{"gene":"PSMA5","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"Human PSMA5 (α5 subunit of the 20S proteasome) was expressed, purified, and refolded from E. coli inclusion bodies; the refolded protein exists predominantly as a tetramer as determined by gel filtration chromatography and dynamic light scattering, consistent with its role as part of the outer alpha-ring of the 20S proteasome.","method":"Recombinant protein expression, dilution refolding, size-exclusion chromatography, dynamic light scattering, gel filtration chromatography","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution and biophysical characterization in a single study, no functional mutagenesis","pmids":["15135414"],"is_preprint":false},{"year":2012,"finding":"Anti-PSMA5 polyclonal antibodies can immunoprecipitate native endogenous and overexpressed FLAG-tagged PSMA5 from human cell lines, confirming that PSMA5 exists in a native protein complex accessible to co-immunoprecipitation.","method":"Western blot, immunoprecipitation of endogenous and FLAG-tagged PSMA5 from human cell lines","journal":"Hybridoma (2005)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (immunoprecipitation), no functional follow-up","pmids":["22894781"],"is_preprint":false},{"year":2022,"finding":"PSMA5 knockdown in lung adenocarcinoma (LUAD) cells inhibited proliferation, invasion, and metastasis in vitro and in vivo, induced apoptosis, and sensitized cells to cisplatin; mechanistically, PSMA5 overexpression activated the JAK/STAT signaling pathway to suppress apoptosis, placing PSMA5 upstream of JAK/STAT in LUAD cells.","method":"siRNA knockdown, overexpression, apoptosis assays, invasion/migration assays, xenograft in vivo model, Western blot for JAK/STAT pathway components","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with multiple orthogonal readouts and in vivo validation, single lab","pmids":["35605971"],"is_preprint":false},{"year":2019,"finding":"PSMA5 knockdown in prostate cancer cells inhibited proliferation, induced apoptosis, and restricted migration and invasion; additionally, PSMA5 knockdown in bortezomib-resistant cells restored sensitivity to bortezomib, indicating PSMA5 contributes to bortezomib resistance.","method":"siRNA knockdown, CCK-8 viability assay, FACS apoptosis analysis, scratch assay, Transwell invasion assay, bortezomib resistance assay","journal":"Anti-cancer drugs","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal functional assays including drug resistance, single lab","pmids":["30807553"],"is_preprint":false},{"year":2024,"finding":"HCC cells secrete PSMA5-containing exosomes that are internalized by macrophages; exosomal PSMA5 promotes M2 macrophage polarization and activates JAK2/STAT3 signaling in macrophages, thereby facilitating HCC cell migration, invasion, and in vivo tumorigenesis. Knockdown of PSMA5 in HCC cells reduced exosomal PSMA5, blocked these effects, and suppressed tumor progression.","method":"Exosome isolation and fluorescence labeling/internalization assay, siRNA knockdown, co-culture of macrophages with HCC-derived exosomes, ELISA, qRT-PCR, IHC, Western blot for JAK2/STAT3, xenograft assay","journal":"Immunity, inflammation and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (exosome internalization, co-culture, in vivo xenograft, pathway Western blot), single lab","pmids":["38415977"],"is_preprint":false},{"year":2024,"finding":"IRF9 transcriptionally regulates PSMA5 expression; knockdown of IRF9 in RAW264.7 macrophages suppressed PSMA5 levels, altered the M1/M2 macrophage polarization ratio, and reduced pro-inflammatory cytokine secretion. In a CIA mouse model, sh-IRF9 macrophages modulated RA progression by downregulating PSMA5 and skewing macrophage polarization, placing IRF9 upstream of PSMA5 in the macrophage polarization pathway.","method":"Bioinformatics correlation analysis, qPCR, Western blot, IRF9 knockdown in RAW264.7 cells, CIA mouse model, cytokine measurement","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement based on knockdown and correlation without direct promoter or binding assay confirming transcriptional regulation of PSMA5 by IRF9; single lab","pmids":["39170377"],"is_preprint":false}],"current_model":"PSMA5 is the α5 subunit of the outer alpha-ring of the 20S core proteasome (existing as a tetramer in solution) where it participates in proteasomal protein degradation; in cancer cells it activates the JAK/STAT (JAK2/STAT3) signaling pathway to suppress apoptosis and promote proliferation, invasion, and bortezomib resistance, and can be packaged into tumor-derived exosomes that transfer PSMA5 to macrophages to drive M2 polarization via JAK2/STAT3; upstream, the transcription factor IRF9 positively regulates PSMA5 expression to control macrophage polarization."},"narrative":{"mechanistic_narrative":"PSMA5 is the α5 subunit of the outer alpha-ring of the 20S core proteasome, contributing to proteasomal protein degradation; in solution the refolded recombinant protein assembles predominantly as a tetramer, consistent with its structural role in the alpha-ring [PMID:15135414], and endogenous PSMA5 resides in a native protein complex accessible to co-immunoprecipitation [PMID:22894781]. Beyond its core structural role, PSMA5 functions as a pro-tumorigenic driver: in lung adenocarcinoma it acts upstream of JAK/STAT signaling, where its overexpression suppresses apoptosis and its knockdown inhibits proliferation, invasion, and metastasis while sensitizing cells to cisplatin [PMID:35605971], and in prostate cancer its loss similarly induces apoptosis, restricts migration and invasion, and restores bortezomib sensitivity [PMID:30807553]. In hepatocellular carcinoma, PSMA5 is packaged into tumor-derived exosomes that are internalized by macrophages, where it activates JAK2/STAT3 signaling to drive M2 polarization and promote tumor progression [PMID:38415977]. Upstream, IRF9 positively regulates PSMA5 expression to control macrophage polarization [PMID:39170377].","teleology":[{"year":2004,"claim":"Established the biochemical and oligomeric behavior of human PSMA5 in isolation, defining it as the α5 subunit that self-associates as a tetramer consistent with outer alpha-ring assembly.","evidence":"Recombinant expression, refolding, size-exclusion chromatography and dynamic light scattering of purified PSMA5","pmids":["15135414"],"confidence":"Medium","gaps":["Does not demonstrate function within the assembled 20S proteasome","No mutagenesis defining subunit interfaces","In vitro reconstitution only, no cellular validation"]},{"year":2012,"claim":"Confirmed that PSMA5 exists in a native, co-immunoprecipitable protein complex in human cells, validating reagents for capturing endogenous PSMA5.","evidence":"Immunoprecipitation of endogenous and FLAG-tagged PSMA5 with anti-PSMA5 antibodies in human cell lines","pmids":["22894781"],"confidence":"Low","gaps":["Single method without identification of complex partners","No functional follow-up","Does not define stoichiometry or proteasome incorporation"]},{"year":2019,"claim":"Linked PSMA5 to cancer cell survival and proteasome-inhibitor resistance, showing its loss reverses bortezomib resistance in prostate cancer.","evidence":"siRNA knockdown with viability, apoptosis, migration/invasion, and bortezomib resistance assays in prostate cancer cells","pmids":["30807553"],"confidence":"Medium","gaps":["Mechanism connecting PSMA5 to bortezomib resistance not resolved","No in vivo validation","Single lineage, single lab"]},{"year":2022,"claim":"Placed PSMA5 upstream of JAK/STAT signaling as an anti-apoptotic, pro-metastatic driver in lung adenocarcinoma and a determinant of cisplatin sensitivity.","evidence":"siRNA knockdown and overexpression with apoptosis/invasion assays, xenograft model, and JAK/STAT pathway Western blots","pmids":["35605971"],"confidence":"Medium","gaps":["Direct molecular link between PSMA5 and JAK/STAT activation not defined","Whether the effect depends on proteasomal activity unknown","Single lab"]},{"year":2024,"claim":"Extended PSMA5 function to intercellular signaling, showing tumor exosomal PSMA5 reprograms macrophages toward M2 polarization via JAK2/STAT3 to promote HCC progression.","evidence":"Exosome internalization assays, macrophage co-culture, siRNA knockdown, JAK2/STAT3 Western blots, and xenograft model in HCC","pmids":["38415977"],"confidence":"Medium","gaps":["Mechanism of PSMA5 sorting into exosomes unknown","How exosomal PSMA5 engages JAK2/STAT3 in recipient cells not resolved","Single lab"]},{"year":2024,"claim":"Positioned IRF9 upstream of PSMA5 in controlling macrophage polarization and inflammatory cytokine output.","evidence":"Bioinformatics correlation, IRF9 knockdown in RAW264.7 macrophages, cytokine measurement, and a CIA mouse model","pmids":["39170377"],"confidence":"Low","gaps":["No direct promoter or binding assay confirming transcriptional regulation of PSMA5 by IRF9","Correlative pathway placement","Single lab"]},{"year":null,"claim":"It remains unresolved whether the cancer- and macrophage-related JAK/STAT phenotypes depend on PSMA5's canonical proteasome function or a moonlighting activity, and how exosomal PSMA5 is sorted and acts in recipient cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanism linking proteasomal degradation activity to JAK/STAT signaling","No structural or biochemical account of exosomal packaging","Direct PSMA5 interactors in signaling contexts not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5]}],"complexes":["20S proteasome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P28066","full_name":"Proteasome subunit alpha type-5","aliases":["Macropain zeta chain","Multicatalytic endopeptidase complex zeta chain","Proteasome subunit alpha-5","alpha-5","Proteasome zeta chain"],"length_aa":241,"mass_kda":26.4,"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)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P28066/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA5","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143106","cell_line_id":"CID000118","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMD11","stoichiometry":10.0},{"gene":"PSMA7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000118","total_profiled":1310},"omim":[{"mim_id":"256040","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 1; PRAAS1","url":"https://www.omim.org/entry/256040"},{"mim_id":"177046","title":"PROTEASOME SUBUNIT, BETA-TYPE, 8; PSMB8","url":"https://www.omim.org/entry/177046"},{"mim_id":"176844","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 5; PSMA5","url":"https://www.omim.org/entry/176844"},{"mim_id":"176842","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 2; PSMA2","url":"https://www.omim.org/entry/176842"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA5"},"hgnc":{"alias_symbol":["ZETA"],"prev_symbol":[]},"alphafold":{"accession":"P28066","domains":[{"cath_id":"3.60.20.10","chopping":"36-238","consensus_level":"medium","plddt":95.2915,"start":36,"end":238}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28066","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28066-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28066-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA5","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA5"},"sequence":{"accession":"P28066","fasta_url":"https://rest.uniprot.org/uniprotkb/P28066.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28066/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28066"}},"corpus_meta":[{"pmid":"35605971","id":"PMC_35605971","title":"PSMA5 contributes to progression of lung adenocarcinoma in association with the JAK/STAT pathway.","date":"2022","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35605971","citation_count":27,"is_preprint":false},{"pmid":"30807553","id":"PMC_30807553","title":"PSMA5 promotes the tumorigenic process of prostate cancer and is related to bortezomib resistance.","date":"2019","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/30807553","citation_count":19,"is_preprint":false},{"pmid":"38891856","id":"PMC_38891856","title":"Preclinical Evaluation of Biodistribution and Toxicity of [211At]PSMA-5 in Mice and Primates for the Targeted Alpha Therapy against Prostate Cancer.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38891856","citation_count":17,"is_preprint":false},{"pmid":"22818443","id":"PMC_22818443","title":"Conjugated linoleic acid synthesis-related protein proteasome subunit α 5 (PSMA5) is increased by vaccenic acid treatment in goat mammary tissue.","date":"2012","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/22818443","citation_count":14,"is_preprint":false},{"pmid":"38415977","id":"PMC_38415977","title":"Knockdown of liver cancer cell-secreted exosomal PSMA5 controls macrophage polarization to restrain cancer progression by blocking JAK2/STAT3 signaling.","date":"2024","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/38415977","citation_count":13,"is_preprint":false},{"pmid":"15135414","id":"PMC_15135414","title":"Purification and refolding of human alpha5-subunit (PSMA5) of the 20S proteasome, expressed as inclusion bodies in Escherichia coli.","date":"2004","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/15135414","citation_count":8,"is_preprint":false},{"pmid":"22894781","id":"PMC_22894781","title":"Polyclonal antibodies against human proteasome subunits PSMA3, PSMA5, and PSMB5.","date":"2012","source":"Hybridoma (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/22894781","citation_count":5,"is_preprint":false},{"pmid":"39170377","id":"PMC_39170377","title":"Role and mechanism of IRF9 in promoting the progression of rheumatoid arthritis by regulating macrophage polarization via PSMA5.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39170377","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6638,"output_tokens":1665,"usd":0.022444,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8458,"output_tokens":2271,"usd":0.049533,"stage2_stop_reason":"end_turn"},"total_usd":0.071977,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Human PSMA5 (α5 subunit of the 20S proteasome) was expressed, purified, and refolded from E. coli inclusion bodies; the refolded protein exists predominantly as a tetramer as determined by gel filtration chromatography and dynamic light scattering, consistent with its role as part of the outer alpha-ring of the 20S proteasome.\",\n      \"method\": \"Recombinant protein expression, dilution refolding, size-exclusion chromatography, dynamic light scattering, gel filtration chromatography\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution and biophysical characterization in a single study, no functional mutagenesis\",\n      \"pmids\": [\"15135414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Anti-PSMA5 polyclonal antibodies can immunoprecipitate native endogenous and overexpressed FLAG-tagged PSMA5 from human cell lines, confirming that PSMA5 exists in a native protein complex accessible to co-immunoprecipitation.\",\n      \"method\": \"Western blot, immunoprecipitation of endogenous and FLAG-tagged PSMA5 from human cell lines\",\n      \"journal\": \"Hybridoma (2005)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (immunoprecipitation), no functional follow-up\",\n      \"pmids\": [\"22894781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMA5 knockdown in lung adenocarcinoma (LUAD) cells inhibited proliferation, invasion, and metastasis in vitro and in vivo, induced apoptosis, and sensitized cells to cisplatin; mechanistically, PSMA5 overexpression activated the JAK/STAT signaling pathway to suppress apoptosis, placing PSMA5 upstream of JAK/STAT in LUAD cells.\",\n      \"method\": \"siRNA knockdown, overexpression, apoptosis assays, invasion/migration assays, xenograft in vivo model, Western blot for JAK/STAT pathway components\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with multiple orthogonal readouts and in vivo validation, single lab\",\n      \"pmids\": [\"35605971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMA5 knockdown in prostate cancer cells inhibited proliferation, induced apoptosis, and restricted migration and invasion; additionally, PSMA5 knockdown in bortezomib-resistant cells restored sensitivity to bortezomib, indicating PSMA5 contributes to bortezomib resistance.\",\n      \"method\": \"siRNA knockdown, CCK-8 viability assay, FACS apoptosis analysis, scratch assay, Transwell invasion assay, bortezomib resistance assay\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal functional assays including drug resistance, single lab\",\n      \"pmids\": [\"30807553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HCC cells secrete PSMA5-containing exosomes that are internalized by macrophages; exosomal PSMA5 promotes M2 macrophage polarization and activates JAK2/STAT3 signaling in macrophages, thereby facilitating HCC cell migration, invasion, and in vivo tumorigenesis. Knockdown of PSMA5 in HCC cells reduced exosomal PSMA5, blocked these effects, and suppressed tumor progression.\",\n      \"method\": \"Exosome isolation and fluorescence labeling/internalization assay, siRNA knockdown, co-culture of macrophages with HCC-derived exosomes, ELISA, qRT-PCR, IHC, Western blot for JAK2/STAT3, xenograft assay\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (exosome internalization, co-culture, in vivo xenograft, pathway Western blot), single lab\",\n      \"pmids\": [\"38415977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRF9 transcriptionally regulates PSMA5 expression; knockdown of IRF9 in RAW264.7 macrophages suppressed PSMA5 levels, altered the M1/M2 macrophage polarization ratio, and reduced pro-inflammatory cytokine secretion. In a CIA mouse model, sh-IRF9 macrophages modulated RA progression by downregulating PSMA5 and skewing macrophage polarization, placing IRF9 upstream of PSMA5 in the macrophage polarization pathway.\",\n      \"method\": \"Bioinformatics correlation analysis, qPCR, Western blot, IRF9 knockdown in RAW264.7 cells, CIA mouse model, cytokine measurement\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement based on knockdown and correlation without direct promoter or binding assay confirming transcriptional regulation of PSMA5 by IRF9; single lab\",\n      \"pmids\": [\"39170377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA5 is the α5 subunit of the outer alpha-ring of the 20S core proteasome (existing as a tetramer in solution) where it participates in proteasomal protein degradation; in cancer cells it activates the JAK/STAT (JAK2/STAT3) signaling pathway to suppress apoptosis and promote proliferation, invasion, and bortezomib resistance, and can be packaged into tumor-derived exosomes that transfer PSMA5 to macrophages to drive M2 polarization via JAK2/STAT3; upstream, the transcription factor IRF9 positively regulates PSMA5 expression to control macrophage polarization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA5 is the α5 subunit of the outer alpha-ring of the 20S core proteasome, contributing to proteasomal protein degradation; in solution the refolded recombinant protein assembles predominantly as a tetramer, consistent with its structural role in the alpha-ring [#0], and endogenous PSMA5 resides in a native protein complex accessible to co-immunoprecipitation [#1]. Beyond its core structural role, PSMA5 functions as a pro-tumorigenic driver: in lung adenocarcinoma it acts upstream of JAK/STAT signaling, where its overexpression suppresses apoptosis and its knockdown inhibits proliferation, invasion, and metastasis while sensitizing cells to cisplatin [#2], and in prostate cancer its loss similarly induces apoptosis, restricts migration and invasion, and restores bortezomib sensitivity [#3]. In hepatocellular carcinoma, PSMA5 is packaged into tumor-derived exosomes that are internalized by macrophages, where it activates JAK2/STAT3 signaling to drive M2 polarization and promote tumor progression [#4]. Upstream, IRF9 positively regulates PSMA5 expression to control macrophage polarization [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the biochemical and oligomeric behavior of human PSMA5 in isolation, defining it as the α5 subunit that self-associates as a tetramer consistent with outer alpha-ring assembly.\",\n      \"evidence\": \"Recombinant expression, refolding, size-exclusion chromatography and dynamic light scattering of purified PSMA5\",\n      \"pmids\": [\"15135414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not demonstrate function within the assembled 20S proteasome\", \"No mutagenesis defining subunit interfaces\", \"In vitro reconstitution only, no cellular validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed that PSMA5 exists in a native, co-immunoprecipitable protein complex in human cells, validating reagents for capturing endogenous PSMA5.\",\n      \"evidence\": \"Immunoprecipitation of endogenous and FLAG-tagged PSMA5 with anti-PSMA5 antibodies in human cell lines\",\n      \"pmids\": [\"22894781\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method without identification of complex partners\", \"No functional follow-up\", \"Does not define stoichiometry or proteasome incorporation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked PSMA5 to cancer cell survival and proteasome-inhibitor resistance, showing its loss reverses bortezomib resistance in prostate cancer.\",\n      \"evidence\": \"siRNA knockdown with viability, apoptosis, migration/invasion, and bortezomib resistance assays in prostate cancer cells\",\n      \"pmids\": [\"30807553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PSMA5 to bortezomib resistance not resolved\", \"No in vivo validation\", \"Single lineage, single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PSMA5 upstream of JAK/STAT signaling as an anti-apoptotic, pro-metastatic driver in lung adenocarcinoma and a determinant of cisplatin sensitivity.\",\n      \"evidence\": \"siRNA knockdown and overexpression with apoptosis/invasion assays, xenograft model, and JAK/STAT pathway Western blots\",\n      \"pmids\": [\"35605971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PSMA5 and JAK/STAT activation not defined\", \"Whether the effect depends on proteasomal activity unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended PSMA5 function to intercellular signaling, showing tumor exosomal PSMA5 reprograms macrophages toward M2 polarization via JAK2/STAT3 to promote HCC progression.\",\n      \"evidence\": \"Exosome internalization assays, macrophage co-culture, siRNA knockdown, JAK2/STAT3 Western blots, and xenograft model in HCC\",\n      \"pmids\": [\"38415977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PSMA5 sorting into exosomes unknown\", \"How exosomal PSMA5 engages JAK2/STAT3 in recipient cells not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Positioned IRF9 upstream of PSMA5 in controlling macrophage polarization and inflammatory cytokine output.\",\n      \"evidence\": \"Bioinformatics correlation, IRF9 knockdown in RAW264.7 macrophages, cytokine measurement, and a CIA mouse model\",\n      \"pmids\": [\"39170377\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct promoter or binding assay confirming transcriptional regulation of PSMA5 by IRF9\", \"Correlative pathway placement\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the cancer- and macrophage-related JAK/STAT phenotypes depend on PSMA5's canonical proteasome function or a moonlighting activity, and how exosomal PSMA5 is sorted and acts in recipient cells.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism linking proteasomal degradation activity to JAK/STAT signaling\", \"No structural or biochemical account of exosomal packaging\", \"Direct PSMA5 interactors in signaling contexts not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"20S proteasome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}