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes interaction, pathway placed by rescue experiments, in vivo xenograft validation; single lab","pmids":["37436074"],"is_preprint":false},{"year":2009,"finding":"PSMC4 (PSMC4/Rpt3) is present on the sperm acrosomal surface as part of the 19S proteasome complex. Depletion of sperm-surface ATP by apyrase altered the band pattern of PSMC4 (and PSMC1) in Western blotting, suggesting that extracellular ATP is required for integrity of the sperm 19S proteasomal complex and sperm-zona pellucida interactions during fertilization.","method":"Western blotting, ATP depletion with apyrase, in vitro fertilization assay, luminescence ATP assay","journal":"Systems biology in reproductive medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Western blot band-shift observation; functional role inferred from broader proteasome inhibition data; single lab, indirect evidence for PSMC4 specifically","pmids":["19462288"],"is_preprint":false}],"current_model":"PSMC4 (TBP7/RPT3/S6) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome, essential for proteasomal activity and early embryogenesis; it interacts with TRAP1 in the endoplasmic reticulum to control ubiquitination and degradation of specific client proteins (including CDK1 and mitochondrial proteins), binds the oncoprotein gankyrin via its C-terminal 78 amino acids, interacts with transcription factors (TBP, orphan nuclear receptor MB67) as part of an ~800 kDa non-proteasomal complex, forms an assembly intermediate with PSMC5 and PAAF1 that is monitored by the HERC1 quality-control ubiquitin ligase, is required for cell extension formation via Smad3/ROCK signaling, and regulates prostate cancer progression through a CBX3-EGFR-PI3K-AKT-mTOR axis."},"narrative":{"mechanistic_narrative":"PSMC4 (TBP7/RPT3/S6) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome, where it functions as an integral, ATP-dependent component of the ubiquitin-proteasome degradation machinery [PMID:8060531, PMID:9473509]. Its central region carries the four conserved ATPase motifs of the proteasomal ATPase family alongside an N-terminal leucine zipper [PMID:8607789]. PSMC4 is essential and non-redundant in vivo: its loss causes pre-implantation embryonic lethality with defective blastocyst development that cannot be rescued by Psmc3 [PMID:10945464], and muscle-specific deletion produces impaired myofiber growth, dysregulated proteasome activity, defective autophagosome formation, and sarcomere disorganization, placing it at a node coupling proteasomal and autophagic protein turnover [PMID:25380823]. During base assembly, unassembled PSMC4 forms a PSMC4–PSMC5–PAAF1 intermediate that the HERC1 ubiquitin ligase recognizes through PAAF1 to clear excess subunits as a quality-control step [PMID:34446601]. Beyond canonical proteasome function, PSMC4 acts in a distinct ER-localized complex with the chaperone TRAP1, where the pair controls ubiquitination and stability of nuclear-encoded client proteins including CDK1, governing the G2-M cell-cycle transition [PMID:21979464, PMID:24113185, PMID:28678347]. PSMC4 also engages disease-relevant partners: it binds the C-terminal 78 residues of the oncoprotein gankyrin in a complex with CDK4 [PMID:11779854], interacts with synphilin-1 and is found in Lewy bodies, with co-overexpression reducing proteasomal activity and increasing inclusion formation [PMID:17327361], and drives prostate carcinoma proliferation and migration through a CBX3–EGFR–PI3K–AKT–mTOR axis [PMID:37436074]. It additionally participates with TBP and other proteasomal ATPases in a non-proteasomal ~800 kDa transcription-associated complex [PMID:10526239] and represses transactivation by the orphan nuclear receptor MB67 [PMID:8603043].","teleology":[{"year":1994,"claim":"Established the identity of PSMC4 as a bona fide structural component of the proteasome, defining its core cellular context.","evidence":"Direct peptide sequencing of subunit 6 (S6) purified from the human erythrocyte 26S protease","pmids":["8060531"],"confidence":"High","gaps":["Did not define ATPase catalytic mechanism","No structural placement within the 19S ring"]},{"year":1996,"claim":"Linked PSMC4 to transcriptional regulation by showing it binds and inhibits a nuclear hormone receptor, hinting at functions beyond proteolysis.","evidence":"Yeast two-hybrid and coexpression transactivation assays with the orphan receptor MB67","pmids":["8603043"],"confidence":"Medium","gaps":["Mechanism of MB67 inhibition unresolved","Unclear if dependent on proteasome assembly"]},{"year":1996,"claim":"Defined the domain architecture, identifying the conserved ATPase motifs and leucine zipper that underlie its enzymatic and assembly roles.","evidence":"cDNA cloning and protein sequence analysis of the rat orthologue","pmids":["8607789"],"confidence":"Medium","gaps":["Sequence inference only; no functional ATPase assay","Leucine zipper binding partner unknown"]},{"year":1999,"claim":"Showed PSMC4 partitions into a non-proteasomal TBP-containing ~800 kDa complex, separating its transcription-associated role from the 26S particle.","evidence":"TBP pull-down, 2-D electrophoresis, far-Western and microsequencing","pmids":["10526239"],"confidence":"Medium","gaps":["Direct TBP binding inferred for PSMC4, not demonstrated by far-Western","Functional role of the complex unestablished"]},{"year":2000,"claim":"Demonstrated that PSMC4 is essential and non-redundant for early development, distinguishing it from paralogous ATPases.","evidence":"Psmc4 knockout mice with pre-implantation lethality, compared against Psmc3 knockout","pmids":["10945464"],"confidence":"High","gaps":["Cell-type-specific requirements not resolved","Molecular cause of blastocyst defect not defined"]},{"year":2002,"claim":"Identified gankyrin as a C-terminal-binding oncoprotein partner, connecting PSMC4 to oncogenic CDK4 complexes.","evidence":"Yeast two-hybrid, deletional mapping, and co-IP of gankyrin, PSMC4, and CDK4","pmids":["11779854"],"confidence":"High","gaps":["Functional consequence of the trimeric complex not measured","Whether gankyrin alters proteasome function unclear"]},{"year":2007,"claim":"Tied PSMC4 to neurodegenerative protein aggregation, showing its interaction with synphilin-1 impairs proteasome activity and promotes inclusions.","evidence":"Yeast two-hybrid, co-IP, colocalization, proteasome activity assay, and IHC of PD brain","pmids":["17327361"],"confidence":"High","gaps":["Causal role in PD pathology not established","Mechanism linking interaction to reduced activity unclear"]},{"year":2011,"claim":"Revealed an unexpected ER-localized PSMC4–TRAP1 complex controlling ubiquitination of mitochondrial client proteins and stress-induced cell death.","evidence":"MS interactome, FRET, confocal microscopy, fractionation, and shRNA silencing with ubiquitination assays","pmids":["21979464"],"confidence":"High","gaps":["Full client repertoire incompletely defined","How an ATPase subunit relocalizes to ER unresolved"]},{"year":2013,"claim":"Placed the PSMC4–TRAP1 complex as the limiting control of CDK1 stability during G2-M progression.","evidence":"Co-IP, ubiquitination assays, and siRNA in cancer cells, extended in patient-validated follow-up","pmids":["24113185","28678347"],"confidence":"High","gaps":["Direct PSMC4 contribution versus TRAP1 not fully separated","Ubiquitin ligase responsible for CDK1 not identified here"]},{"year":2014,"claim":"Showed PSMC4 is required in vivo for proteasome function and for crosstalk with autophagy in muscle tissue.","evidence":"Muscle-specific conditional knockout with histology, EM, proteasome and autophagy assays","pmids":["25380823"],"confidence":"High","gaps":["Mechanism of impaired autophagosome formation undefined","Whether non-proteasomal PSMC4 roles contribute unclear"]},{"year":2021,"claim":"Defined a proteasome base-assembly intermediate and its quality-control surveillance, embedding PSMC4 in an assembly checkpoint.","evidence":"Reciprocal co-IP, MS, ubiquitination assays, and HERC1 disease-mutant analysis","pmids":["34446601"],"confidence":"High","gaps":["Kinetics of PSMC4 incorporation not resolved","Whether PSMC4 itself is a HERC1 substrate unclear"]},{"year":2023,"claim":"Connected PSMC4 to cancer progression through a CBX3-EGFR-PI3K-AKT-mTOR signaling axis.","evidence":"siRNA knockdown, co-IP, RNA-seq, rescue experiments, and xenograft model in prostate carcinoma","pmids":["37436074"],"confidence":"Medium","gaps":["Whether regulation of CBX3 is proteasome-dependent unclear","Single-lab; not validated in additional tumor types"]},{"year":null,"claim":"How PSMC4 toggles between its canonical 19S proteasomal role and its multiple non-proteasomal complexes (ER/TRAP1, TBP-transcription, signaling) remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model distinguishing free versus assembled PSMC4 functions","Signals partitioning PSMC4 to ER versus proteasome unknown","Direct ATPase enzymology of human PSMC4 not characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,13,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,12]}],"complexes":["26S proteasome (19S regulatory particle)","PSMC4-PSMC5-PAAF1 assembly intermediate","ER-localized TRAP1-TBP7 complex","TBP-ATPase ~800 kDa transcription complex"],"partners":["TRAP1","PSMC5","PAAF1","HERC1","CDK1","GANKYRIN","SYNPHILIN-1","CBX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43686","full_name":"26S proteasome regulatory subunit 6B","aliases":["26S proteasome AAA-ATPase subunit RPT3","MB67-interacting protein","MIP224","Proteasome 26S subunit ATPase 4","Tat-binding protein 7","TBP-7"],"length_aa":418,"mass_kda":47.4,"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. PSMC4 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/P43686/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC4","classification":"Common Essential","n_dependent_lines":1196,"n_total_lines":1208,"dependency_fraction":0.9900662251655629},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000013275","cell_line_id":"CID000124","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA1","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},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000124","total_profiled":1310},"omim":[{"mim_id":"602707","title":"PROTEASOME 26S SUBUNIT, ATPase, 4; PSMC4","url":"https://www.omim.org/entry/602707"},{"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":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMC4"},"hgnc":{"alias_symbol":["TBP7","S6","MGC8570","MGC13687","MGC23214","TBP-7","RPT3"],"prev_symbol":["MIP224"]},"alphafold":{"accession":"P43686","domains":[{"cath_id":"2.40.50.140","chopping":"85-141","consensus_level":"high","plddt":85.1826,"start":85,"end":141},{"cath_id":"3.40.50.300","chopping":"152-331","consensus_level":"high","plddt":82.8972,"start":152,"end":331},{"cath_id":"1.10.8.60","chopping":"337-412","consensus_level":"high","plddt":86.2824,"start":337,"end":412},{"cath_id":"1.20.5","chopping":"40-83","consensus_level":"medium","plddt":89.3459,"start":40,"end":83}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43686","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43686-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43686-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC4","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC4"},"sequence":{"accession":"P43686","fasta_url":"https://rest.uniprot.org/uniprotkb/P43686.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43686/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43686"}},"corpus_meta":[{"pmid":"15287981","id":"PMC_15287981","title":"Statistical 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\"journal\": \"Biological chemistry Hoppe-Seyler\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein sequencing of purified 26S proteasome subunit matched TBP7 sequence, replicated by subsequent biochemical and immunological studies\",\n      \"pmids\": [\"8060531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PSMC4 (MIP224/TBP7) interacts specifically with MB67, an orphan nuclear hormone receptor, and coexpression of MIP224 inhibits transactivation by MB67 in mammalian cells. This interaction was also detected with other CAD-containing proteins (MSS1, TRIP1) in yeast.\",\n      \"method\": \"Yeast two-hybrid screen, coexpression transactivation assay in mammalian cells\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional transactivation assay in mammalian cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"8603043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The N-terminal region of PSMC4 (TBP7) contains a leucine zipper domain, and its central region contains four conserved ATPase motifs (Gx4GKT, DEID, SAT, H/QRxGRx2R) characteristic of ATP-dependent RNA/DNA helicases, with strictly conserved spacing between motifs across proteasomal ATPases.\",\n      \"method\": \"cDNA cloning and protein sequence analysis of rat TBP7 orthologue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence analysis only, but consistent across multiple orthologues; structural motifs independently confirmed in human and rat sequences\",\n      \"pmids\": [\"8607789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PSMC4 (TBP7) gene was mapped to human chromosome 19q13.11-q13.13 by fluorescence in situ hybridization, and immunoblot analysis confirmed its association with the purified 26S proteasome. TBP7 showed heterogeneity in electrical charge.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), immunoblot analysis of purified 26S proteasome\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping and biochemical confirmation of proteasome association, single lab\",\n      \"pmids\": [\"9473509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PSMC4 (TBP7) and other proteasomal ATPases (MSS1, TBP1, SUG1, S4) form a complex with TATA-binding protein (TBP) and a novel transcriptional activator TIP120 (~800 kDa complex), but this TBP-ATPase complex is distinct from the 26S proteasome or its 19S regulatory unit. Direct TBP binding was demonstrated for SUG1 and S4 by far-Western; the remaining ATPases including TBP7 were found in the TIP preparations by 2-D electrophoresis and microsequencing.\",\n      \"method\": \"TBP pull-down, 2-D electrophoresis, far-Western analysis, protein microsequencing, Western blotting\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods in single lab; direct TBP binding for TBP7 was inferred from pull-down rather than direct far-Western\",\n      \"pmids\": [\"10526239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Psmc4-deficient mice die before implantation with defective blastocyst development, demonstrating that PSMC4 is essential for early embryogenesis and has non-compensatory functions in vivo (not rescued by Psmc3).\",\n      \"method\": \"Gene targeting (knockout mice), embryonic lethality analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined developmental phenotype; parallel comparison with Psmc3 knockout establishes non-redundancy\",\n      \"pmids\": [\"10945464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSMC4 (S6/TBP7) subunit of the 26S proteasome localizes to the heterochromatic region of nuclei in insect muscle fibres undergoing programmed cell death, as determined by immunogold electron microscopy, suggesting a nuclear role for this ATPase subunit during PCD.\",\n      \"method\": \"Immunogold electron microscopy on Manduca sexta intersegmental muscles\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by immunogold EM in single study; functional consequence of nuclear localization not fully established\",\n      \"pmids\": [\"11175258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Gankyrin (a liver oncoprotein) interacts with the C-terminal 78 amino acids of PSMC4 (S6/TBP7) ATPase, both in its free form and when associated with the 19S regulatory complex. Overexpression of tagged gankyrin in cultured cells co-precipitates PSMC4 and endogenous CDK4, suggesting a trimeric complex.\",\n      \"method\": \"Yeast two-hybrid screen, deletional mutagenesis, co-immunoprecipitation from cultured cells, precipitation of tagged proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid identification confirmed by co-IP in mammalian cells, domain mapped by deletional mutagenesis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"11779854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PSMC4 (Tbp7), an ATPase subunit of the 26S proteasome, co-immunoprecipitates with cytokeratin-8 (CK-8), ubiquitin, UBB+1, and proteasomal subunit beta5 in a high-molecular-weight complex associated with Mallory body formation. This complex increases upon incubation with ATP, suggesting active proteasomal engagement with cytokeratin aggregates.\",\n      \"method\": \"Cytokeratin-8 immunoprecipitation, Western blot, in vitro incubation with proteasomal fractions and ATP\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and in vitro reconstitution experiment in single lab with consistent results across two studies\",\n      \"pmids\": [\"12231209\", \"11784119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PSMC4 (S6 ATPase/tbp7) directly interacts with synphilin-1 (an alpha-synuclein-interacting protein implicated in Parkinson's disease). Co-overexpression of PSMC4 and synphilin-1 leads to colocalization in aggresome-like inclusions, reduced proteasomal activity, and increased inclusion formation compared to synphilin-1 alone. PSMC4 was also identified as a component of Lewy bodies in PD patient brains.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization, proteasome activity assay, immunohistochemistry in PD brain\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction confirmed by yeast two-hybrid and co-IP, functional consequence (reduced proteasomal activity) measured, localization in patient tissue confirmed by IHC, multiple orthogonal methods\",\n      \"pmids\": [\"17327361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PSMC4 (TBP7), an AAA-ATPase 19S proteasomal subunit, directly interacts with TRAP1 (mitochondrial HSP90) in the endoplasmic reticulum (ER), not in mitochondria. TRAP1 and TBP7 colocalize in the ER as demonstrated by biochemical fractionation, confocal microscopy, and FRET analysis. TBP7 and/or TRAP1 silencing enhances protein ubiquitination and stress-induced cell death, and TRAP1 controls ubiquitination/degradation of specific nuclear-encoded mitochondrial proteins through this ER-localized interaction.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, confocal microscopy, FRET, subcellular fractionation, shRNA silencing, ubiquitination assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — FRET confirms direct interaction, ER localization established by multiple orthogonal methods (fractionation, confocal, EM), functional consequences of silencing measured; replicated in subsequent TRAP1 papers\",\n      \"pmids\": [\"21979464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nrf1 transcription factor drives expression of PSMC4 as a target gene. siRNA-mediated silencing of β-TrCP (which degrades Nrf1 in the nucleus) markedly augments PSMC4 expression, establishing PSMC4 as a downstream target of the Nrf1/β-TrCP regulatory axis.\",\n      \"method\": \"siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean siRNA knockdown with defined transcriptional readout, single lab, single method for this specific finding\",\n      \"pmids\": [\"21911472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Muscle-specific deletion of Rpt3 (Psmc4) in mice causes profound muscle growth defects, decreased force production, dysregulated proteasomal activity, impaired autophagosome formation despite upregulated autophagy pathway, accumulation of basophilic inclusions, and sarcomere disorganization. This establishes PSMC4 as essential for maintaining myofiber integrity and muscle growth in vivo.\",\n      \"method\": \"Conditional knockout mice (muscle-specific Cre), histology, electron microscopy, proteasome activity assays, autophagy pathway analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal readouts (force production, proteasome activity, autophagy, morphology); mechanistically placed PSMC4 as required for proteasome activity in muscle and for crosstalk with autophagy\",\n      \"pmids\": [\"25380823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The ER-localized TRAP1/TBP7 (PSMC4) complex controls ubiquitination and degradation of CDK1 (and MAD2). TRAP1 interacts with CDK1 and prevents its ubiquitination in cooperation with TBP7; this is the limiting step in TRAP1 regulation of G2-M cell cycle transition.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, gene expression profiling, immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays establish the mechanistic link; pathway placement supported by rescue experiments; single lab\",\n      \"pmids\": [\"24113185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRAP1 prevents CDK1 ubiquitination through cooperation with the proteasome regulatory particle TBP7 (PSMC4), establishing TBP7 as a co-factor in TRAP1-dependent quality control of CDK1 during G2-M transition. TRAP1 silencing causes enhanced CDK1 ubiquitination, failure of nuclear CDK1/cyclin B1 translocation, and MAD2 degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, CDK1 inhibitor rescue experiments, gene expression profiling in breast/colorectal/lung carcinoma cells and tumor specimens\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway established by co-IP, ubiquitination assays, and epistatic rescue; validated across multiple cell lines and patient specimens; independently consistent with prior TRAP1/TBP7 studies\",\n      \"pmids\": [\"28678347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSMC4 (26S proteasome regulatory subunit 6B) was identified by affinity pull-down and LC-MS/MS as a direct binding target of neuroprotective pyrazolone small molecules. Binding of these molecules to PSMC4 (and PSMC1) was associated with proteasome activation in PC12-SOD1(G93A) cells.\",\n      \"method\": \"Affinity probe pull-down, LC-MS/MS proteomics, competitive displacement with inhibitors, fluorogenic proteasome substrate assay\",\n      \"journal\": \"ACS chemical neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity pull-down confirmed by competition assay, functional proteasome activation measured; single lab\",\n      \"pmids\": [\"25001311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Unassembled PSMC4 forms a complex with PSMC5 and the assembly chaperone PAAF1 (PSMC4-PSMC5-PAAF1 complex) as an intermediate during proteasome base assembly. HERC1 ubiquitin ligase recognizes this unassembled intermediate via PAAF1 (which only dissociates after complete assembly) and targets PSMC5 for degradation; a neurodegeneration-causing missense mutant of HERC1 is impaired in recognizing the PSMC5-PAAF1 complex.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, HERC1 mutant analysis in mammalian cells\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex composition defined by reciprocal co-IP and MS, functional ubiquitination assay performed, disease-relevant mutant tested; published in high-tier journal with multiple orthogonal methods\",\n      \"pmids\": [\"34446601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMC4 is enriched >10-fold in membrane-penetrating cell extensions compared to cell bodies in 3T3 fibroblasts. siRNA knockdown of PSMC4 reduces formation of cell extensions (~42%), collagen compaction (~1.5-fold), and pericellular collagen degradation (~1.7-fold). Recruitment of PSMC4 to extensions depends on Smad3 and ROCK-II signaling pathways.\",\n      \"method\": \"Tandem mass tagged mass spectrometry, immunostaining, immunoblotting, siRNA knockdown, collagen gel compaction assay, pathway inhibitor experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization confirmed by MS and immunostaining; functional knockdown phenotype measured with multiple readouts; pathway placement by inhibitor experiments; single lab\",\n      \"pmids\": [\"29476834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMC4 promotes prostate carcinoma cell proliferation, cell cycle progression, and migration through regulation of CBX3 levels and downstream EGFR-PI3K-AKT-mTOR signaling. PSMC4 knockdown reduces CBX3 and EGFR levels and inhibits PI3K-AKT-mTOR; CBX3 overexpression rescues EGFR levels. PSMC4 and CBX3 interact as shown by co-IP.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, RNA-seq, Western blotting, xenograft tumor model, cell proliferation/apoptosis/migration assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes interaction, pathway placed by rescue experiments, in vivo xenograft validation; single lab\",\n      \"pmids\": [\"37436074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMC4 (PSMC4/Rpt3) is present on the sperm acrosomal surface as part of the 19S proteasome complex. Depletion of sperm-surface ATP by apyrase altered the band pattern of PSMC4 (and PSMC1) in Western blotting, suggesting that extracellular ATP is required for integrity of the sperm 19S proteasomal complex and sperm-zona pellucida interactions during fertilization.\",\n      \"method\": \"Western blotting, ATP depletion with apyrase, in vitro fertilization assay, luminescence ATP assay\",\n      \"journal\": \"Systems biology in reproductive medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Western blot band-shift observation; functional role inferred from broader proteasome inhibition data; single lab, indirect evidence for PSMC4 specifically\",\n      \"pmids\": [\"19462288\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC4 (TBP7/RPT3/S6) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome, essential for proteasomal activity and early embryogenesis; it interacts with TRAP1 in the endoplasmic reticulum to control ubiquitination and degradation of specific client proteins (including CDK1 and mitochondrial proteins), binds the oncoprotein gankyrin via its C-terminal 78 amino acids, interacts with transcription factors (TBP, orphan nuclear receptor MB67) as part of an ~800 kDa non-proteasomal complex, forms an assembly intermediate with PSMC5 and PAAF1 that is monitored by the HERC1 quality-control ubiquitin ligase, is required for cell extension formation via Smad3/ROCK signaling, and regulates prostate cancer progression through a CBX3-EGFR-PI3K-AKT-mTOR axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMC4 (TBP7/RPT3/S6) is an AAA-ATPase subunit of the 19S regulatory particle of the 26S proteasome, where it functions as an integral, ATP-dependent component of the ubiquitin-proteasome degradation machinery [#0, #3]. Its central region carries the four conserved ATPase motifs of the proteasomal ATPase family alongside an N-terminal leucine zipper [#2]. PSMC4 is essential and non-redundant in vivo: its loss causes pre-implantation embryonic lethality with defective blastocyst development that cannot be rescued by Psmc3 [#5], and muscle-specific deletion produces impaired myofiber growth, dysregulated proteasome activity, defective autophagosome formation, and sarcomere disorganization, placing it at a node coupling proteasomal and autophagic protein turnover [#12]. During base assembly, unassembled PSMC4 forms a PSMC4–PSMC5–PAAF1 intermediate that the HERC1 ubiquitin ligase recognizes through PAAF1 to clear excess subunits as a quality-control step [#16]. Beyond canonical proteasome function, PSMC4 acts in a distinct ER-localized complex with the chaperone TRAP1, where the pair controls ubiquitination and stability of nuclear-encoded client proteins including CDK1, governing the G2-M cell-cycle transition [#10, #13, #14]. PSMC4 also engages disease-relevant partners: it binds the C-terminal 78 residues of the oncoprotein gankyrin in a complex with CDK4 [#7], interacts with synphilin-1 and is found in Lewy bodies, with co-overexpression reducing proteasomal activity and increasing inclusion formation [#9], and drives prostate carcinoma proliferation and migration through a CBX3–EGFR–PI3K–AKT–mTOR axis [#18]. It additionally participates with TBP and other proteasomal ATPases in a non-proteasomal ~800 kDa transcription-associated complex [#4] and represses transactivation by the orphan nuclear receptor MB67 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the identity of PSMC4 as a bona fide structural component of the proteasome, defining its core cellular context.\",\n      \"evidence\": \"Direct peptide sequencing of subunit 6 (S6) purified from the human erythrocyte 26S protease\",\n      \"pmids\": [\"8060531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define ATPase catalytic mechanism\", \"No structural placement within the 19S ring\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linked PSMC4 to transcriptional regulation by showing it binds and inhibits a nuclear hormone receptor, hinting at functions beyond proteolysis.\",\n      \"evidence\": \"Yeast two-hybrid and coexpression transactivation assays with the orphan receptor MB67\",\n      \"pmids\": [\"8603043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MB67 inhibition unresolved\", \"Unclear if dependent on proteasome assembly\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the domain architecture, identifying the conserved ATPase motifs and leucine zipper that underlie its enzymatic and assembly roles.\",\n      \"evidence\": \"cDNA cloning and protein sequence analysis of the rat orthologue\",\n      \"pmids\": [\"8607789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence inference only; no functional ATPase assay\", \"Leucine zipper binding partner unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed PSMC4 partitions into a non-proteasomal TBP-containing ~800 kDa complex, separating its transcription-associated role from the 26S particle.\",\n      \"evidence\": \"TBP pull-down, 2-D electrophoresis, far-Western and microsequencing\",\n      \"pmids\": [\"10526239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TBP binding inferred for PSMC4, not demonstrated by far-Western\", \"Functional role of the complex unestablished\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that PSMC4 is essential and non-redundant for early development, distinguishing it from paralogous ATPases.\",\n      \"evidence\": \"Psmc4 knockout mice with pre-implantation lethality, compared against Psmc3 knockout\",\n      \"pmids\": [\"10945464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific requirements not resolved\", \"Molecular cause of blastocyst defect not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified gankyrin as a C-terminal-binding oncoprotein partner, connecting PSMC4 to oncogenic CDK4 complexes.\",\n      \"evidence\": \"Yeast two-hybrid, deletional mapping, and co-IP of gankyrin, PSMC4, and CDK4\",\n      \"pmids\": [\"11779854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the trimeric complex not measured\", \"Whether gankyrin alters proteasome function unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Tied PSMC4 to neurodegenerative protein aggregation, showing its interaction with synphilin-1 impairs proteasome activity and promotes inclusions.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, colocalization, proteasome activity assay, and IHC of PD brain\",\n      \"pmids\": [\"17327361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal role in PD pathology not established\", \"Mechanism linking interaction to reduced activity unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an unexpected ER-localized PSMC4–TRAP1 complex controlling ubiquitination of mitochondrial client proteins and stress-induced cell death.\",\n      \"evidence\": \"MS interactome, FRET, confocal microscopy, fractionation, and shRNA silencing with ubiquitination assays\",\n      \"pmids\": [\"21979464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full client repertoire incompletely defined\", \"How an ATPase subunit relocalizes to ER unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed the PSMC4–TRAP1 complex as the limiting control of CDK1 stability during G2-M progression.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and siRNA in cancer cells, extended in patient-validated follow-up\",\n      \"pmids\": [\"24113185\", \"28678347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PSMC4 contribution versus TRAP1 not fully separated\", \"Ubiquitin ligase responsible for CDK1 not identified here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PSMC4 is required in vivo for proteasome function and for crosstalk with autophagy in muscle tissue.\",\n      \"evidence\": \"Muscle-specific conditional knockout with histology, EM, proteasome and autophagy assays\",\n      \"pmids\": [\"25380823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of impaired autophagosome formation undefined\", \"Whether non-proteasomal PSMC4 roles contribute unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a proteasome base-assembly intermediate and its quality-control surveillance, embedding PSMC4 in an assembly checkpoint.\",\n      \"evidence\": \"Reciprocal co-IP, MS, ubiquitination assays, and HERC1 disease-mutant analysis\",\n      \"pmids\": [\"34446601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of PSMC4 incorporation not resolved\", \"Whether PSMC4 itself is a HERC1 substrate unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected PSMC4 to cancer progression through a CBX3-EGFR-PI3K-AKT-mTOR signaling axis.\",\n      \"evidence\": \"siRNA knockdown, co-IP, RNA-seq, rescue experiments, and xenograft model in prostate carcinoma\",\n      \"pmids\": [\"37436074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether regulation of CBX3 is proteasome-dependent unclear\", \"Single-lab; not validated in additional tumor types\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMC4 toggles between its canonical 19S proteasomal role and its multiple non-proteasomal complexes (ER/TRAP1, TBP-transcription, signaling) remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model distinguishing free versus assembled PSMC4 functions\", \"Signals partitioning PSMC4 to ER versus proteasome unknown\", \"Direct ATPase enzymology of human PSMC4 not characterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 13, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"complexes\": [\n      \"26S proteasome (19S regulatory particle)\",\n      \"PSMC4-PSMC5-PAAF1 assembly intermediate\",\n      \"ER-localized TRAP1-TBP7 complex\",\n      \"TBP-ATPase ~800 kDa transcription complex\"\n    ],\n    \"partners\": [\n      \"TRAP1\",\n      \"PSMC5\",\n      \"PAAF1\",\n      \"HERC1\",\n      \"CDK1\",\n      \"gankyrin\",\n      \"synphilin-1\",\n      \"CBX3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}