{"gene":"PSMA4","run_date":"2026-06-14T21:15:18+00:00","timeline":{"discoveries":[{"year":2023,"finding":"PSMA4 (Psma4) interacts directly with ISLR (Islr), and this interaction mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) subunit in adipocytes. Islr knockout increased Insrα levels and enhanced insulin sensitivity in obese mice.","method":"Co-immunoprecipitation (Islr-Psma4 interaction), siRNA knockdown of Islr in white adipose tissue, Islr knockout mouse model with Insrα protein level quantification and insulin sensitivity assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated and functional consequence (Insrα degradation) confirmed by KO/KD, single lab but multiple orthogonal methods","pmids":["37116777"],"is_preprint":false},{"year":2024,"finding":"Under free fatty acid (FFA) stimulation, TIR8 directly interacts with PSMA4, and this interaction facilitates TIR8 degradation (presumably via the proteasome), contributing to PPARα downregulation in hepatocytes during NASH progression.","method":"Mass spectrometry interaction screen in TIR8 knockout mouse model, ectopic TIR8 expression experiments, FFA stimulation assays demonstrating TIR8-PSMA4 direct interaction","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction reported from mass spectrometry screen with limited mechanistic follow-up described in abstract","pmids":["38851532"],"is_preprint":false},{"year":2014,"finding":"PSMA4 (proteasome subunit alpha type-4) physically binds to crocin (a bioactive carotenoid from saffron), as identified by affinity chromatography with crocin-conjugated agarose beads followed by 2D gel and MALDI-TOF/TOF mass spectrometry.","method":"Affinity chromatography (crocin-agarose pulldown), 2D PAGE, MALDI-TOF/TOF mass spectrometry","journal":"Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single affinity pulldown screen identifying many proteins, no functional follow-up for PSMA4 specifically","pmids":["24393168"],"is_preprint":false}],"current_model":"PSMA4 is a proteasome alpha subunit that serves as a docking/entry point for ubiquitin-independent proteasomal degradation: it directly interacts with ISLR to mediate degradation of insulin receptor alpha in adipocytes, and is also recruited by TIR8 under lipotoxic conditions to facilitate TIR8 degradation, thereby linking proteasomal protein turnover to insulin signaling and hepatic lipid metabolism."},"narrative":{"mechanistic_narrative":"PSMA4 is a proteasome alpha-type subunit that functions as a docking point for ubiquitin-independent proteasomal degradation, coupling protein turnover to metabolic signaling [PMID:37116777]. In adipocytes, PSMA4 binds directly to ISLR, and this interaction drives ubiquitin-independent degradation of the insulin receptor alpha subunit; loss of ISLR raises INSRα levels and improves insulin sensitivity in obese mice, placing PSMA4 within the control of insulin signaling [PMID:37116777]. Beyond this characterized role, the available corpus provides no structural model of PSMA4 or definition of how target specificity is achieved.","teleology":[{"year":2014,"claim":"An unbiased screen for binding partners of the saffron carotenoid crocin first physically linked PSMA4 to a small-molecule ligand, providing an early biochemical handle on the protein.","evidence":"crocin-agarose affinity chromatography with 2D PAGE and MALDI-TOF/TOF mass spectrometry","pmids":["24393168"],"confidence":"Low","gaps":["Single affinity pulldown identifying many proteins with no functional follow-up for PSMA4","Does not establish any cellular or proteasomal function","No demonstration that crocin binding alters PSMA4 activity"]},{"year":2023,"claim":"Identification of a direct PSMA4–ISLR interaction established PSMA4 as a docking subunit for ubiquitin-independent degradation of the insulin receptor, mechanistically connecting the proteasome to insulin sensitivity.","evidence":"Co-immunoprecipitation, ISLR siRNA knockdown in white adipose tissue, and ISLR knockout mice with INSRα quantification and insulin sensitivity assays","pmids":["37116777"],"confidence":"Medium","gaps":["Structural basis of ISLR recognition and the route of INSRα entry into the proteasome unresolved","Whether PSMA4 contributes target specificity or acts as a generic docking site is unknown","Single-lab study"]},{"year":2024,"claim":"A second metabolic partner, TIR8, was found to bind PSMA4 under lipotoxic conditions, extending PSMA4-mediated degradation to hepatic lipid metabolism and PPARα regulation.","evidence":"Mass spectrometry interaction screen in TIR8 knockout mice with ectopic TIR8 expression and FFA stimulation assays","pmids":["38851532"],"confidence":"Low","gaps":["Interaction derived from a mass spectrometry screen with limited mechanistic follow-up","Proteasomal route of TIR8 degradation inferred rather than directly demonstrated","No reciprocal validation of the PSMA4–TIR8 interaction reported"]},{"year":null,"claim":"It remains unknown how PSMA4 selects its degradation targets and whether ISLR- and TIR8-dependent degradation represent a shared mechanism of ubiquitin-independent substrate entry through this alpha subunit.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PSMA4 within the assembled proteasome","Determinants of substrate specificity uncharacterized","Whether PSMA4 acts as a general or substrate-specific docking site is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["proteasome"],"partners":["ISLR","TIR8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25789","full_name":"Proteasome subunit alpha type-4","aliases":["Macropain subunit C9","Multicatalytic endopeptidase complex subunit C9","Proteasome component C9","Proteasome subunit L","Proteasome subunit alpha-3","alpha-3"],"length_aa":261,"mass_kda":29.5,"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/P25789/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA4","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000041357","cell_line_id":"CID000096","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMD3","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMD13","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000096","total_profiled":1310},"omim":[{"mim_id":"613386","title":"PROTEASOME MATURATION PROTEIN; POMP","url":"https://www.omim.org/entry/613386"},{"mim_id":"612052","title":"SMOKING AS A QUANTITATIVE TRAIT LOCUS 3; SQTL3","url":"https://www.omim.org/entry/612052"},{"mim_id":"176846","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 4; PSMA4","url":"https://www.omim.org/entry/176846"},{"mim_id":"176842","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 2; PSMA2","url":"https://www.omim.org/entry/176842"},{"mim_id":"118509","title":"CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 4; CHRNB4","url":"https://www.omim.org/entry/118509"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA4"},"hgnc":{"alias_symbol":["HC9","HsT17706"],"prev_symbol":[]},"alphafold":{"accession":"P25789","domains":[{"cath_id":"3.60.20.10","chopping":"17-259","consensus_level":"high","plddt":94.4935,"start":17,"end":259}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25789","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25789-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25789-F1-predicted_aligned_error_v6.png","plddt_mean":93.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA4","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA4"},"sequence":{"accession":"P25789","fasta_url":"https://rest.uniprot.org/uniprotkb/P25789.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25789/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25789"}},"corpus_meta":[{"pmid":"25744645","id":"PMC_25744645","title":"Association of PSMA4 polymorphisms with lung cancer susceptibility and response to cisplatin-based chemotherapy in a Chinese Han population.","date":"2015","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/25744645","citation_count":28,"is_preprint":false},{"pmid":"24393168","id":"PMC_24393168","title":"Proteomic screening of molecular targets of crocin.","date":"2014","source":"Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24393168","citation_count":16,"is_preprint":false},{"pmid":"20599997","id":"PMC_20599997","title":"Cryptosporidium parvum: radiation-induced alteration of the oocyst proteome.","date":"2010","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/20599997","citation_count":7,"is_preprint":false},{"pmid":"20195826","id":"PMC_20195826","title":"Evaluation of plasma carcinogenic markers in rat hepatic tumors models induced by rat hepatoma N1-S1 cells and benzo[a]pyrene.","date":"2010","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/20195826","citation_count":7,"is_preprint":false},{"pmid":"38851532","id":"PMC_38851532","title":"TIR8 protects against nonalcoholic steatohepatitis by antagonizing lipotoxicity-induced PPARα downregulation and reducing the sensitivity of hepatocytes to LPS.","date":"2024","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38851532","citation_count":6,"is_preprint":false},{"pmid":"37116777","id":"PMC_37116777","title":"Islr regulates insulin sensitivity by interacting with Psma4 to control insulin receptor alpha levels in obese mice.","date":"2023","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37116777","citation_count":4,"is_preprint":false},{"pmid":"24518713","id":"PMC_24518713","title":"Association between TGM5, PPAP2B and PSMA4 polymorphisms and NSCLC in never-smoking Chinese population.","date":"2013","source":"Journal of cancer research and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24518713","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"sonnet_model":"claude-sonnet-4-6","sonnet_input_tokens":5659,"sonnet_output_tokens":840,"sonnet_usd":0.0296,"sonnet_elapsed_seconds":15.6,"stage1_stop_reason":"end_turn"},"stage2":{"opus_model":"claude-opus-4-8","opus_input_tokens":7334,"opus_output_tokens":1419,"opus_usd":0.0721,"opus_elapsed_seconds":17.3,"stage2_stop_reason":"end_turn"},"total_usd":0.1017},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMA4 (Psma4) interacts directly with ISLR (Islr), and this interaction mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) subunit in adipocytes. Islr knockout increased Insrα levels and enhanced insulin sensitivity in obese mice.\",\n      \"method\": \"Co-immunoprecipitation (Islr-Psma4 interaction), siRNA knockdown of Islr in white adipose tissue, Islr knockout mouse model with Insrα protein level quantification and insulin sensitivity assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated and functional consequence (Insrα degradation) confirmed by KO/KD, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37116777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under free fatty acid (FFA) stimulation, TIR8 directly interacts with PSMA4, and this interaction facilitates TIR8 degradation (presumably via the proteasome), contributing to PPARα downregulation in hepatocytes during NASH progression.\",\n      \"method\": \"Mass spectrometry interaction screen in TIR8 knockout mouse model, ectopic TIR8 expression experiments, FFA stimulation assays demonstrating TIR8-PSMA4 direct interaction\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction reported from mass spectrometry screen with limited mechanistic follow-up described in abstract\",\n      \"pmids\": [\"38851532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSMA4 (proteasome subunit alpha type-4) physically binds to crocin (a bioactive carotenoid from saffron), as identified by affinity chromatography with crocin-conjugated agarose beads followed by 2D gel and MALDI-TOF/TOF mass spectrometry.\",\n      \"method\": \"Affinity chromatography (crocin-agarose pulldown), 2D PAGE, MALDI-TOF/TOF mass spectrometry\",\n      \"journal\": \"Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single affinity pulldown screen identifying many proteins, no functional follow-up for PSMA4 specifically\",\n      \"pmids\": [\"24393168\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA4 is a proteasome alpha subunit that serves as a docking/entry point for ubiquitin-independent proteasomal degradation: it directly interacts with ISLR to mediate degradation of insulin receptor alpha in adipocytes, and is also recruited by TIR8 under lipotoxic conditions to facilitate TIR8 degradation, thereby linking proteasomal protein turnover to insulin signaling and hepatic lipid metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA4 is a proteasome alpha-type subunit that functions as a docking point for ubiquitin-independent proteasomal degradation, coupling protein turnover to metabolic signaling [#0]. In adipocytes, PSMA4 binds directly to ISLR, and this interaction drives ubiquitin-independent degradation of the insulin receptor alpha subunit; loss of ISLR raises INSRα levels and improves insulin sensitivity in obese mice, placing PSMA4 within the control of insulin signaling [#0]. Beyond this characterized role, the available corpus provides no structural model of PSMA4 or definition of how target specificity is achieved.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"An unbiased screen for binding partners of the saffron carotenoid crocin first physically linked PSMA4 to a small-molecule ligand, providing an early biochemical handle on the protein.\",\n      \"evidence\": \"crocin-agarose affinity chromatography with 2D PAGE and MALDI-TOF/TOF mass spectrometry\",\n      \"pmids\": [\"24393168\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single affinity pulldown identifying many proteins with no functional follow-up for PSMA4\", \"Does not establish any cellular or proteasomal function\", \"No demonstration that crocin binding alters PSMA4 activity\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of a direct PSMA4–ISLR interaction established PSMA4 as a docking subunit for ubiquitin-independent degradation of the insulin receptor, mechanistically connecting the proteasome to insulin sensitivity.\",\n      \"evidence\": \"Co-immunoprecipitation, ISLR siRNA knockdown in white adipose tissue, and ISLR knockout mice with INSRα quantification and insulin sensitivity assays\",\n      \"pmids\": [\"37116777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ISLR recognition and the route of INSRα entry into the proteasome unresolved\", \"Whether PSMA4 contributes target specificity or acts as a generic docking site is unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A second metabolic partner, TIR8, was found to bind PSMA4 under lipotoxic conditions, extending PSMA4-mediated degradation to hepatic lipid metabolism and PPARα regulation.\",\n      \"evidence\": \"Mass spectrometry interaction screen in TIR8 knockout mice with ectopic TIR8 expression and FFA stimulation assays\",\n      \"pmids\": [\"38851532\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Interaction derived from a mass spectrometry screen with limited mechanistic follow-up\", \"Proteasomal route of TIR8 degradation inferred rather than directly demonstrated\", \"No reciprocal validation of the PSMA4–TIR8 interaction reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PSMA4 selects its degradation targets and whether ISLR- and TIR8-dependent degradation represent a shared mechanism of ubiquitin-independent substrate entry through this alpha subunit.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PSMA4 within the assembled proteasome\", \"Determinants of substrate specificity uncharacterized\", \"Whether PSMA4 acts as a general or substrate-specific docking site is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"proteasome\"],\n    \"partners\": [\"ISLR\", \"TIR8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"PSMA4","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"uncited_synthesis","uniprot_band":"medium","rules_fired":"R6,R8","issue":"R6: narrative-cited PMIDs vs gene2pubmed overlap = 0.00% (n_cited=3, n_g2p=271); R8: 1/3 claims uncited (33%)"},"evaluation":{"pairwise":"tie"}}