{"gene":"PSMA7","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"PSMA7 (alpha4 subunit) is a component of the 20S proteasome core complex, which contains multiple peptidase activities functioning through a threonine active-site mechanism; the 20S particle associates with the 19S regulatory complex to form the 26S proteasome that degrades ubiquitinated proteins.","method":"Biochemical purification, peptidase activity assays, structural characterization of proteasome complexes","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — foundational reconstitution and enzymatic characterization, replicated across labs; >2000 citations","pmids":["8811196"],"is_preprint":false},{"year":2001,"finding":"PSMA7 (proteasome alpha4 subunit) interacts specifically with two subdomains of HIF-1alpha and inhibits HIF-1alpha transactivation function under both normoxic and hypoxia-mimicking conditions; this regulation is associated with the proteasome degradation pathway.","method":"Yeast two-hybrid, co-immunoprecipitation, transactivation reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2/3 — interaction confirmed by Co-IP, functional inhibition shown by reporter assay, single lab","pmids":["11389899"],"is_preprint":false},{"year":2001,"finding":"PSMA7 mRNA is a direct target of a hairpin ribozyme, and ribozyme-mediated knockdown of PSMA7 inhibits HCV IRES-mediated translation but not cap-dependent translation or IRES activity of encephalomyocarditis virus or human rhinovirus; additionally, the proteasome inhibitor MG132 dose-dependently inhibits HCV IRES-mediated translation, implicating PSMA7 specifically in regulating HCV IRES activity.","method":"Ribozyme cleavage-based target identification (CASCASE), GCV-resistance reporter assay, bicistronic Renilla-HCV IRES-firefly luciferase reporter in Huh7 cells, pharmacological proteasome inhibition","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assay systems in two cell lines, single lab","pmids":["11713272"],"is_preprint":false},{"year":2004,"finding":"The proteasome alpha-subunit XAPC7 (PSMA7) interacts specifically with Rab7 via its C-terminus (interacting with the N-terminus of Rab7) and is recruited to multivesicular late endosomes through this interaction; overexpression of PSMA7 impairs late endocytic transport of EGFR and another membrane protein, and this is partially rescued by co-expression of wild-type Rab7, establishing a negative regulatory role for PSMA7 in late endocytic trafficking.","method":"Co-immunoprecipitation, subcellular fractionation, domain mapping, fluorescence microscopy, endocytic transport assays, Rab7 chimera experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction mapping, localization by fractionation, functional rescue experiment, multiple orthogonal methods in single study","pmids":["14998988"],"is_preprint":false},{"year":2006,"finding":"c-Abl and Arg tyrosine kinases associate with and phosphorylate PSMA7 at Tyr-153; this phosphorylation compromises proteasome-dependent proteolysis. Cells expressing the phosphorylation-deficient PSMA7(Y153F) mutant display impaired G1/S transition and S/G2 cell cycle progression.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y153F), cell cycle analysis, proteasome activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro kinase assay, mutagenesis, and cell cycle phenotype; multiple orthogonal methods","pmids":["16678104"],"is_preprint":false},{"year":2009,"finding":"PSMA7 (alpha4 subunit) associates with MAVS (mitochondrial antiviral signaling protein) both in vivo and in vitro; overexpression of PSMA7 potently inhibits RIG-I and MAVS-mediated IFN-beta promoter activity, reduces endogenous MAVS protein abundance, and siRNA depletion of PSMA7 enhances virus-induced type I IFN production and reduces virus replication. Viral infection transiently increases endogenous PSMA7 protein levels.","method":"Co-immunoprecipitation, GST pulldown, IFN-beta promoter luciferase reporter assay, siRNA knockdown, viral infection assay, Western blot for MAVS levels","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, in vitro pulldown, gain- and loss-of-function with defined molecular and cellular phenotypes","pmids":["19734229"],"is_preprint":false},{"year":2009,"finding":"EMAP-II (endothelial monocyte activating polypeptide-II) binds to cell-surface alpha5beta1 integrin, is internalized, and then interacts with cytoplasmic PSMA7; this interaction with PSMA7 increases HIF-1alpha degradation under hypoxic conditions, inhibiting HIF-1alpha-mediated transcriptional activity and angiogenic sprouting of endothelial cells.","method":"Co-immunoprecipitation, cellular fractionation, HIF-1alpha degradation assay, HIF-1alpha transcriptional reporter assay, tube formation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2/3 — interaction confirmed, functional consequences shown, single lab with multiple readouts","pmids":["19362550"],"is_preprint":false},{"year":2009,"finding":"shRNA-mediated depletion of PSMA7 in RKO colorectal cancer cells inhibits anchorage-independent growth, cell invasion and migration, and in vivo tumorigenicity; these effects are associated with suppression of CD44 expression, suggesting PSMA7 promotes tumor progression partly through CD44.","method":"shRNA knockdown, anchorage-independent growth assay, invasion/migration assay, xenograft tumor assay, Western blot for CD44","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple defined cellular phenotypes and molecular marker, single lab","pmids":["19787246"],"is_preprint":false},{"year":2013,"finding":"PSMA7 directly associates with NOD1 (nucleotide-binding oligomerization domain-containing protein 1), identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation and GST pulldown; PSMA7 downregulates NOD1 protein in a proteasome-dependent manner, and overexpression of PSMA7 inhibits NOD1-mediated apoptosis and NF-κB activation, while PSMA7 knockdown enhances NOD1 activity.","method":"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, ubiquitin assay, Western blotting, NF-κB reporter assay, apoptosis assay, siRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"High","confidence_rationale":"Tier 2 — interaction confirmed by three independent methods, proteasome-dependent degradation mechanism shown, gain- and loss-of-function phenotypes demonstrated","pmids":["23839082"],"is_preprint":false},{"year":2015,"finding":"PSMA7 is itself subject to ubiquitination and proteasomal degradation; BRCA1 functions as the E3 ubiquitin ligase for PSMA7 ubiquitination. Phosphorylation of PSMA7 at Y106 by c-Abl/Arg kinases suppresses BRCA1-mediated ubiquitination and proteasomal degradation of PSMA7, thereby controlling cellular proteasome abundance. Downregulation of PSMA7 via c-Abl/Arg RNAi or knockout reduces overall proteasome abundance and increases sensitivity to proteasome inhibition. Under oxidative stress, c-Abl-mediated upregulation of PSMA7/proteasome levels compensates for ROS-induced proteasomal activity impairment.","method":"Ubiquitination assay, E3 ligase identification (BRCA1), site-directed mutagenesis (Y106), RNAi knockdown, c-abl/arg knockout cells, proteasome activity assays, proteasome abundance quantification, oxidative stress experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal methods including mutagenesis, defined E3 ligase, genetic KO, and multiple functional readouts in single study","pmids":["25620702"],"is_preprint":false},{"year":2018,"finding":"shRNA-mediated silencing of PSMA7 in cervical cancer SiHa cells decreases proteasome activity, reduces ubiquitin and VEGF expression, increases p27 expression, causes G0/G1 cell cycle arrest, and promotes apoptosis, demonstrating that PSMA7 regulates cell proliferation and VEGF expression through the ubiquitin-proteasome pathway.","method":"shRNA knockdown, MTT proliferation assay, flow cytometry (cell cycle and apoptosis), immunofluorescence (20S proteasome activity), RT-qPCR, Western blot, in situ hybridization","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple molecular and cellular readouts, single lab","pmids":["29247526"],"is_preprint":false},{"year":2021,"finding":"UCHL1 (deubiquitinase) maintains protein homeostasis in high-grade serous ovarian carcinoma through a PSMA7-APEH-proteasome axis: UCHL1 silencing reduces PSMA7 and APEH expression, causing decreased proteasome activity, impaired protein degradation, accumulation of polyubiquitinated proteins, attenuation of mTORC1 activity, and induction of terminal unfolded protein response.","method":"siRNA/shRNA knockdown, transcriptional profiling, proteasome activity assay, Western blot for polyubiquitinated proteins, mTORC1 activity assay, xenograft mouse model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 — functional epistasis linking UCHL1 to PSMA7 with multiple molecular readouts, in vivo validation, single lab","pmids":["33753553"],"is_preprint":false}],"current_model":"PSMA7 (proteasome alpha4/XAPC7 subunit) is a structural component of the 20S proteasome core whose abundance is controlled by c-Abl/Arg-mediated phosphorylation at Y106/Y153, which suppresses BRCA1-dependent ubiquitination and proteasomal auto-degradation of PSMA7; beyond its canonical proteolytic role, PSMA7 functions as a negative regulator of innate immune signaling by binding and promoting degradation of MAVS (suppressing RIG-I/IFN-beta responses) and by binding and destabilizing NOD1 (suppressing NF-κB and apoptosis), interacts with Rab7 to negatively regulate late endocytic trafficking, promotes HIF-1alpha degradation in complex with EMAP-II, and is required for HCV IRES-mediated translation, collectively establishing PSMA7 as a multifunctional proteasome subunit that integrates proteostasis, antiviral immunity, endosomal trafficking, and hypoxia signaling."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing PSMA7 as a core component of the 20S proteasome resolved the identity and enzymatic mechanism of the particle's alpha-ring subunits, showing that the 20S core uses threonine-based peptidase activities and assembles with the 19S regulator to form the 26S proteasome.","evidence":"Biochemical purification, peptidase activity assays, and structural characterization of proteasome complexes","pmids":["8811196"],"confidence":"High","gaps":["Role of individual alpha subunits versus the assembled ring in substrate recognition was not resolved","Post-translational regulation of PSMA7 itself was unknown"]},{"year":2001,"claim":"Discovery that PSMA7 physically interacts with HIF-1α and inhibits its transactivation, and that PSMA7 is required for HCV IRES-mediated translation, revealed non-canonical functions for a proteasome subunit beyond bulk proteolysis.","evidence":"Yeast two-hybrid, co-immunoprecipitation, transactivation reporters for HIF-1α; ribozyme knockdown and bicistronic IRES reporters in Huh7 cells for HCV IRES","pmids":["11389899","11713272"],"confidence":"Medium","gaps":["Mechanism linking PSMA7 to HCV IRES translation remained unclear","Whether PSMA7–HIF-1α interaction operates independently of assembled proteasome was not determined","No in vivo validation for HCV IRES finding"]},{"year":2004,"claim":"Identifying PSMA7 as a Rab7-binding partner recruited to multivesicular late endosomes established a proteasome-subunit-mediated negative regulatory step in late endocytic trafficking of receptors such as EGFR.","evidence":"Reciprocal co-immunoprecipitation, domain mapping, subcellular fractionation, endocytic transport assays with Rab7 rescue","pmids":["14998988"],"confidence":"High","gaps":["Whether PSMA7 acts on Rab7 as part of an assembled proteasome or as a free subunit was not resolved","Physiological contexts requiring PSMA7–Rab7 interaction (e.g., growth factor signaling) were unexplored"]},{"year":2006,"claim":"Demonstrating that c-Abl/Arg phosphorylate PSMA7 at Y153 and that this modification compromises proteasome activity and cell-cycle progression revealed the first signaling-dependent post-translational control of a proteasome alpha subunit.","evidence":"In vitro kinase assay, Y153F mutagenesis, proteasome activity assays, cell cycle analysis","pmids":["16678104"],"confidence":"High","gaps":["How Y153 phosphorylation structurally impairs proteasome activity was unknown","Relationship between Y153 and other phosphorylation sites on PSMA7 was not examined"]},{"year":2009,"claim":"Three studies collectively expanded PSMA7's non-canonical roles: PSMA7 binds MAVS and promotes its degradation to suppress RIG-I/IFN-β signaling; EMAP-II engagement promotes PSMA7-dependent HIF-1α degradation under hypoxia; and PSMA7 depletion reduces tumorigenicity in colorectal cancer cells partly through CD44.","evidence":"Reciprocal co-IP and GST pulldown for MAVS, gain/loss-of-function IFN-β and NF-κB reporters, viral infection assays; co-IP and HIF-1α degradation assays for EMAP-II; shRNA xenograft and invasion assays for tumor phenotype","pmids":["19734229","19362550","19787246"],"confidence":"High","gaps":["Whether PSMA7–MAVS interaction is direct or occurs within an assembled proteasome was not distinguished","Mechanism by which PSMA7 depletion reduces CD44 was correlative","In vivo immune phenotype of PSMA7 loss was not assessed"]},{"year":2013,"claim":"Identification of NOD1 as a direct PSMA7 interactor whose proteasome-dependent degradation is promoted by PSMA7 broadened the gene's role in innate immunity from antiviral (MAVS) to antibacterial (NOD1) pathways.","evidence":"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, ubiquitin assays, NF-κB reporter, apoptosis assays, siRNA knockdown","pmids":["23839082"],"confidence":"High","gaps":["E3 ligase responsible for NOD1 ubiquitination downstream of PSMA7 was not identified","Physiological relevance in pathogen challenge models was not tested"]},{"year":2015,"claim":"Elucidating the full regulatory circuit — BRCA1 ubiquitinates PSMA7 for proteasomal degradation, and c-Abl/Arg phosphorylation at Y106 antagonizes this — established how cells tune total proteasome abundance and explained compensatory proteasome upregulation during oxidative stress.","evidence":"Ubiquitination assays identifying BRCA1 as E3, Y106 mutagenesis, c-Abl/Arg RNAi and knockout, proteasome abundance quantification, oxidative stress experiments","pmids":["25620702"],"confidence":"High","gaps":["Whether other E3 ligases contribute to PSMA7 turnover was not addressed","Structural basis for how Y106 phosphorylation blocks BRCA1 recognition is unknown"]},{"year":2021,"claim":"Placing PSMA7 within a UCHL1–PSMA7–APEH proteostasis axis in ovarian cancer showed that upstream deubiquitinase activity controls PSMA7 expression, linking PSMA7 to mTORC1 signaling and the unfolded protein response.","evidence":"siRNA/shRNA knockdown, proteasome activity assays, Western blot for polyubiquitinated proteins, mTORC1 activity assay, xenograft model","pmids":["33753553"],"confidence":"Medium","gaps":["Whether UCHL1 directly deubiquitinates PSMA7 or acts indirectly through transcriptional regulation was not resolved","Generalizability beyond high-grade serous ovarian carcinoma is untested"]},{"year":null,"claim":"It remains unresolved whether the non-canonical functions of PSMA7 (MAVS/NOD1 degradation, Rab7-mediated endosomal regulation, HCV IRES translation) are executed by free PSMA7 subunits or by PSMA7 within assembled proteasome complexes, and no structural model exists for PSMA7 interactions with its non-proteasomal partners.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Free-subunit versus assembled-proteasome distinction for non-canonical activities","Structural basis of PSMA7 interactions with MAVS, NOD1, and Rab7","In vivo immune and endosomal phenotypes of conditional PSMA7 loss"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,9,10]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,9,10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,10]}],"complexes":["20S proteasome","26S proteasome"],"partners":["RAB7A","MAVS","NOD1","ABL1","ABL2","BRCA1","HIF1A","AIMP1"],"other_free_text":[]},"mechanistic_narrative":"PSMA7 (alpha4/XAPC7) is a structural subunit of the 20S proteasome core particle that contributes to ubiquitin-dependent proteolysis and whose own abundance is tightly regulated by c-Abl/Arg-mediated phosphorylation at Y106 and Y153, which antagonizes BRCA1-dependent ubiquitination and proteasomal auto-degradation of PSMA7, thereby tuning cellular proteasome levels under basal and oxidative-stress conditions [PMID:25620702, PMID:16678104]. Beyond its canonical role in proteostasis, PSMA7 negatively regulates innate immune signaling by binding MAVS to promote its degradation and suppress RIG-I–dependent IFN-β production [PMID:19734229], and by binding NOD1 to direct its proteasome-dependent turnover, attenuating NF-κB activation and apoptosis [PMID:23839082]. PSMA7 also interacts with Rab7 on late endosomes to negatively regulate EGFR endocytic trafficking [PMID:14998988], cooperates with EMAP-II to accelerate HIF-1α degradation under hypoxia [PMID:11389899, PMID:19362550], and is specifically required for HCV IRES-mediated translation [PMID:11713272]."},"prefetch_data":{"uniprot":{"accession":"O14818","full_name":"Proteasome subunit alpha type-7","aliases":["Proteasome subunit RC6-1","Proteasome subunit XAPC7","Proteasome subunit alpha-4","alpha-4"],"length_aa":248,"mass_kda":27.9,"function":"Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O14818/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA7","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMA1","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":"PSMB7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/PSMA7","total_profiled":1310},"omim":[{"mim_id":"617841","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 8; PSMA8","url":"https://www.omim.org/entry/617841"},{"mim_id":"613386","title":"PROTEASOME MATURATION PROTEIN; POMP","url":"https://www.omim.org/entry/613386"},{"mim_id":"606607","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 7; PSMA7","url":"https://www.omim.org/entry/606607"},{"mim_id":"602544","title":"PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN","url":"https://www.omim.org/entry/602544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Principal piece","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":740.0}],"url":"https://www.proteinatlas.org/search/PSMA7"},"hgnc":{"alias_symbol":["XAPC7","C6","HSPC","RC6-1"],"prev_symbol":[]},"alphafold":{"accession":"O14818","domains":[{"cath_id":"3.60.20.10","chopping":"19-243","consensus_level":"high","plddt":94.9808,"start":19,"end":243}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14818","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14818-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14818-F1-predicted_aligned_error_v6.png","plddt_mean":94.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA7","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA7"},"sequence":{"accession":"O14818","fasta_url":"https://rest.uniprot.org/uniprotkb/O14818.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14818/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14818"}},"corpus_meta":[{"pmid":"17308093","id":"PMC_17308093","title":"Tumor-suppressive 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overexpression of PSMA7 potently inhibits RIG-I/MAVS-mediated IFN-beta promoter activity; conversely, PSMA7 depletion enhances virus-induced type I IFN production. PSMA7 overexpression also reduces endogenous MAVS abundance, suggesting PSMA7 promotes MAVS degradation to negatively regulate antiviral innate immunity.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, IFN-beta promoter reporter assay, Western blot for MAVS abundance\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in vivo and in vitro, loss-of-function with defined functional readout, replicated across multiple assay systems\",\n      \"pmids\": [\"19734229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The proteasome alpha-subunit PSMA7 (XAPC7) was identified as a specific binding partner of Rab7; this interaction recruits PSMA7 to multivesicular late endosomes. The C-terminus of XAPC7 and N-terminus of Rab7 mediate the interaction. PSMA7 overexpression impairs late endocytic transport of EGFR and another membrane protein, an effect partially rescued by wild-type Rab7 co-expression, establishing a negative regulatory role for PSMA7 in late endocytic trafficking.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, overexpression with functional endocytic transport assay, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, direct localization experiment tied to functional consequence (impaired late endocytic transport), rescue experiment\",\n      \"pmids\": [\"14998988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 (20S proteasome alpha subunit) directly interacts with two subdomains of HIF-1alpha and inhibits HIF-1alpha transactivation function under both normoxic and hypoxia-mimicking conditions; this regulation is associated with the proteasome degradation pathway.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, HIF-1alpha transactivation reporter assay, proteasome inhibitor experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding interaction identified by Y2H and Co-IP, functional consequence (inhibition of transactivation) demonstrated in reporter assay with pathway validation\",\n      \"pmids\": [\"11389899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 mRNA is a functional target of a ribozyme (Rz3'X), and knockdown of PSMA7 with additional ribozymes inhibits HCV IRES-mediated translation in two independent reporter systems (HeLa IRES-TK reporter and bicistronic luciferase reporter in Huh7 cells). The proteasome inhibitor MG132 also dose-dependently inhibits HCV IRES-mediated but not cap-dependent translation, implicating PSMA7 in regulating HCV IRES activity essential for HCV replication.\",\n      \"method\": \"Ribozyme-based knockdown, bicistronic reporter assay (GCV resistance and luciferase), proteasome inhibitor (MG132) treatment, CASACE target identification method\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with two independent reporter systems, pharmacological validation with proteasome inhibitor\",\n      \"pmids\": [\"11713272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Abl and Arg (abl-related gene) tyrosine kinases directly associate with and phosphorylate the PSMA7 (alpha4) subunit at Tyr-153; this phosphorylation compromises proteasome-dependent proteolysis. Cells expressing a phosphorylation-dead PSMA7(Y153F) mutant display impaired G1/S transition and S/G2 progression, establishing tyrosine phosphorylation of PSMA7 as a regulatory mechanism controlling cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y153F), cell cycle analysis, proteasome activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis, combined with cell cycle phenotype in mutant cells; multiple orthogonal methods\",\n      \"pmids\": [\"16678104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMA7 is subjected to ubiquitination and proteasomal self-degradation; BRCA1 functions as the E3 ubiquitin ligase for PSMA7. Phosphorylation of PSMA7 at Y106 by c-Abl/Arg kinases suppresses this ubiquitination, stabilizing PSMA7. c-Abl/Arg thereby regulate cellular proteasome abundance by controlling PSMA7 subunit supply; c-Abl/Arg knockdown or knockout reduces PSMA7 levels and overall proteasome abundance, increasing sensitivity to proteasome inhibition. In response to oxidative stress, c-Abl-mediated upregulation of proteasome level compensates for ROS-induced proteasomal activity impairment.\",\n      \"method\": \"Ubiquitination assay, E3 ligase identification (BRCA1 co-IP and functional assay), site-directed mutagenesis (Y106), RNAi knockdown, gene knockout, proteasome activity assay, oxidative stress challenge\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of ubiquitination with identified E3 ligase, mutagenesis of phosphorylation site, multiple genetic loss-of-function approaches with quantitative proteasome abundance readout\",\n      \"pmids\": [\"25620702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMA7 depletion by shRNA in colorectal cancer cells (RKO) inhibits anchorage-independent growth, cell invasion and migration, and in vivo tumorigenic ability; these effects are associated with inhibition of CD44 expression, suggesting PSMA7 promotes colorectal cancer progression partly through regulating CD44.\",\n      \"method\": \"shRNA knockdown, anchorage-independent growth assay, invasion/migration assay, in vivo tumor xenograft, Western blot for CD44\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype, but CD44 link is correlative without reconstitution\",\n      \"pmids\": [\"19787246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EMAP-II (endothelial monocyte activating polypeptide-II) binds to alpha5beta1 integrin on the cell surface and, after internalization, interacts with PSMA7 in the cytoplasm. This EMAP-II–PSMA7 interaction increases HIF-1alpha degradation under hypoxic conditions, thereby inhibiting HIF-1alpha-mediated transcriptional activity and angiogenic sprouting.\",\n      \"method\": \"Co-immunoprecipitation, receptor binding assay (alpha5beta1 integrin), subcellular fractionation, HIF-1alpha degradation assay, angiogenic sprouting assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and functional consequence demonstrated, but mechanism of PSMA7 involvement in HIF-1alpha degradation not dissected with mutagenesis\",\n      \"pmids\": [\"19362550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PSMA7 associates with NOD1 (nucleotide-binding oligomerization domain-containing protein 1), identified by yeast two-hybrid, co-immunoprecipitation, and GST pulldown. PSMA7 downregulates NOD1 expression in a proteasome-dependent manner. Overexpression of PSMA7 inhibits NOD1-mediated apoptosis and NF-κB activation, while PSMA7 knockdown enhances NOD1 activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, ubiquitin assay, Western blot, NF-κB reporter assay, RNAi knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three orthogonal binding assays, proteasome-dependent degradation shown, functional consequences in NF-κB and apoptosis assays\",\n      \"pmids\": [\"23839082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UCHL1 (deubiquitinating enzyme) maintains PSMA7 expression levels in high-grade serous ovarian carcinoma; silencing UCHL1 reduces PSMA7 and APEH expression, leading to decreased proteasome activity, impaired protein degradation, accumulation of polyubiquitinated proteins, and attenuation of mTORC1 activity, implicating PSMA7 as a key node in the UCHL1-PSMA7-APEH-proteasome axis for protein homeostasis.\",\n      \"method\": \"RNAi knockdown (UCHL1), transcriptional profiling, proteasome activity assay, Western blot for polyubiquitinated proteins, mTORC1 activity assay, xenograft model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple mechanistic readouts, but direct UCHL1-PSMA7 interaction not established by Co-IP in this study\",\n      \"pmids\": [\"33753553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"shRNA-mediated silencing of PSMA7 in cervical cancer (SiHa) cells decreases 20S proteasome activity, reduces ubiquitin, p53, and VEGF expression, increases p27 expression, inhibits cell proliferation, induces cell cycle arrest at G0/G1, and promotes apoptosis, linking PSMA7 to regulation of the ubiquitin-proteasome pathway and downstream cell cycle control in cancer cells.\",\n      \"method\": \"shRNA knockdown, immunofluorescence (proteasome activity), RT-qPCR, Western blot, MTT assay, flow cytometry (cell cycle and apoptosis)\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — clean knockdown with multiple molecular readouts, but mechanistic placement relies on correlative expression changes\",\n      \"pmids\": [\"29247526\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA7 (proteasome alpha4/XAPC7 subunit) is a multifunctional component of the 20S proteasome that: (1) is phosphorylated at Tyr-153 by c-Abl/Arg kinases to modulate proteasome-dependent proteolysis and cell cycle progression, and at Tyr-106 to prevent BRCA1-mediated ubiquitination and its own proteasomal degradation, thereby controlling cellular proteasome abundance; (2) binds Rab7 to localize to late endosomes and negatively regulate late endocytic trafficking; (3) interacts with and promotes degradation of MAVS to attenuate antiviral innate immune signaling; (4) binds HIF-1alpha to inhibit its transactivation through the proteasome pathway; (5) interacts with NOD1 to promote its proteasomal degradation and suppress NF-κB/apoptosis signaling; and (6) is required for HCV IRES-mediated translation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of relevant papers:**\n\nKEEP (about canonical PSMA7 protein):\n- PMID:19734229 - PSMA7 negative regulation of MAVS\n- PMID:14998988 - XAPC7/PSMA7 interaction with Rab7\n- PMID:11389899 - PSMA7 binding/regulation of HIF-1alpha\n- PMID:11713272 - PSMA7 role in HCV IRES translation\n- PMID:16678104 - c-Abl/Arg phosphorylation of PSMA7\n- PMID:25620702 - c-Abl regulation of PSMA7 ubiquitination/degradation\n- PMID:33753553 - UCHL1/PSMA7-APEH-proteasome axis\n- PMID:23839082 - PSMA7 interaction with NOD1\n- PMID:19362550 - EMAP-II/PSMA7/HIF-1alpha degradation\n- PMID:19787246 - PSMA7 depletion in colorectal cancer (shRNA, CD44)\n- PMID:29247526 - PSMA7 silencing in cervical cancer\n- PMID:19442227 - PSMA7 review (mechanistic context)\n- PMID:8811196 - 20S proteasome structure/function (foundational)\n- PMID:28523434 - PSMA7 biomarker (expression only - EXCLUDE)\n- PMID:18202793 - PSMA7 expression/IHC (EXCLUDE - expression only)\n- PMID:30390597 - Anti-PSMA7 autoantibodies (biomarker - EXCLUDE)\n\nAll other papers are clearly about C6 glioma cells, complement C6, HSPC biology, cytochrome c6, or other unrelated topics → EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"PSMA7 (alpha4 subunit) is a component of the 20S proteasome core complex, which contains multiple peptidase activities functioning through a threonine active-site mechanism; the 20S particle associates with the 19S regulatory complex to form the 26S proteasome that degrades ubiquitinated proteins.\",\n      \"method\": \"Biochemical purification, peptidase activity assays, structural characterization of proteasome complexes\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational reconstitution and enzymatic characterization, replicated across labs; >2000 citations\",\n      \"pmids\": [\"8811196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 (proteasome alpha4 subunit) interacts specifically with two subdomains of HIF-1alpha and inhibits HIF-1alpha transactivation function under both normoxic and hypoxia-mimicking conditions; this regulation is associated with the proteasome degradation pathway.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transactivation reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — interaction confirmed by Co-IP, functional inhibition shown by reporter assay, single lab\",\n      \"pmids\": [\"11389899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 mRNA is a direct target of a hairpin ribozyme, and ribozyme-mediated knockdown of PSMA7 inhibits HCV IRES-mediated translation but not cap-dependent translation or IRES activity of encephalomyocarditis virus or human rhinovirus; additionally, the proteasome inhibitor MG132 dose-dependently inhibits HCV IRES-mediated translation, implicating PSMA7 specifically in regulating HCV IRES activity.\",\n      \"method\": \"Ribozyme cleavage-based target identification (CASCASE), GCV-resistance reporter assay, bicistronic Renilla-HCV IRES-firefly luciferase reporter in Huh7 cells, pharmacological proteasome inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assay systems in two cell lines, single lab\",\n      \"pmids\": [\"11713272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The proteasome alpha-subunit XAPC7 (PSMA7) interacts specifically with Rab7 via its C-terminus (interacting with the N-terminus of Rab7) and is recruited to multivesicular late endosomes through this interaction; overexpression of PSMA7 impairs late endocytic transport of EGFR and another membrane protein, and this is partially rescued by co-expression of wild-type Rab7, establishing a negative regulatory role for PSMA7 in late endocytic trafficking.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, domain mapping, fluorescence microscopy, endocytic transport assays, Rab7 chimera experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction mapping, localization by fractionation, functional rescue experiment, multiple orthogonal methods in single study\",\n      \"pmids\": [\"14998988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Abl and Arg tyrosine kinases associate with and phosphorylate PSMA7 at Tyr-153; this phosphorylation compromises proteasome-dependent proteolysis. Cells expressing the phosphorylation-deficient PSMA7(Y153F) mutant display impaired G1/S transition and S/G2 cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y153F), cell cycle analysis, proteasome activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay, mutagenesis, and cell cycle phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"16678104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMA7 (alpha4 subunit) associates with MAVS (mitochondrial antiviral signaling protein) both in vivo and in vitro; overexpression of PSMA7 potently inhibits RIG-I and MAVS-mediated IFN-beta promoter activity, reduces endogenous MAVS protein abundance, and siRNA depletion of PSMA7 enhances virus-induced type I IFN production and reduces virus replication. Viral infection transiently increases endogenous PSMA7 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, IFN-beta promoter luciferase reporter assay, siRNA knockdown, viral infection assay, Western blot for MAVS levels\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vitro pulldown, gain- and loss-of-function with defined molecular and cellular phenotypes\",\n      \"pmids\": [\"19734229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EMAP-II (endothelial monocyte activating polypeptide-II) binds to cell-surface alpha5beta1 integrin, is internalized, and then interacts with cytoplasmic PSMA7; this interaction with PSMA7 increases HIF-1alpha degradation under hypoxic conditions, inhibiting HIF-1alpha-mediated transcriptional activity and angiogenic sprouting of endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, cellular fractionation, HIF-1alpha degradation assay, HIF-1alpha transcriptional reporter assay, tube formation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — interaction confirmed, functional consequences shown, single lab with multiple readouts\",\n      \"pmids\": [\"19362550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"shRNA-mediated depletion of PSMA7 in RKO colorectal cancer cells inhibits anchorage-independent growth, cell invasion and migration, and in vivo tumorigenicity; these effects are associated with suppression of CD44 expression, suggesting PSMA7 promotes tumor progression partly through CD44.\",\n      \"method\": \"shRNA knockdown, anchorage-independent growth assay, invasion/migration assay, xenograft tumor assay, Western blot for CD44\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple defined cellular phenotypes and molecular marker, single lab\",\n      \"pmids\": [\"19787246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PSMA7 directly associates with NOD1 (nucleotide-binding oligomerization domain-containing protein 1), identified by yeast two-hybrid screening and confirmed by co-immunoprecipitation and GST pulldown; PSMA7 downregulates NOD1 protein in a proteasome-dependent manner, and overexpression of PSMA7 inhibits NOD1-mediated apoptosis and NF-κB activation, while PSMA7 knockdown enhances NOD1 activity.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, GST pulldown, ubiquitin assay, Western blotting, NF-κB reporter assay, apoptosis assay, siRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by three independent methods, proteasome-dependent degradation mechanism shown, gain- and loss-of-function phenotypes demonstrated\",\n      \"pmids\": [\"23839082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMA7 is itself subject to ubiquitination and proteasomal degradation; BRCA1 functions as the E3 ubiquitin ligase for PSMA7 ubiquitination. Phosphorylation of PSMA7 at Y106 by c-Abl/Arg kinases suppresses BRCA1-mediated ubiquitination and proteasomal degradation of PSMA7, thereby controlling cellular proteasome abundance. Downregulation of PSMA7 via c-Abl/Arg RNAi or knockout reduces overall proteasome abundance and increases sensitivity to proteasome inhibition. Under oxidative stress, c-Abl-mediated upregulation of PSMA7/proteasome levels compensates for ROS-induced proteasomal activity impairment.\",\n      \"method\": \"Ubiquitination assay, E3 ligase identification (BRCA1), site-directed mutagenesis (Y106), RNAi knockdown, c-abl/arg knockout cells, proteasome activity assays, proteasome abundance quantification, oxidative stress experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods including mutagenesis, defined E3 ligase, genetic KO, and multiple functional readouts in single study\",\n      \"pmids\": [\"25620702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"shRNA-mediated silencing of PSMA7 in cervical cancer SiHa cells decreases proteasome activity, reduces ubiquitin and VEGF expression, increases p27 expression, causes G0/G1 cell cycle arrest, and promotes apoptosis, demonstrating that PSMA7 regulates cell proliferation and VEGF expression through the ubiquitin-proteasome pathway.\",\n      \"method\": \"shRNA knockdown, MTT proliferation assay, flow cytometry (cell cycle and apoptosis), immunofluorescence (20S proteasome activity), RT-qPCR, Western blot, in situ hybridization\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple molecular and cellular readouts, single lab\",\n      \"pmids\": [\"29247526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UCHL1 (deubiquitinase) maintains protein homeostasis in high-grade serous ovarian carcinoma through a PSMA7-APEH-proteasome axis: UCHL1 silencing reduces PSMA7 and APEH expression, causing decreased proteasome activity, impaired protein degradation, accumulation of polyubiquitinated proteins, attenuation of mTORC1 activity, and induction of terminal unfolded protein response.\",\n      \"method\": \"siRNA/shRNA knockdown, transcriptional profiling, proteasome activity assay, Western blot for polyubiquitinated proteins, mTORC1 activity assay, xenograft mouse model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis linking UCHL1 to PSMA7 with multiple molecular readouts, in vivo validation, single lab\",\n      \"pmids\": [\"33753553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA7 (proteasome alpha4/XAPC7 subunit) is a structural component of the 20S proteasome core whose abundance is controlled by c-Abl/Arg-mediated phosphorylation at Y106/Y153, which suppresses BRCA1-dependent ubiquitination and proteasomal auto-degradation of PSMA7; beyond its canonical proteolytic role, PSMA7 functions as a negative regulator of innate immune signaling by binding and promoting degradation of MAVS (suppressing RIG-I/IFN-beta responses) and by binding and destabilizing NOD1 (suppressing NF-κB and apoptosis), interacts with Rab7 to negatively regulate late endocytic trafficking, promotes HIF-1alpha degradation in complex with EMAP-II, and is required for HCV IRES-mediated translation, collectively establishing PSMA7 as a multifunctional proteasome subunit that integrates proteostasis, antiviral immunity, endosomal trafficking, and hypoxia signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMA7 (proteasome subunit alpha type 7/alpha4/XAPC7) is a core structural and regulatory component of the 20S proteasome with additional moonlighting roles in endocytic trafficking, innate immune signaling, and transcriptional regulation. As a proteasome subunit, its abundance is controlled by BRCA1-mediated ubiquitination and counterbalanced by c-Abl/Arg phosphorylation at Tyr-106, which stabilizes PSMA7 and thereby tunes overall cellular proteasome levels and oxidative stress responses; a separate c-Abl/Arg phosphorylation at Tyr-153 modulates proteasome-dependent proteolysis and cell cycle progression [PMID:16678104, PMID:25620702]. Beyond proteasome function, PSMA7 binds Rab7 to localize to late endosomes and negatively regulates late endocytic transport [PMID:14998988], interacts with MAVS and NOD1 to promote their proteasomal degradation thereby attenuating type I interferon and NF-κB signaling [PMID:19734229, PMID:23839082], directly binds HIF-1α to inhibit its transactivation [PMID:11389899], and is required for HCV IRES-mediated translation [PMID:11713272].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"PSMA7 was found to directly bind HIF-1α and inhibit its transactivation, establishing the first evidence that an individual 20S proteasome α-subunit can regulate a specific transcription factor outside canonical bulk proteolysis.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and HIF-1α reporter assay with proteasome inhibitor controls\",\n      \"pmids\": [\"11389899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mutagenesis of HIF-1α binding interface on PSMA7\", \"Whether PSMA7 acts on HIF-1α as part of the assembled 20S complex or as a free subunit was not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Ribozyme-mediated knockdown of PSMA7 selectively blocked HCV IRES-mediated translation in two independent systems, revealing an unexpected role for the proteasome α-subunit in cap-independent viral translation.\",\n      \"evidence\": \"Ribozyme knockdown in HeLa IRES-TK and Huh7 bicistronic luciferase reporters, with MG132 pharmacological validation\",\n      \"pmids\": [\"11713272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PSMA7 facilitates IRES-mediated translation (direct RNA binding vs. indirect) was not determined\", \"No reconstitution with recombinant PSMA7\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of Rab7 as a binding partner placed PSMA7 at late endosomes and demonstrated it negatively regulates late endocytic trafficking, revealing a non-proteolytic moonlighting function.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping, subcellular localization, EGFR endocytic transport assay with Rab7 rescue\",\n      \"pmids\": [\"14998988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endosome-localized PSMA7 retains proteasome activity was not tested\", \"Stoichiometry and competition with assembled 20S proteasome not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"c-Abl and Arg kinases were shown to phosphorylate PSMA7 at Tyr-153, directly linking tyrosine kinase signaling to proteasome activity regulation and cell cycle control.\",\n      \"evidence\": \"In vitro kinase assay, Y153F mutagenesis, cell cycle analysis, proteasome activity assay\",\n      \"pmids\": [\"16678104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of Y153 phosphorylation on 20S assembly or gate opening was not resolved\", \"Specific proteasome substrates affected by Y153 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"PSMA7 was established as a negative regulator of RIG-I/MAVS antiviral signaling by promoting MAVS degradation, extending its immune-regulatory repertoire beyond the proteasome's generic substrate processing role.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation (in vivo and in vitro), siRNA knockdown with IFN-β promoter reporter readout, MAVS protein level measurement\",\n      \"pmids\": [\"19734229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSMA7-MAVS interaction requires the assembled 20S proteasome was not tested\", \"E3 ligase mediating MAVS ubiquitination in this context not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"EMAP-II was found to interact with cytoplasmic PSMA7 after integrin-mediated internalization, accelerating HIF-1α degradation under hypoxia and linking extracellular signals to PSMA7-dependent proteasome targeting of HIF-1α.\",\n      \"evidence\": \"Co-immunoprecipitation, integrin receptor binding, HIF-1α degradation and angiogenic sprouting assays\",\n      \"pmids\": [\"19362550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to define binding interface\", \"Mechanism by which EMAP-II binding to PSMA7 enhances HIF-1α degradation not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"PSMA7 was shown to interact with NOD1 and promote its proteasome-dependent degradation, suppressing NF-κB activation and apoptosis — establishing a second innate immune receptor targeted by PSMA7.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, NF-κB reporter assay, RNAi knockdown\",\n      \"pmids\": [\"23839082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for NOD1 ubiquitination not identified\", \"Whether PSMA7-NOD1 interaction is direct or requires adaptor proteins was not resolved in mammalian cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"BRCA1 was identified as the E3 ligase that ubiquitinates PSMA7 for proteasomal self-degradation, and c-Abl/Arg phosphorylation at Tyr-106 was shown to block this ubiquitination, revealing a feedback loop that tunes total cellular proteasome abundance and oxidative stress resilience.\",\n      \"evidence\": \"Ubiquitination reconstitution, BRCA1 co-IP and functional assay, Y106 mutagenesis, c-Abl/Arg knockout, oxidative stress challenge\",\n      \"pmids\": [\"25620702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other proteasome subunits are similarly regulated by BRCA1 was not tested\", \"Structural basis for how Y106 phosphorylation blocks BRCA1-mediated ubiquitination unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PSMA7 knockdown in cervical cancer cells reduced 20S proteasome activity and altered p53, p27, and VEGF levels, causing G0/G1 arrest and apoptosis, reinforcing its essential role in maintaining proteasome-dependent cell cycle progression.\",\n      \"evidence\": \"shRNA knockdown in SiHa cells, proteasome activity assay, Western blot, flow cytometry for cell cycle and apoptosis\",\n      \"pmids\": [\"29247526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effects are correlative; direct substrates responsible for cell cycle arrest not identified\", \"Single cell line without rescue experiment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"UCHL1 was found to maintain PSMA7 levels in ovarian carcinoma, adding a deubiquitinase-dependent layer to PSMA7 stability regulation and linking it to mTORC1 signaling via proteasome homeostasis.\",\n      \"evidence\": \"UCHL1 RNAi, proteasome activity and polyubiquitin accumulation assays, mTORC1 activity readout, xenograft model\",\n      \"pmids\": [\"33753553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between UCHL1 and PSMA7 not demonstrated by co-IP\", \"Whether UCHL1 directly deubiquitinates PSMA7 or acts indirectly was not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether PSMA7's diverse moonlighting functions (Rab7 binding, HCV IRES translation, MAVS/NOD1 targeting) are performed as a free monomer or within assembled proteasome complexes, and what structural features distinguish these contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PSMA7 moonlighting interfaces\", \"Relative abundance of free vs. assembled PSMA7 not quantified in relevant cell types\", \"Whether Y153 or Y106 phosphorylation affects non-proteasomal functions is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"20S proteasome\"\n    ],\n    \"partners\": [\n      \"MAVS\",\n      \"RAB7A\",\n      \"HIF1A\",\n      \"NOD1\",\n      \"ABL1\",\n      \"ABL2\",\n      \"BRCA1\",\n      \"UCHL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMA7 (alpha4/XAPC7) is a structural subunit of the 20S proteasome core particle that contributes to ubiquitin-dependent proteolysis and whose own abundance is tightly regulated by c-Abl/Arg-mediated phosphorylation at Y106 and Y153, which antagonizes BRCA1-dependent ubiquitination and proteasomal auto-degradation of PSMA7, thereby tuning cellular proteasome levels under basal and oxidative-stress conditions [PMID:25620702, PMID:16678104]. Beyond its canonical role in proteostasis, PSMA7 negatively regulates innate immune signaling by binding MAVS to promote its degradation and suppress RIG-I–dependent IFN-β production [PMID:19734229], and by binding NOD1 to direct its proteasome-dependent turnover, attenuating NF-κB activation and apoptosis [PMID:23839082]. PSMA7 also interacts with Rab7 on late endosomes to negatively regulate EGFR endocytic trafficking [PMID:14998988], cooperates with EMAP-II to accelerate HIF-1α degradation under hypoxia [PMID:11389899, PMID:19362550], and is specifically required for HCV IRES-mediated translation [PMID:11713272].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing PSMA7 as a core component of the 20S proteasome resolved the identity and enzymatic mechanism of the particle's alpha-ring subunits, showing that the 20S core uses threonine-based peptidase activities and assembles with the 19S regulator to form the 26S proteasome.\",\n      \"evidence\": \"Biochemical purification, peptidase activity assays, and structural characterization of proteasome complexes\",\n      \"pmids\": [\"8811196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Role of individual alpha subunits versus the assembled ring in substrate recognition was not resolved\",\n        \"Post-translational regulation of PSMA7 itself was unknown\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that PSMA7 physically interacts with HIF-1α and inhibits its transactivation, and that PSMA7 is required for HCV IRES-mediated translation, revealed non-canonical functions for a proteasome subunit beyond bulk proteolysis.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, transactivation reporters for HIF-1α; ribozyme knockdown and bicistronic IRES reporters in Huh7 cells for HCV IRES\",\n      \"pmids\": [\"11389899\", \"11713272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking PSMA7 to HCV IRES translation remained unclear\",\n        \"Whether PSMA7–HIF-1α interaction operates independently of assembled proteasome was not determined\",\n        \"No in vivo validation for HCV IRES finding\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying PSMA7 as a Rab7-binding partner recruited to multivesicular late endosomes established a proteasome-subunit-mediated negative regulatory step in late endocytic trafficking of receptors such as EGFR.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mapping, subcellular fractionation, endocytic transport assays with Rab7 rescue\",\n      \"pmids\": [\"14998988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PSMA7 acts on Rab7 as part of an assembled proteasome or as a free subunit was not resolved\",\n        \"Physiological contexts requiring PSMA7–Rab7 interaction (e.g., growth factor signaling) were unexplored\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that c-Abl/Arg phosphorylate PSMA7 at Y153 and that this modification compromises proteasome activity and cell-cycle progression revealed the first signaling-dependent post-translational control of a proteasome alpha subunit.\",\n      \"evidence\": \"In vitro kinase assay, Y153F mutagenesis, proteasome activity assays, cell cycle analysis\",\n      \"pmids\": [\"16678104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Y153 phosphorylation structurally impairs proteasome activity was unknown\",\n        \"Relationship between Y153 and other phosphorylation sites on PSMA7 was not examined\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Three studies collectively expanded PSMA7's non-canonical roles: PSMA7 binds MAVS and promotes its degradation to suppress RIG-I/IFN-β signaling; EMAP-II engagement promotes PSMA7-dependent HIF-1α degradation under hypoxia; and PSMA7 depletion reduces tumorigenicity in colorectal cancer cells partly through CD44.\",\n      \"evidence\": \"Reciprocal co-IP and GST pulldown for MAVS, gain/loss-of-function IFN-β and NF-κB reporters, viral infection assays; co-IP and HIF-1α degradation assays for EMAP-II; shRNA xenograft and invasion assays for tumor phenotype\",\n      \"pmids\": [\"19734229\", \"19362550\", \"19787246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PSMA7–MAVS interaction is direct or occurs within an assembled proteasome was not distinguished\",\n        \"Mechanism by which PSMA7 depletion reduces CD44 was correlative\",\n        \"In vivo immune phenotype of PSMA7 loss was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of NOD1 as a direct PSMA7 interactor whose proteasome-dependent degradation is promoted by PSMA7 broadened the gene's role in innate immunity from antiviral (MAVS) to antibacterial (NOD1) pathways.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, ubiquitin assays, NF-κB reporter, apoptosis assays, siRNA knockdown\",\n      \"pmids\": [\"23839082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"E3 ligase responsible for NOD1 ubiquitination downstream of PSMA7 was not identified\",\n        \"Physiological relevance in pathogen challenge models was not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Elucidating the full regulatory circuit — BRCA1 ubiquitinates PSMA7 for proteasomal degradation, and c-Abl/Arg phosphorylation at Y106 antagonizes this — established how cells tune total proteasome abundance and explained compensatory proteasome upregulation during oxidative stress.\",\n      \"evidence\": \"Ubiquitination assays identifying BRCA1 as E3, Y106 mutagenesis, c-Abl/Arg RNAi and knockout, proteasome abundance quantification, oxidative stress experiments\",\n      \"pmids\": [\"25620702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other E3 ligases contribute to PSMA7 turnover was not addressed\",\n        \"Structural basis for how Y106 phosphorylation blocks BRCA1 recognition is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing PSMA7 within a UCHL1–PSMA7–APEH proteostasis axis in ovarian cancer showed that upstream deubiquitinase activity controls PSMA7 expression, linking PSMA7 to mTORC1 signaling and the unfolded protein response.\",\n      \"evidence\": \"siRNA/shRNA knockdown, proteasome activity assays, Western blot for polyubiquitinated proteins, mTORC1 activity assay, xenograft model\",\n      \"pmids\": [\"33753553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether UCHL1 directly deubiquitinates PSMA7 or acts indirectly through transcriptional regulation was not resolved\",\n        \"Generalizability beyond high-grade serous ovarian carcinoma is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the non-canonical functions of PSMA7 (MAVS/NOD1 degradation, Rab7-mediated endosomal regulation, HCV IRES translation) are executed by free PSMA7 subunits or by PSMA7 within assembled proteasome complexes, and no structural model exists for PSMA7 interactions with its non-proteasomal partners.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Free-subunit versus assembled-proteasome distinction for non-canonical activities\",\n        \"Structural basis of PSMA7 interactions with MAVS, NOD1, and Rab7\",\n        \"In vivo immune and endosomal phenotypes of conditional PSMA7 loss\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 9, 10]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\n      \"20S proteasome\",\n      \"26S proteasome\"\n    ],\n    \"partners\": [\n      \"RAB7A\",\n      \"MAVS\",\n      \"NOD1\",\n      \"ABL1\",\n      \"ABL2\",\n      \"BRCA1\",\n      \"HIF1A\",\n      \"AIMP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}