{"gene":"PSMA7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"PSMA7 (XAPC7) interacts specifically with the GTP-bound form of Rab7 via its C-terminus (interacting with the N-terminus of Rab7), and is recruited to multivesicular late endosomes through this interaction. XAPC7 was not found on early or recycling endosomes. Overexpression of XAPC7 impaired late endocytic transport of membrane proteins including EGFR, and this impairment was partially rescued by co-expression of wild-type Rab7, establishing a negative regulatory role for XAPC7 in late endocytic transport.","method":"Co-immunoprecipitation, GST pulldown, domain-mapping mutagenesis, fluorescence microscopy/subcellular fractionation, functional endocytic transport assays with overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus pulldown with domain mapping, functional rescue with wild-type Rab7, localization studies with multiple orthogonal methods in one rigorous study","pmids":["14998988"],"is_preprint":false},{"year":2001,"finding":"PSMA7 interacts with two subdomains of HIF-1alpha and inhibits HIF-1alpha transactivation function under both normoxic and hypoxia-mimicking conditions; this regulatory effect is associated with the proteasome pathway.","method":"Co-immunoprecipitation, yeast two-hybrid or pulldown (interaction mapping), transactivation reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus functional transactivation assay, single lab, two orthogonal methods","pmids":["11389899"],"is_preprint":false},{"year":2001,"finding":"PSMA7 is required for HCV IRES-mediated translation. Ribozyme-mediated knockdown of PSMA7 mRNA inhibited HCV IRES activity in reporter cell systems, and the proteasome inhibitor MG132 exerted a dose-dependent inhibitory effect on HCV IRES-mediated translation but not on cap-dependent translation. This establishes a specific role for PSMA7 in HCV IRES-dependent translation.","method":"Ribozyme-based knockdown of PSMA7 in HeLa and Huh7 reporter cell lines, pharmacological proteasome inhibition (MG132), bicistronic reporter assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with multiple ribozymes plus pharmacological inhibition, two orthogonal methods, single lab","pmids":["11713272"],"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 mutant PSMA7(Y153F) display impaired G1/S and S/G2 cell cycle progression.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y153F), cell cycle analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, Co-IP, and defined cell cycle phenotype from phosphorylation mutant, multiple orthogonal methods in one study","pmids":["16678104"],"is_preprint":false},{"year":2009,"finding":"PSMA7 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 and reduces endogenous MAVS abundance. Conversely, siRNA-mediated depletion of PSMA7 enhances virus-induced type I IFN production and reduces virus replication. Virus infection transiently increases endogenous PSMA7 protein levels, suggesting PSMA7 functions as a negative regulator of MAVS-mediated innate immunity.","method":"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, IFN-beta promoter reporter assay, viral replication assay, immunoblotting for MAVS abundance","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with multiple functional readouts (IFN production, viral replication, MAVS degradation), multiple orthogonal methods","pmids":["19734229"],"is_preprint":false},{"year":2009,"finding":"EMAP-II binds to cell surface alpha5beta1 integrin on endothelial cells, is internalized, and then interacts with cytoplasmic PSMA7 (a proteasome component). This interaction increases HIF-1alpha degradation under hypoxic conditions, resulting in inhibition of HIF-1alpha-mediated transcriptional activity and angiogenic sprouting.","method":"Co-immunoprecipitation, binding/internalization assays, HIF-1alpha stability/degradation assays, angiogenic sprouting assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus functional HIF-1alpha degradation and angiogenesis assays, single lab","pmids":["19362550"],"is_preprint":false},{"year":2013,"finding":"PSMA7 associates with NOD1 (nucleotide-binding oligomerization domain-containing protein 1) as determined by yeast two-hybrid screening, 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 knockdown of PSMA7 enhances NOD1 activity.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, Western blotting, ubiquitin assay, NF-κB reporter assay, apoptosis assay","journal":"Cellular physiology and biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent interaction methods (Y2H, Co-IP, GST pulldown) plus functional assays for NOD1 pathway activity and proteasome-dependent degradation","pmids":["23839082"],"is_preprint":false},{"year":2015,"finding":"PSMA7 is subject to ubiquitination and proteasomal degradation. BRCA1 functions specifically as the E3 ubiquitin ligase for PSMA7 ubiquitination. Phosphorylation of PSMA7 at Y106 by c-Abl/Arg suppresses this ubiquitination and degradation, thereby stabilizing PSMA7. c-Abl/Arg regulates cellular proteasome abundance by controlling PSMA7 subunit supply. In response to oxidative stress, c-Abl-mediated upregulation of proteasome levels compensates for ROS-induced proteasomal activity impairment.","method":"Ubiquitination assay, co-immunoprecipitation, siRNA/shRNA knockdown, site-directed mutagenesis (Y106), proteasome activity measurement, oxidative stress treatment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination with identified E3 ligase (BRCA1), phospho-site mutagenesis, proteasome abundance measurements in multiple genetic models (RNAi KD and KO cells)","pmids":["25620702"],"is_preprint":false},{"year":2005,"finding":"XAPC7 (PSMA7) directly interacts with Rab7 GTPase; the interaction was validated and domain requirements confirmed. XAPC7 associates with the 20S proteasome and participates in endocytic trafficking machinery through this Rab7 interaction, providing a molecular link between the endocytic and cytosolic degradative machineries.","method":"Co-immunoprecipitation, GST pulldown, 20S proteasome association assays, endosome fractionation","journal":"Methods in enzymology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — confirmatory pulldown and Co-IP methods reporting domain requirements, single lab, largely replicating and extending the 2004 JBC study","pmids":["16473627"],"is_preprint":false},{"year":2009,"finding":"shRNA-mediated depletion of PSMA7 in colorectal cancer RKO cells inhibited anchorage-independent growth, cell invasion, and migration, and strongly suppressed in vivo tumorigenicity. These effects were associated with inhibition of CD44 expression, suggesting PSMA7 promotes cancer progression at least partly through regulation of CD44.","method":"shRNA knockdown, anchorage-independent growth assay, Transwell invasion/migration assay, xenograft tumor model, immunoblotting for CD44","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotypes plus mechanistic link to CD44, single lab","pmids":["19787246"],"is_preprint":false},{"year":2021,"finding":"UCHL1 (deubiquitinase) maintains protein homeostasis in high-grade serous ovarian carcinoma through a PSMA7-APEH-proteasome axis. Silencing UCHL1 reduces PSMA7 and APEH expression, resulting in decreased proteasome activity, impaired protein degradation, accumulation of polyubiquitinated proteins, and abrogated cancer cell growth.","method":"siRNA/shRNA knockdown of UCHL1, proteasome activity assay, immunoblotting for PSMA7/APEH/polyubiquitinated proteins, xenograft in vivo growth assay, transcriptional profiling","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss-of-function with multiple readouts (proteasome activity, protein accumulation, in vivo growth), single lab","pmids":["33753553"],"is_preprint":false},{"year":2018,"finding":"shRNA-mediated silencing of PSMA7 in cervical cancer SiHa cells decreased 20S proteasome activity, reduced PSMA7, ubiquitin, p53, and VEGF expression, increased p27 expression, inhibited cell proliferation and S-phase entry, promoted G0/G1 arrest, and increased apoptosis, demonstrating that PSMA7 regulates the ubiquitin-proteasome pathway to control cell cycle and VEGF expression.","method":"shRNA knockdown, immunofluorescence for 20S proteasome activity, RT-qPCR, Western blot, MTT proliferation assay, flow cytometry for cell cycle and apoptosis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with multiple functional readouts (activity assay, cell cycle, apoptosis), single lab","pmids":["29247526"],"is_preprint":false},{"year":2011,"finding":"XAPC7 (PSMA7) protein is predominantly cytoplasmic in 786-O and Chang liver cell lines, but is distributed in both cytoplasm and nucleus in 293T cells, demonstrating cell-line-dependent subcellular localization of PSMA7.","method":"Eukaryotic expression of DsRed1-XAPC7 fusion protein, fluorescence microscopy in three cell lines","journal":"Xi bao yu fen zi mian yi xue za zhi (Chinese journal of cellular and molecular immunology)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single fluorescence localization experiment without functional consequence, single lab","pmids":["21557907"],"is_preprint":false},{"year":2025,"finding":"Melittin suppresses NSCLC cell metastasis by targeting USP10 (a deubiquitinase) and promoting RNF20-mediated ubiquitination and degradation of PSMA7. Co-IP experiments confirmed that PSMA7 interacts with both USP10 and RNF20. PSMA7 overexpression reversed the inhibitory effect of melittin on NSCLC metastasis in vitro, placing PSMA7 downstream of the USP10/RNF20 ubiquitination axis in EMT regulation.","method":"Co-immunoprecipitation, proteomics, cycloheximide chase, MG132 proteasome inhibitor assay, PSMA7 overexpression rescue, Transwell/wound healing migration assays, in vivo metastasis model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for USP10 and RNF20 interactions plus proteasomal degradation assays and functional rescue, single lab, multiple orthogonal methods","pmids":["41254650"],"is_preprint":false},{"year":2025,"finding":"CRISPR screening in zebrafish embryos identified PSMA7 as part of a proteasome factor subnetwork (with POMP, PSMA6, PSMD3, PSMD6) required for heart development, based on protein-protein interaction network analysis and functional CRISPR screening.","method":"Systems genetics (PPI network analysis), CRISPR-based screening in zebrafish embryos","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPR screen identifies candidate role in heart development but mechanistic follow-up focused on pomp and psmd6, not psma7 specifically; single lab, preliminary evidence for PSMA7","pmids":[],"is_preprint":true}],"current_model":"PSMA7 is an alpha-type (alpha4) subunit of the 20S proteasome that functions beyond passive proteolysis: it is phosphorylated at Tyr-153 and Tyr-106 by c-Abl/Arg tyrosine kinases, which both inhibits proteasome-dependent proteolysis and prevents BRCA1-mediated ubiquitination and degradation of PSMA7 itself, thereby regulating cellular proteasome abundance; it interacts with and promotes degradation of MAVS (negatively regulating antiviral innate immune signaling), HIF-1alpha (suppressing hypoxic transcription), and NOD1 (suppressing NF-κB and apoptosis); it binds specifically to the Rab7 GTPase and is recruited to late endosomes where it negatively regulates late endocytic transport; it is required for HCV IRES-mediated translation; and its protein stability is controlled by the deubiquitinase USP10 and the E3 ligase RNF20."},"narrative":{"mechanistic_narrative":"PSMA7 is an alpha-type subunit of the 20S proteasome that couples core proteolytic capacity to specific regulatory circuits in trafficking, signaling, and stress responses rather than acting solely as a passive structural component [PMID:16678104, PMID:25620702]. Its activity is gated by tyrosine phosphorylation: c-Abl and Arg kinases associate with PSMA7 and phosphorylate it at Tyr-153, which compromises proteasome-dependent proteolysis and is required for normal G1/S and S/G2 cell cycle progression [PMID:16678104]; phosphorylation at Tyr-106 blocks BRCA1-mediated ubiquitination and degradation of PSMA7 itself, stabilizing the subunit and allowing c-Abl to raise cellular proteasome abundance to compensate for oxidative-stress-induced loss of proteasome activity [PMID:25620702]. Through its association with the 20S proteasome, PSMA7 promotes proteasome-dependent turnover of multiple regulatory substrates: it associates with MAVS and suppresses RIG-I/MAVS-driven type I interferon production, acting as a negative regulator of antiviral innate immunity [PMID:19734229]; it binds HIF-1alpha and inhibits its transactivation function, an effect amplified when internalized EMAP-II engages cytoplasmic PSMA7 to drive HIF-1alpha degradation and limit angiogenic sprouting [PMID:11389899, PMID:19362550]; and it associates with NOD1 to downregulate NOD1-mediated NF-kB activation and apoptosis [PMID:23839082]. Independently of bulk degradation, GTP-bound Rab7 recruits PSMA7 to multivesicular late endosomes, where PSMA7 negatively regulates late endocytic transport of membrane proteins such as EGFR, linking proteasomal machinery to the endocytic pathway [PMID:14998988, PMID:16473627]. PSMA7 is also required specifically for HCV IRES-mediated translation [PMID:11713272]. In cancer models, PSMA7 supports proliferation, invasion, and tumorigenicity, and its abundance is set by opposing deubiquitinase and E3 ligase activities, including a UCHL1-PSMA7-APEH proteasome axis and a USP10/RNF20 axis controlling PSMA7 stability [PMID:19787246, PMID:33753553, PMID:41254650].","teleology":[{"year":2001,"claim":"Established that PSMA7 is not merely a degradation subunit but can act as a negative regulator of a specific transcription factor, linking the proteasome to hypoxic signaling.","evidence":"Co-IP/interaction mapping and transactivation reporter assays for HIF-1alpha","pmids":["11389899"],"confidence":"Medium","gaps":["Did not define whether inhibition is via direct HIF-1alpha degradation or sequestration","Single lab, no in vivo validation"]},{"year":2001,"claim":"Showed PSMA7 has a translation-related role, being specifically required for HCV IRES-dependent but not cap-dependent translation.","evidence":"Ribozyme knockdown plus MG132 inhibition in bicistronic reporter cell lines","pmids":["11713272"],"confidence":"Medium","gaps":["Molecular mechanism by which PSMA7 supports IRES activity not resolved","No direct PSMA7-IRES or PSMA7-ribosome interaction shown"]},{"year":2004,"claim":"Resolved a non-proteolytic role by showing GTP-Rab7 recruits PSMA7 to late endosomes to negatively regulate endocytic transport, connecting proteasome subunits to membrane trafficking.","evidence":"Reciprocal Co-IP, GST pulldown with domain mapping, microscopy/fractionation, and endocytic transport assays with Rab7 rescue","pmids":["14998988"],"confidence":"High","gaps":["Whether the 20S proteasome itself is required at endosomes vs free PSMA7 unclear","Endogenous-level (non-overexpression) confirmation limited"]},{"year":2005,"claim":"Confirmed and extended the Rab7 interaction, positioning PSMA7 as a molecular link between endocytic and cytosolic degradative machineries.","evidence":"Co-IP, GST pulldown, 20S proteasome association and endosome fractionation","pmids":["16473627"],"confidence":"Medium","gaps":["Largely confirmatory of the 2004 study","Functional consequence of proteasome-endosome coupling not independently tested"]},{"year":2006,"claim":"Identified a kinase-controlled switch: c-Abl/Arg phosphorylation of PSMA7 at Tyr-153 modulates proteasome proteolysis and cell cycle progression, establishing post-translational regulation of proteasome function through this subunit.","evidence":"Co-IP, in vitro kinase assay, Y153F mutagenesis, cell cycle analysis","pmids":["16678104"],"confidence":"High","gaps":["Mechanism by which Tyr-153 phosphorylation alters 20S catalytic activity not structurally defined","Direct substrates whose turnover is altered not enumerated"]},{"year":2009,"claim":"Defined PSMA7 as a negative regulator of antiviral innate immunity by promoting MAVS turnover and dampening type I IFN responses.","evidence":"Reciprocal Co-IP, siRNA knockdown, IFN-beta reporter, viral replication and MAVS abundance immunoblotting","pmids":["19734229"],"confidence":"High","gaps":["Whether PSMA7 acts through full 20S/26S degradation or a direct effect on MAVS unresolved","Upstream signal triggering virus-induced PSMA7 increase unknown"]},{"year":2009,"claim":"Connected extracellular EMAP-II/integrin signaling to PSMA7-driven HIF-1alpha degradation, providing a physiological route to suppress angiogenesis.","evidence":"Co-IP, internalization assays, HIF-1alpha degradation and angiogenic sprouting assays","pmids":["19362550"],"confidence":"Medium","gaps":["How internalized EMAP-II reaches cytoplasmic PSMA7 not mechanistically defined","Single lab"]},{"year":2009,"claim":"Demonstrated a pro-tumorigenic role for PSMA7 in colorectal cancer, linking its loss to suppressed growth, invasion, and CD44 expression.","evidence":"shRNA knockdown with anchorage-independent growth, invasion/migration, xenograft, and CD44 immunoblotting","pmids":["19787246"],"confidence":"Medium","gaps":["Mechanistic link from PSMA7 to CD44 not established","Whether effect reflects general proteasome dependence vs PSMA7-specific function unclear"]},{"year":2013,"claim":"Identified NOD1 as a PSMA7 partner and showed proteasome-dependent downregulation of NOD1 suppresses NF-kB and apoptosis, extending PSMA7's immune-regulatory range.","evidence":"Y2H, Co-IP, GST pulldown, ubiquitin assay, NF-kB reporter and apoptosis assays","pmids":["23839082"],"confidence":"High","gaps":["E3 ligase directing NOD1 ubiquitination not identified","In vivo relevance to bacterial sensing not tested"]},{"year":2015,"claim":"Established a feedback loop controlling proteasome abundance: BRCA1 ubiquitinates PSMA7 for degradation, while c-Abl/Arg phosphorylation at Tyr-106 stabilizes it, enabling proteasome upregulation under oxidative stress.","evidence":"In vitro ubiquitination with BRCA1, Y106 mutagenesis, RNAi/KO models, proteasome activity and oxidative stress assays","pmids":["25620702"],"confidence":"High","gaps":["How PSMA7 subunit supply quantitatively sets assembled proteasome levels not fully defined","Crosstalk between Tyr-153 and Tyr-106 phosphorylation unresolved"]},{"year":2018,"claim":"Showed PSMA7 loss reduces 20S proteasome activity and shifts cell-cycle/apoptosis balance in cervical cancer, reinforcing its role in proteasome-dependent proliferation control.","evidence":"shRNA knockdown, proteasome activity, RT-qPCR/Western, proliferation, cell-cycle and apoptosis flow cytometry","pmids":["29247526"],"confidence":"Medium","gaps":["Changes in p53/p27/VEGF may be downstream of general proteasome loss","No direct substrate causality demonstrated"]},{"year":2021,"claim":"Placed PSMA7 within a UCHL1-PSMA7-APEH axis sustaining protein homeostasis and proteasome activity in ovarian carcinoma.","evidence":"UCHL1 knockdown, proteasome activity, polyubiquitin/PSMA7/APEH immunoblotting, xenograft, transcriptional profiling","pmids":["33753553"],"confidence":"Medium","gaps":["Whether UCHL1 directly deubiquitinates PSMA7 not shown","Mechanism coupling APEH to proteasome activity unclear"]},{"year":2025,"claim":"Identified opposing deubiquitinase/E3 ligase control of PSMA7 stability (USP10 stabilizing, RNF20 degrading) downstream of melittin in NSCLC metastasis and EMT.","evidence":"Co-IP for USP10 and RNF20, CHX chase, MG132, PSMA7 overexpression rescue, migration and in vivo metastasis assays","pmids":["41254650"],"confidence":"Medium","gaps":["Direct ubiquitination of PSMA7 by RNF20 not reconstituted","How PSMA7 promotes EMT mechanistically not defined"]},{"year":2025,"claim":"Implicated PSMA7 as part of a proteasome subnetwork required for heart development.","evidence":"PPI network analysis and CRISPR screening in zebrafish embryos (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint; PSMA7-specific mechanistic follow-up focused on other subunits","No tissue-specific mechanism for PSMA7 in cardiogenesis established"]},{"year":null,"claim":"It remains unresolved whether PSMA7's many substrate-specific regulatory effects (MAVS, HIF-1alpha, NOD1) occur through assembled 20S/26S proteasome activity or through distinct functions of the free subunit, and how tyrosine phosphorylation structurally reprograms proteasome activity.","evidence":"No timeline study directly distinguishes free-subunit vs assembled-proteasome mechanisms across these substrates","pmids":[],"confidence":"Low","gaps":["No structural model of phospho-PSMA7 in the proteasome","Substrate-selectivity mechanism unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,11]}],"complexes":["20S proteasome"],"partners":["RAB7A","MAVS","HIF1A","NOD1","ABL1","BRCA1","USP10","RNF20"],"other_free_text":[]}},"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":"28523434","id":"PMC_28523434","title":"Salivary exosomal PSMA7: a promising biomarker of inflammatory bowel disease.","date":"2017","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/28523434","citation_count":113,"is_preprint":false},{"pmid":"28199850","id":"PMC_28199850","title":"Flow Dynamics and HSPC Homing in Bone Marrow Microvessels.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28199850","citation_count":108,"is_preprint":false},{"pmid":"33651979","id":"PMC_33651979","title":"Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production.","date":"2021","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/33651979","citation_count":93,"is_preprint":false},{"pmid":"32176506","id":"PMC_32176506","title":"Mechanical Properties Determination of DMPC, DPPC, DSPC, and HSPC Solid-Ordered Bilayers.","date":"2020","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/32176506","citation_count":87,"is_preprint":false},{"pmid":"33620431","id":"PMC_33620431","title":"In vivo HSPC gene therapy with base editors allows for efficient reactivation of fetal γ-globin in β-YAC mice.","date":"2021","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/33620431","citation_count":79,"is_preprint":false},{"pmid":"19734229","id":"PMC_19734229","title":"Negative regulation of MAVS-mediated innate immune response by PSMA7.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19734229","citation_count":77,"is_preprint":false},{"pmid":"14998988","id":"PMC_14998988","title":"The proteasome alpha-subunit XAPC7 interacts specifically with Rab7 and late endosomes.","date":"2004","source":"The Journal of biological 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specifically with the GTP-bound form of Rab7 via its C-terminus (interacting with the N-terminus of Rab7), and is recruited to multivesicular late endosomes through this interaction. XAPC7 was not found on early or recycling endosomes. Overexpression of XAPC7 impaired late endocytic transport of membrane proteins including EGFR, and this impairment was partially rescued by co-expression of wild-type Rab7, establishing a negative regulatory role for XAPC7 in late endocytic transport.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, domain-mapping mutagenesis, fluorescence microscopy/subcellular fractionation, functional endocytic transport assays with overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus pulldown with domain mapping, functional rescue with wild-type Rab7, localization studies with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"14998988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 interacts with two subdomains of HIF-1alpha and inhibits HIF-1alpha transactivation function under both normoxic and hypoxia-mimicking conditions; this regulatory effect is associated with the proteasome pathway.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid or pulldown (interaction mapping), transactivation reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus functional transactivation assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"11389899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSMA7 is required for HCV IRES-mediated translation. Ribozyme-mediated knockdown of PSMA7 mRNA inhibited HCV IRES activity in reporter cell systems, and the proteasome inhibitor MG132 exerted a dose-dependent inhibitory effect on HCV IRES-mediated translation but not on cap-dependent translation. This establishes a specific role for PSMA7 in HCV IRES-dependent translation.\",\n      \"method\": \"Ribozyme-based knockdown of PSMA7 in HeLa and Huh7 reporter cell lines, pharmacological proteasome inhibition (MG132), bicistronic reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with multiple ribozymes plus pharmacological inhibition, two orthogonal methods, single lab\",\n      \"pmids\": [\"11713272\"],\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 mutant PSMA7(Y153F) display impaired G1/S and S/G2 cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y153F), cell cycle analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, Co-IP, and defined cell cycle phenotype from phosphorylation mutant, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16678104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSMA7 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 and reduces endogenous MAVS abundance. Conversely, siRNA-mediated depletion of PSMA7 enhances virus-induced type I IFN production and reduces virus replication. Virus infection transiently increases endogenous PSMA7 protein levels, suggesting PSMA7 functions as a negative regulator of MAVS-mediated innate immunity.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, IFN-beta promoter reporter assay, viral replication assay, immunoblotting for MAVS abundance\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with multiple functional readouts (IFN production, viral replication, MAVS degradation), multiple orthogonal methods\",\n      \"pmids\": [\"19734229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EMAP-II binds to cell surface alpha5beta1 integrin on endothelial cells, is internalized, and then interacts with cytoplasmic PSMA7 (a proteasome component). This interaction increases HIF-1alpha degradation under hypoxic conditions, resulting in inhibition of HIF-1alpha-mediated transcriptional activity and angiogenic sprouting.\",\n      \"method\": \"Co-immunoprecipitation, binding/internalization assays, HIF-1alpha stability/degradation assays, angiogenic sprouting assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus functional HIF-1alpha degradation and angiogenesis assays, single lab\",\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) as determined by yeast two-hybrid screening, 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 knockdown of PSMA7 enhances NOD1 activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pulldown, Western blotting, ubiquitin assay, NF-κB reporter assay, apoptosis assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent interaction methods (Y2H, Co-IP, GST pulldown) plus functional assays for NOD1 pathway activity and proteasome-dependent degradation\",\n      \"pmids\": [\"23839082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMA7 is subject to ubiquitination and proteasomal degradation. BRCA1 functions specifically as the E3 ubiquitin ligase for PSMA7 ubiquitination. Phosphorylation of PSMA7 at Y106 by c-Abl/Arg suppresses this ubiquitination and degradation, thereby stabilizing PSMA7. c-Abl/Arg regulates cellular proteasome abundance by controlling PSMA7 subunit supply. In response to oxidative stress, c-Abl-mediated upregulation of proteasome levels compensates for ROS-induced proteasomal activity impairment.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, siRNA/shRNA knockdown, site-directed mutagenesis (Y106), proteasome activity measurement, oxidative stress treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination with identified E3 ligase (BRCA1), phospho-site mutagenesis, proteasome abundance measurements in multiple genetic models (RNAi KD and KO cells)\",\n      \"pmids\": [\"25620702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"XAPC7 (PSMA7) directly interacts with Rab7 GTPase; the interaction was validated and domain requirements confirmed. XAPC7 associates with the 20S proteasome and participates in endocytic trafficking machinery through this Rab7 interaction, providing a molecular link between the endocytic and cytosolic degradative machineries.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, 20S proteasome association assays, endosome fractionation\",\n      \"journal\": \"Methods in enzymology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — confirmatory pulldown and Co-IP methods reporting domain requirements, single lab, largely replicating and extending the 2004 JBC study\",\n      \"pmids\": [\"16473627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"shRNA-mediated depletion of PSMA7 in colorectal cancer RKO cells inhibited anchorage-independent growth, cell invasion, and migration, and strongly suppressed in vivo tumorigenicity. These effects were associated with inhibition of CD44 expression, suggesting PSMA7 promotes cancer progression at least partly through regulation of CD44.\",\n      \"method\": \"shRNA knockdown, anchorage-independent growth assay, Transwell invasion/migration assay, xenograft tumor model, immunoblotting for CD44\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular and in vivo phenotypes plus mechanistic link to CD44, single lab\",\n      \"pmids\": [\"19787246\"],\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. Silencing UCHL1 reduces PSMA7 and APEH expression, resulting in decreased proteasome activity, impaired protein degradation, accumulation of polyubiquitinated proteins, and abrogated cancer cell growth.\",\n      \"method\": \"siRNA/shRNA knockdown of UCHL1, proteasome activity assay, immunoblotting for PSMA7/APEH/polyubiquitinated proteins, xenograft in vivo growth assay, transcriptional profiling\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss-of-function with multiple readouts (proteasome activity, protein accumulation, in vivo growth), single lab\",\n      \"pmids\": [\"33753553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"shRNA-mediated silencing of PSMA7 in cervical cancer SiHa cells decreased 20S proteasome activity, reduced PSMA7, ubiquitin, p53, and VEGF expression, increased p27 expression, inhibited cell proliferation and S-phase entry, promoted G0/G1 arrest, and increased apoptosis, demonstrating that PSMA7 regulates the ubiquitin-proteasome pathway to control cell cycle and VEGF expression.\",\n      \"method\": \"shRNA knockdown, immunofluorescence for 20S proteasome activity, RT-qPCR, Western blot, MTT proliferation assay, flow cytometry for cell cycle and apoptosis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with multiple functional readouts (activity assay, cell cycle, apoptosis), single lab\",\n      \"pmids\": [\"29247526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"XAPC7 (PSMA7) protein is predominantly cytoplasmic in 786-O and Chang liver cell lines, but is distributed in both cytoplasm and nucleus in 293T cells, demonstrating cell-line-dependent subcellular localization of PSMA7.\",\n      \"method\": \"Eukaryotic expression of DsRed1-XAPC7 fusion protein, fluorescence microscopy in three cell lines\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi (Chinese journal of cellular and molecular immunology)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single fluorescence localization experiment without functional consequence, single lab\",\n      \"pmids\": [\"21557907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Melittin suppresses NSCLC cell metastasis by targeting USP10 (a deubiquitinase) and promoting RNF20-mediated ubiquitination and degradation of PSMA7. Co-IP experiments confirmed that PSMA7 interacts with both USP10 and RNF20. PSMA7 overexpression reversed the inhibitory effect of melittin on NSCLC metastasis in vitro, placing PSMA7 downstream of the USP10/RNF20 ubiquitination axis in EMT regulation.\",\n      \"method\": \"Co-immunoprecipitation, proteomics, cycloheximide chase, MG132 proteasome inhibitor assay, PSMA7 overexpression rescue, Transwell/wound healing migration assays, in vivo metastasis model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for USP10 and RNF20 interactions plus proteasomal degradation assays and functional rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41254650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR screening in zebrafish embryos identified PSMA7 as part of a proteasome factor subnetwork (with POMP, PSMA6, PSMD3, PSMD6) required for heart development, based on protein-protein interaction network analysis and functional CRISPR screening.\",\n      \"method\": \"Systems genetics (PPI network analysis), CRISPR-based screening in zebrafish embryos\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPR screen identifies candidate role in heart development but mechanistic follow-up focused on pomp and psmd6, not psma7 specifically; single lab, preliminary evidence for PSMA7\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PSMA7 is an alpha-type (alpha4) subunit of the 20S proteasome that functions beyond passive proteolysis: it is phosphorylated at Tyr-153 and Tyr-106 by c-Abl/Arg tyrosine kinases, which both inhibits proteasome-dependent proteolysis and prevents BRCA1-mediated ubiquitination and degradation of PSMA7 itself, thereby regulating cellular proteasome abundance; it interacts with and promotes degradation of MAVS (negatively regulating antiviral innate immune signaling), HIF-1alpha (suppressing hypoxic transcription), and NOD1 (suppressing NF-κB and apoptosis); it binds specifically to the Rab7 GTPase and is recruited to late endosomes where it negatively regulates late endocytic transport; it is required for HCV IRES-mediated translation; and its protein stability is controlled by the deubiquitinase USP10 and the E3 ligase RNF20.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA7 is an alpha-type subunit of the 20S proteasome that couples core proteolytic capacity to specific regulatory circuits in trafficking, signaling, and stress responses rather than acting solely as a passive structural component [#3, #7]. Its activity is gated by tyrosine phosphorylation: c-Abl and Arg kinases associate with PSMA7 and phosphorylate it at Tyr-153, which compromises proteasome-dependent proteolysis and is required for normal G1/S and S/G2 cell cycle progression [#3]; phosphorylation at Tyr-106 blocks BRCA1-mediated ubiquitination and degradation of PSMA7 itself, stabilizing the subunit and allowing c-Abl to raise cellular proteasome abundance to compensate for oxidative-stress-induced loss of proteasome activity [#7]. Through its association with the 20S proteasome, PSMA7 promotes proteasome-dependent turnover of multiple regulatory substrates: it associates with MAVS and suppresses RIG-I/MAVS-driven type I interferon production, acting as a negative regulator of antiviral innate immunity [#4]; it binds HIF-1alpha and inhibits its transactivation function, an effect amplified when internalized EMAP-II engages cytoplasmic PSMA7 to drive HIF-1alpha degradation and limit angiogenic sprouting [#1, #5]; and it associates with NOD1 to downregulate NOD1-mediated NF-kB activation and apoptosis [#6]. Independently of bulk degradation, GTP-bound Rab7 recruits PSMA7 to multivesicular late endosomes, where PSMA7 negatively regulates late endocytic transport of membrane proteins such as EGFR, linking proteasomal machinery to the endocytic pathway [#0, #8]. PSMA7 is also required specifically for HCV IRES-mediated translation [#2]. In cancer models, PSMA7 supports proliferation, invasion, and tumorigenicity, and its abundance is set by opposing deubiquitinase and E3 ligase activities, including a UCHL1-PSMA7-APEH proteasome axis and a USP10/RNF20 axis controlling PSMA7 stability [#9, #10, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that PSMA7 is not merely a degradation subunit but can act as a negative regulator of a specific transcription factor, linking the proteasome to hypoxic signaling.\",\n      \"evidence\": \"Co-IP/interaction mapping and transactivation reporter assays for HIF-1alpha\",\n      \"pmids\": [\"11389899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define whether inhibition is via direct HIF-1alpha degradation or sequestration\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed PSMA7 has a translation-related role, being specifically required for HCV IRES-dependent but not cap-dependent translation.\",\n      \"evidence\": \"Ribozyme knockdown plus MG132 inhibition in bicistronic reporter cell lines\",\n      \"pmids\": [\"11713272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which PSMA7 supports IRES activity not resolved\", \"No direct PSMA7-IRES or PSMA7-ribosome interaction shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved a non-proteolytic role by showing GTP-Rab7 recruits PSMA7 to late endosomes to negatively regulate endocytic transport, connecting proteasome subunits to membrane trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pulldown with domain mapping, microscopy/fractionation, and endocytic transport assays with Rab7 rescue\",\n      \"pmids\": [\"14998988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the 20S proteasome itself is required at endosomes vs free PSMA7 unclear\", \"Endogenous-level (non-overexpression) confirmation limited\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Confirmed and extended the Rab7 interaction, positioning PSMA7 as a molecular link between endocytic and cytosolic degradative machineries.\",\n      \"evidence\": \"Co-IP, GST pulldown, 20S proteasome association and endosome fractionation\",\n      \"pmids\": [\"16473627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely confirmatory of the 2004 study\", \"Functional consequence of proteasome-endosome coupling not independently tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a kinase-controlled switch: c-Abl/Arg phosphorylation of PSMA7 at Tyr-153 modulates proteasome proteolysis and cell cycle progression, establishing post-translational regulation of proteasome function through this subunit.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, Y153F mutagenesis, cell cycle analysis\",\n      \"pmids\": [\"16678104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Tyr-153 phosphorylation alters 20S catalytic activity not structurally defined\", \"Direct substrates whose turnover is altered not enumerated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined PSMA7 as a negative regulator of antiviral innate immunity by promoting MAVS turnover and dampening type I IFN responses.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, IFN-beta reporter, viral replication and MAVS abundance immunoblotting\",\n      \"pmids\": [\"19734229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSMA7 acts through full 20S/26S degradation or a direct effect on MAVS unresolved\", \"Upstream signal triggering virus-induced PSMA7 increase unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected extracellular EMAP-II/integrin signaling to PSMA7-driven HIF-1alpha degradation, providing a physiological route to suppress angiogenesis.\",\n      \"evidence\": \"Co-IP, internalization assays, HIF-1alpha degradation and angiogenic sprouting assays\",\n      \"pmids\": [\"19362550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How internalized EMAP-II reaches cytoplasmic PSMA7 not mechanistically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a pro-tumorigenic role for PSMA7 in colorectal cancer, linking its loss to suppressed growth, invasion, and CD44 expression.\",\n      \"evidence\": \"shRNA knockdown with anchorage-independent growth, invasion/migration, xenograft, and CD44 immunoblotting\",\n      \"pmids\": [\"19787246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from PSMA7 to CD44 not established\", \"Whether effect reflects general proteasome dependence vs PSMA7-specific function unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified NOD1 as a PSMA7 partner and showed proteasome-dependent downregulation of NOD1 suppresses NF-kB and apoptosis, extending PSMA7's immune-regulatory range.\",\n      \"evidence\": \"Y2H, Co-IP, GST pulldown, ubiquitin assay, NF-kB reporter and apoptosis assays\",\n      \"pmids\": [\"23839082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase directing NOD1 ubiquitination not identified\", \"In vivo relevance to bacterial sensing not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a feedback loop controlling proteasome abundance: BRCA1 ubiquitinates PSMA7 for degradation, while c-Abl/Arg phosphorylation at Tyr-106 stabilizes it, enabling proteasome upregulation under oxidative stress.\",\n      \"evidence\": \"In vitro ubiquitination with BRCA1, Y106 mutagenesis, RNAi/KO models, proteasome activity and oxidative stress assays\",\n      \"pmids\": [\"25620702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSMA7 subunit supply quantitatively sets assembled proteasome levels not fully defined\", \"Crosstalk between Tyr-153 and Tyr-106 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PSMA7 loss reduces 20S proteasome activity and shifts cell-cycle/apoptosis balance in cervical cancer, reinforcing its role in proteasome-dependent proliferation control.\",\n      \"evidence\": \"shRNA knockdown, proteasome activity, RT-qPCR/Western, proliferation, cell-cycle and apoptosis flow cytometry\",\n      \"pmids\": [\"29247526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Changes in p53/p27/VEGF may be downstream of general proteasome loss\", \"No direct substrate causality demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed PSMA7 within a UCHL1-PSMA7-APEH axis sustaining protein homeostasis and proteasome activity in ovarian carcinoma.\",\n      \"evidence\": \"UCHL1 knockdown, proteasome activity, polyubiquitin/PSMA7/APEH immunoblotting, xenograft, transcriptional profiling\",\n      \"pmids\": [\"33753553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UCHL1 directly deubiquitinates PSMA7 not shown\", \"Mechanism coupling APEH to proteasome activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified opposing deubiquitinase/E3 ligase control of PSMA7 stability (USP10 stabilizing, RNF20 degrading) downstream of melittin in NSCLC metastasis and EMT.\",\n      \"evidence\": \"Co-IP for USP10 and RNF20, CHX chase, MG132, PSMA7 overexpression rescue, migration and in vivo metastasis assays\",\n      \"pmids\": [\"41254650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of PSMA7 by RNF20 not reconstituted\", \"How PSMA7 promotes EMT mechanistically not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated PSMA7 as part of a proteasome subnetwork required for heart development.\",\n      \"evidence\": \"PPI network analysis and CRISPR screening in zebrafish embryos (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; PSMA7-specific mechanistic follow-up focused on other subunits\", \"No tissue-specific mechanism for PSMA7 in cardiogenesis established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether PSMA7's many substrate-specific regulatory effects (MAVS, HIF-1alpha, NOD1) occur through assembled 20S/26S proteasome activity or through distinct functions of the free subunit, and how tyrosine phosphorylation structurally reprograms proteasome activity.\",\n      \"evidence\": \"No timeline study directly distinguishes free-subunit vs assembled-proteasome mechanisms across these substrates\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of phospho-PSMA7 in the proteasome\", \"Substrate-selectivity mechanism unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [\"20S proteasome\"],\n    \"partners\": [\"RAB7A\", \"MAVS\", \"HIF1A\", \"NOD1\", \"ABL1\", \"BRCA1\", \"USP10\", \"RNF20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}