{"gene":"PSMA6","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1993,"finding":"PSMA6 (p27K/PROS27) was identified as an alpha-type prosomal/proteasome protein. The protein contains multiple potential phosphorylation sites, an NTP-binding fold, and an RNA-binding consensus sequence. A PROS27/β-galactosidase fusion protein was shown to bind a single RNA of ~120 nucleotides from total HeLa cell RNA, and sequence analysis placed PROS27 within the alpha-type sub-family of the prosome–MCP–proteasome protein family.","method":"cDNA cloning, sequence analysis, chromosomal mapping (chromosome 14q13), and RNA-binding assay using fusion protein with HeLa cell RNA","journal":"Molecular & general genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-binding assay with fusion protein and sequence-based structural characterization, single lab but multiple orthogonal methods","pmids":["7681138"],"is_preprint":false},{"year":2006,"finding":"A SNP (rs1048990) in the 5' UTR of PSMA6 enhances PSMA6 transcription. Suppression of PSMA6 expression by siRNA in cultured cells reduced NF-κB activation by stabilizing phosphorylated IκB, establishing PSMA6 (as a 20S proteasome subunit) as a positive regulator of NF-κB activation through IκB degradation.","method":"Reporter/transcription assay demonstrating SNP-enhanced transcription; siRNA knockdown with measurement of NF-κB activation and phosphorylated IκB levels","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined molecular readout (phospho-IκB stabilization and NF-κB activity), single lab with two orthogonal functional methods","pmids":["16845397"],"is_preprint":false},{"year":2017,"finding":"PSMA6, a proteasomal subunit of the 20S catalytic core complex, is required for lung cancer cell survival. Silencing of PSMA6 by shRNA induced apoptosis or G2/M cell cycle arrest in lung cancer cell lines but not in an immortalized normal lung cell line, establishing PSMA6 as an essential component for cancer cell viability.","method":"Semi-genome-wide shRNA screening followed by targeted PSMA6 silencing; cell viability, apoptosis, and cell cycle analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA loss-of-function with specific cellular phenotype (apoptosis and G2/M arrest), single lab, validated in multiple cancer lines","pmids":["28165654"],"is_preprint":false},{"year":2019,"finding":"PSMA6 was identified as an essential gene for pancreatic cancer cell survival via genome-wide CRISPR negative-selection screening. siRNA-mediated depletion confirmed that PSMA6 is critical for spheroid formation and survival in multiple pancreatic ductal adenocarcinoma cell models, and pharmacological proteasome inhibition with bortezomib was especially toxic in PANC-1 cells.","method":"Genome-wide CRISPR negative-selection screen; siRNA validation across multiple PDAC cell lines; spheroid formation assay; flow cytometry; bortezomib cytotoxicity assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen validated by independent siRNA deconvolution across multiple cell lines with defined phenotypic readouts, single lab","pmids":["30898113"],"is_preprint":false},{"year":2010,"finding":"PSMA6 protein expression was significantly reduced in the renal cortex of both STZ-induced and spontaneous OLETF diabetic rat models compared to normal controls, as identified by proteomic profiling of mesangial cells under high-glucose conditions followed by Western blot validation in vivo.","method":"2D gel electrophoresis proteomics of primary rat mesangial cells under high glucose; MALDI-TOF-MS protein identification; Western blot validation in two diabetic rat models","journal":"Biochemistry and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — descriptive proteomics and Western blot showing reduced PSMA6 in diabetic tissue, no functional mechanism established, single lab","pmids":["20651835"],"is_preprint":false}],"current_model":"PSMA6 encodes an alpha-type subunit of the 20S proteasome catalytic core; it contains an RNA-binding domain and was originally identified as a prosomal protein (p27K/PROS27) that binds RNA, and it promotes NF-κB activation by facilitating proteasomal degradation of phosphorylated IκB, with loss-of-function studies showing it is essential for cancer cell survival in lung and pancreatic cancer models."},"narrative":{"mechanistic_narrative":"PSMA6 encodes an alpha-type subunit of the 20S proteasome catalytic core, originally identified as the prosomal protein p27K/PROS27 within the prosome–MCP–proteasome alpha sub-family [PMID:7681138]. The protein carries an RNA-binding consensus sequence, and a PROS27 fusion protein binds a discrete ~120-nucleotide RNA species from total cellular RNA, marking it as an RNA-associated component of the particle [PMID:7681138]. As a constituent of the 20S core, PSMA6 acts as a positive regulator of NF-κB signaling: its depletion stabilizes phosphorylated IκB and reduces NF-κB activation, linking the subunit to proteasomal degradation of phospho-IκB [PMID:16845397]. Loss-of-function studies establish PSMA6 as essential for cancer cell survival — silencing induces apoptosis or G2/M arrest selectively in lung cancer cells [PMID:28165654] and impairs spheroid formation and viability in pancreatic ductal adenocarcinoma models, where proteasome inhibition by bortezomib is especially cytotoxic [PMID:30898113]. Beyond these roles in proteasomal degradation, NF-κB regulation, and cancer cell viability, no further mechanistic detail of PSMA6 catalytic chemistry or assembly has been characterized in the available corpus.","teleology":[{"year":1993,"claim":"Established the molecular identity of PSMA6 as an alpha-type prosome/proteasome subunit and uncovered an unexpected RNA-binding property, framing it as more than a passive structural component.","evidence":"cDNA cloning, sequence analysis with chromosomal mapping, and an RNA-binding assay using a PROS27/β-galactosidase fusion against HeLa RNA","pmids":["7681138"],"confidence":"Medium","gaps":["The functional significance of the ~120-nt RNA interaction is undefined","No structural placement of the subunit within the assembled 20S core","RNA-binding shown only with a fusion construct, not full-length endogenous protein"]},{"year":2006,"claim":"Connected PSMA6 to a defined signaling output by showing the proteasome subunit drives NF-κB activation through degradation of phosphorylated IκB, with a regulatory SNP modulating its expression.","evidence":"Reporter/transcription assay of a 5'UTR SNP plus siRNA knockdown measuring phospho-IκB stabilization and NF-κB activity","pmids":["16845397"],"confidence":"Medium","gaps":["Does not establish whether PSMA6 acts via its catalytic core role or a distinct mechanism","No direct biochemical demonstration of phospho-IκB processing by PSMA6-containing proteasomes","SNP-to-phenotype causality in vivo not resolved"]},{"year":2010,"claim":"Linked PSMA6 abundance to a disease context by showing reduced expression in diabetic renal tissue, raising the possibility of altered proteasomal capacity in nephropathy.","evidence":"2D-gel proteomics of high-glucose mesangial cells with MALDI-TOF identification and Western blot validation in two diabetic rat models","pmids":["20651835"],"confidence":"Low","gaps":["Purely descriptive — no functional mechanism established","Correlation between PSMA6 loss and renal pathology not demonstrated causally","Single lab, model-organism observation"]},{"year":2019,"claim":"Demonstrated that PSMA6 is a survival-essential gene across cancer types, establishing it as a vulnerability whose loss triggers apoptosis/cell-cycle arrest and sensitizes cells to proteasome inhibition.","evidence":"Semi-genome-wide shRNA screen in lung cancer with apoptosis/cell-cycle readouts; genome-wide CRISPR negative-selection screen in PDAC with siRNA deconvolution, spheroid assays, and bortezomib cytotoxicity","pmids":["28165654","30898113"],"confidence":"Medium","gaps":["Selectivity over normal cells shown in limited models","Whether essentiality reflects general proteasome dependence or a PSMA6-specific function is unresolved","No mechanistic link between essentiality and the NF-κB/RNA-binding activities"]},{"year":null,"claim":"The biochemical role of PSMA6's RNA-binding activity and its precise contribution to substrate selection within the 20S core remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified physiological RNA ligand or its function","No structural model of PSMA6 within the assembled proteasome from the corpus","Mechanism connecting subunit-level perturbation to NF-κB and cancer-cell phenotypes not directly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":["20S proteasome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60900","full_name":"Proteasome subunit alpha type-6","aliases":["27 kDa prosomal protein","PROS-27","p27K","Macropain iota chain","Multicatalytic endopeptidase complex iota chain","Proteasome iota chain","Proteasome subunit alpha-1","alpha-1"],"length_aa":246,"mass_kda":27.4,"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/P60900/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMA6","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100902","cell_line_id":"CID000111","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"PSMD11","stoichiometry":10.0},{"gene":"PSMD3","stoichiometry":10.0},{"gene":"PSMA7","stoichiometry":10.0},{"gene":"PSMC2","stoichiometry":10.0},{"gene":"PSMA5","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMD1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000111","total_profiled":1310},"omim":[{"mim_id":"608446","title":"MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/608446"},{"mim_id":"602855","title":"PROTEASOME SUBUNIT, ALPHA-TYPE, 6; PSMA6","url":"https://www.omim.org/entry/602855"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMA6"},"hgnc":{"alias_symbol":["IOTA","PROS27","p27K","MGC22756","MGC2333","MGC23846"],"prev_symbol":[]},"alphafold":{"accession":"P60900","domains":[{"cath_id":"3.60.20.10","chopping":"22-55_66-243","consensus_level":"high","plddt":97.2801,"start":22,"end":243}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60900","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60900-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60900-F1-predicted_aligned_error_v6.png","plddt_mean":96.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMA6","jax_strain_url":"https://www.jax.org/strain/search?query=PSMA6"},"sequence":{"accession":"P60900","fasta_url":"https://rest.uniprot.org/uniprotkb/P60900.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60900/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60900"}},"corpus_meta":[{"pmid":"10984059","id":"PMC_10984059","title":"Eukaryotic 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Part B, Applied biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/25449538","citation_count":42,"is_preprint":false},{"pmid":"34375308","id":"PMC_34375308","title":"Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34375308","citation_count":42,"is_preprint":false},{"pmid":"25716558","id":"PMC_25716558","title":"Effects of baicalin on collagen Ι and collagen ΙΙΙ expression in pulmonary arteries of rats with hypoxic pulmonary hypertension.","date":"2015","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25716558","citation_count":41,"is_preprint":false},{"pmid":"31805501","id":"PMC_31805501","title":"Polymerase iota - an odd sibling among Y family polymerases.","date":"2019","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/31805501","citation_count":40,"is_preprint":false},{"pmid":"34797868","id":"PMC_34797868","title":"Iota-carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34797868","citation_count":40,"is_preprint":false},{"pmid":"21911469","id":"PMC_21911469","title":"Clostridium perfringens iota-toxin b induces rapid cell necrosis.","date":"2011","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21911469","citation_count":40,"is_preprint":false},{"pmid":"23236484","id":"PMC_23236484","title":"CD44 Promotes intoxication by the clostridial iota-family toxins.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23236484","citation_count":40,"is_preprint":false},{"pmid":"24786829","id":"PMC_24786829","title":"PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis.","date":"2014","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24786829","citation_count":38,"is_preprint":false},{"pmid":"12175336","id":"PMC_12175336","title":"Clostridium perfringens iota toxin: characterization of the cell-associated iota b complex.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12175336","citation_count":37,"is_preprint":false},{"pmid":"24532793","id":"PMC_24532793","title":"The steric gate of DNA polymerase ι regulates ribonucleotide incorporation and deoxyribonucleotide fidelity.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24532793","citation_count":36,"is_preprint":false},{"pmid":"19368886","id":"PMC_19368886","title":"DNA synthesis across an abasic lesion by human DNA polymerase iota.","date":"2009","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/19368886","citation_count":35,"is_preprint":false},{"pmid":"23334392","id":"PMC_23334392","title":"aPKCλ/ι and aPKCζ contribute to podocyte differentiation and glomerular maturation.","date":"2013","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/23334392","citation_count":34,"is_preprint":false},{"pmid":"27057634","id":"PMC_27057634","title":"DNA polymerase iota (Pol ι) promotes invasion and metastasis of esophageal squamous cell carcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27057634","citation_count":29,"is_preprint":false},{"pmid":"16472831","id":"PMC_16472831","title":"The role of DNA polymerase iota in UV mutational spectra.","date":"2006","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/16472831","citation_count":29,"is_preprint":false},{"pmid":"22817454","id":"PMC_22817454","title":"Structure of human DNA polymerase iota and the mechanism of DNA synthesis.","date":"2012","source":"Biochemistry. 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proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/11856176","citation_count":26,"is_preprint":false},{"pmid":"28800062","id":"PMC_28800062","title":"Cellular Entry of Clostridium perfringens Iota-Toxin and Clostridium botulinum C2 Toxin.","date":"2017","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/28800062","citation_count":25,"is_preprint":false},{"pmid":"30610188","id":"PMC_30610188","title":"The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30610188","citation_count":24,"is_preprint":false},{"pmid":"30389910","id":"PMC_30389910","title":"Downregulation of ASPP2 promotes gallbladder cancer metastasis and macrophage recruitment via aPKC-ι/GLI1 pathway.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30389910","citation_count":24,"is_preprint":false},{"pmid":"23248005","id":"PMC_23248005","title":"Ubiquitin mediates the physical and functional interaction between human DNA polymerases η and ι.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23248005","citation_count":24,"is_preprint":false},{"pmid":"21304950","id":"PMC_21304950","title":"Inaccurate DNA synthesis in cell extracts of yeast producing active human DNA polymerase iota.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21304950","citation_count":24,"is_preprint":false},{"pmid":"11244494","id":"PMC_11244494","title":"Differential expression of diacylglycerol kinase iota and L18A mRNAs in the brains of alcohol-preferring AA and alcohol-avoiding ANA rats.","date":"2001","source":"Molecular 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GEP","url":"https://pubmed.ncbi.nlm.nih.gov/16931174","citation_count":23,"is_preprint":false},{"pmid":"37058556","id":"PMC_37058556","title":"Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37058556","citation_count":22,"is_preprint":false},{"pmid":"30898113","id":"PMC_30898113","title":"Genome-wide CRISPR screen reveals PSMA6 to be an essential gene in pancreatic cancer cells.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30898113","citation_count":22,"is_preprint":false},{"pmid":"22882272","id":"PMC_22882272","title":"Genetic variants associated with myocardial infarction in the PSMA6 gene and Chr9p21 are also associated with ischaemic stroke.","date":"2012","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22882272","citation_count":22,"is_preprint":false},{"pmid":"24072773","id":"PMC_24072773","title":"Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24072773","citation_count":22,"is_preprint":false},{"pmid":"30801864","id":"PMC_30801864","title":"Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/30801864","citation_count":22,"is_preprint":false},{"pmid":"27455952","id":"PMC_27455952","title":"DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes.","date":"2016","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27455952","citation_count":22,"is_preprint":false},{"pmid":"17555133","id":"PMC_17555133","title":"SNPs of PSMA6 gene--investigation of possible association with myocardial infarction and type 2 diabetes mellitus.","date":"2007","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/17555133","citation_count":21,"is_preprint":false},{"pmid":"37741234","id":"PMC_37741234","title":"Calcium ions induced ι-carrageenan-based gel-coating deposited on zein nanoparticles for encapsulating the curcumin.","date":"2023","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37741234","citation_count":21,"is_preprint":false},{"pmid":"28165654","id":"PMC_28165654","title":"Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28165654","citation_count":20,"is_preprint":false},{"pmid":"20651835","id":"PMC_20651835","title":"Proteomic profile of primary isolated rat mesangial cells in high-glucose culture condition and decreased expression of PSMA6 in renal cortex of diabetic rats.","date":"2010","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/20651835","citation_count":20,"is_preprint":false},{"pmid":"33716239","id":"PMC_33716239","title":"Silencing circRNA protein kinase C iota (circ-PRKCI) suppresses cell progression and glycolysis of human papillary thyroid cancer through circ-PRKCI/miR-335/E2F3 ceRNA axis.","date":"2021","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/33716239","citation_count":20,"is_preprint":false},{"pmid":"14684752","id":"PMC_14684752","title":"Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14684752","citation_count":20,"is_preprint":false},{"pmid":"34354953","id":"PMC_34354953","title":"DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34354953","citation_count":19,"is_preprint":false},{"pmid":"18358479","id":"PMC_18358479","title":"The -8 UTR C/G polymorphism of PSMA6 gene is associated with susceptibility to myocardial infarction in type 2 diabetic patients.","date":"2008","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/18358479","citation_count":19,"is_preprint":false},{"pmid":"29688013","id":"PMC_29688013","title":"Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.","date":"2018","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29688013","citation_count":19,"is_preprint":false},{"pmid":"30226591","id":"PMC_30226591","title":"Inhibition of atypical protein kinase C‑ι effectively reduces the malignancy of prostate cancer cells by downregulating the NF-κB signaling cascade.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30226591","citation_count":19,"is_preprint":false},{"pmid":"23106263","id":"PMC_23106263","title":"Bypass of a psoralen DNA interstrand cross-link by DNA polymerases β, ι, and κ in vitro.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23106263","citation_count":19,"is_preprint":false},{"pmid":"19272601","id":"PMC_19272601","title":"The functional variant rs1048990 in PSMA6 is associated with susceptibility to myocardial infarction in a Chinese population.","date":"2009","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/19272601","citation_count":18,"is_preprint":false},{"pmid":"19624571","id":"PMC_19624571","title":"Haplotypes encompassing the KIAA0391 and PSMA6 gene cluster confer a genetic link for myocardial infarction and coronary artery disease.","date":"2009","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19624571","citation_count":18,"is_preprint":false},{"pmid":"32513715","id":"PMC_32513715","title":"Atypical protein kinase C iota (PKCλ/ι) ensures mammalian development by establishing the maternal-fetal exchange interface.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32513715","citation_count":18,"is_preprint":false},{"pmid":"27409422","id":"PMC_27409422","title":"14-3-3ζ and aPKC-ι synergistically facilitate epithelial-mesenchymal transition of cholangiocarcinoma via GSK-3β/Snail signaling pathway.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27409422","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49961,"output_tokens":1995,"usd":0.089904,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8136,"output_tokens":2006,"usd":0.045415,"stage2_stop_reason":"end_turn"},"total_usd":0.135319,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about PSMA6 (proteasome subunit alpha type 6, also known as PROS27, p27K, IOTA in the proteasome context).\n\nKey observation: Most papers in this corpus are about completely different proteins that share \"iota\" as part of their name:\n- DNA polymerase iota (POLI/RAD30B) - different gene\n- Atypical protein kinase C iota (PKCι/PRKCI) - different gene\n- Clostridium iota-toxin - bacterial toxin\n- Diacylglycerol kinase iota (DGKι) - different gene\n- Iota-carrageenan - polysaccharide\n- SARS-CoV-2 variants named \"Iota\"\n\nPapers actually about PSMA6 (proteasome subunit alpha type 6):\n- PMID 7681138: The prosomal RNA-binding protein p27K (=PROS27=PSMA6)\n- PMID 16845397: Functional SNP in PSMA6 and myocardial infarction\n- PMID 30898113: CRISPR screen identifies PSMA6 as essential in pancreatic cancer\n- PMID 28165654: PSMA6 as therapeutic target in lung cancer\n- PMID 20651835: PSMA6 expression in diabetic rat models\n- PMID 22882272: PSMA6 SNP and ischemic stroke\n- PMID 17555133: PSMA6 SNPs and myocardial infarction/diabetes\n- PMID 18358479: PSMA6 polymorphism and MI in type 2 diabetics\n- PMID 19272601: PSMA6 variant and MI in Chinese population\n- PMID 19624571: PSMA6 haplotypes and CAD/MI\n\nFrom these, mechanistically relevant papers:\n- PMID 7681138: characterizes p27K/PROS27 as an alpha-type prosomal protein with RNA-binding\n- PMID 16845397: SNP enhances PSMA6 transcription; siRNA knockdown reduces NF-κB activation by stabilizing phosphorylated IκB\n- PMID 30898113: PSMA6 knockdown causes apoptosis/G2M arrest in pancreatic cancer cells\n- PMID 28165654: PSMA6 silencing induces apoptosis or G2/M arrest; it's a 20S proteasome subunit\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"PSMA6 (p27K/PROS27) was identified as an alpha-type prosomal/proteasome protein. The protein contains multiple potential phosphorylation sites, an NTP-binding fold, and an RNA-binding consensus sequence. A PROS27/β-galactosidase fusion protein was shown to bind a single RNA of ~120 nucleotides from total HeLa cell RNA, and sequence analysis placed PROS27 within the alpha-type sub-family of the prosome–MCP–proteasome protein family.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal mapping (chromosome 14q13), and RNA-binding assay using fusion protein with HeLa cell RNA\",\n      \"journal\": \"Molecular & general genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-binding assay with fusion protein and sequence-based structural characterization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"7681138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A SNP (rs1048990) in the 5' UTR of PSMA6 enhances PSMA6 transcription. Suppression of PSMA6 expression by siRNA in cultured cells reduced NF-κB activation by stabilizing phosphorylated IκB, establishing PSMA6 (as a 20S proteasome subunit) as a positive regulator of NF-κB activation through IκB degradation.\",\n      \"method\": \"Reporter/transcription assay demonstrating SNP-enhanced transcription; siRNA knockdown with measurement of NF-κB activation and phosphorylated IκB levels\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined molecular readout (phospho-IκB stabilization and NF-κB activity), single lab with two orthogonal functional methods\",\n      \"pmids\": [\"16845397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSMA6, a proteasomal subunit of the 20S catalytic core complex, is required for lung cancer cell survival. Silencing of PSMA6 by shRNA induced apoptosis or G2/M cell cycle arrest in lung cancer cell lines but not in an immortalized normal lung cell line, establishing PSMA6 as an essential component for cancer cell viability.\",\n      \"method\": \"Semi-genome-wide shRNA screening followed by targeted PSMA6 silencing; cell viability, apoptosis, and cell cycle analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA loss-of-function with specific cellular phenotype (apoptosis and G2/M arrest), single lab, validated in multiple cancer lines\",\n      \"pmids\": [\"28165654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMA6 was identified as an essential gene for pancreatic cancer cell survival via genome-wide CRISPR negative-selection screening. siRNA-mediated depletion confirmed that PSMA6 is critical for spheroid formation and survival in multiple pancreatic ductal adenocarcinoma cell models, and pharmacological proteasome inhibition with bortezomib was especially toxic in PANC-1 cells.\",\n      \"method\": \"Genome-wide CRISPR negative-selection screen; siRNA validation across multiple PDAC cell lines; spheroid formation assay; flow cytometry; bortezomib cytotoxicity assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen validated by independent siRNA deconvolution across multiple cell lines with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"30898113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PSMA6 protein expression was significantly reduced in the renal cortex of both STZ-induced and spontaneous OLETF diabetic rat models compared to normal controls, as identified by proteomic profiling of mesangial cells under high-glucose conditions followed by Western blot validation in vivo.\",\n      \"method\": \"2D gel electrophoresis proteomics of primary rat mesangial cells under high glucose; MALDI-TOF-MS protein identification; Western blot validation in two diabetic rat models\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — descriptive proteomics and Western blot showing reduced PSMA6 in diabetic tissue, no functional mechanism established, single lab\",\n      \"pmids\": [\"20651835\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMA6 encodes an alpha-type subunit of the 20S proteasome catalytic core; it contains an RNA-binding domain and was originally identified as a prosomal protein (p27K/PROS27) that binds RNA, and it promotes NF-κB activation by facilitating proteasomal degradation of phosphorylated IκB, with loss-of-function studies showing it is essential for cancer cell survival in lung and pancreatic cancer models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMA6 encodes an alpha-type subunit of the 20S proteasome catalytic core, originally identified as the prosomal protein p27K/PROS27 within the prosome–MCP–proteasome alpha sub-family [#0]. The protein carries an RNA-binding consensus sequence, and a PROS27 fusion protein binds a discrete ~120-nucleotide RNA species from total cellular RNA, marking it as an RNA-associated component of the particle [#0]. As a constituent of the 20S core, PSMA6 acts as a positive regulator of NF-κB signaling: its depletion stabilizes phosphorylated IκB and reduces NF-κB activation, linking the subunit to proteasomal degradation of phospho-IκB [#1]. Loss-of-function studies establish PSMA6 as essential for cancer cell survival — silencing induces apoptosis or G2/M arrest selectively in lung cancer cells [#2] and impairs spheroid formation and viability in pancreatic ductal adenocarcinoma models, where proteasome inhibition by bortezomib is especially cytotoxic [#3]. Beyond these roles in proteasomal degradation, NF-κB regulation, and cancer cell viability, no further mechanistic detail of PSMA6 catalytic chemistry or assembly has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the molecular identity of PSMA6 as an alpha-type prosome/proteasome subunit and uncovered an unexpected RNA-binding property, framing it as more than a passive structural component.\",\n      \"evidence\": \"cDNA cloning, sequence analysis with chromosomal mapping, and an RNA-binding assay using a PROS27/β-galactosidase fusion against HeLa RNA\",\n      \"pmids\": [\"7681138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional significance of the ~120-nt RNA interaction is undefined\", \"No structural placement of the subunit within the assembled 20S core\", \"RNA-binding shown only with a fusion construct, not full-length endogenous protein\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected PSMA6 to a defined signaling output by showing the proteasome subunit drives NF-κB activation through degradation of phosphorylated IκB, with a regulatory SNP modulating its expression.\",\n      \"evidence\": \"Reporter/transcription assay of a 5'UTR SNP plus siRNA knockdown measuring phospho-IκB stabilization and NF-κB activity\",\n      \"pmids\": [\"16845397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether PSMA6 acts via its catalytic core role or a distinct mechanism\", \"No direct biochemical demonstration of phospho-IκB processing by PSMA6-containing proteasomes\", \"SNP-to-phenotype causality in vivo not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked PSMA6 abundance to a disease context by showing reduced expression in diabetic renal tissue, raising the possibility of altered proteasomal capacity in nephropathy.\",\n      \"evidence\": \"2D-gel proteomics of high-glucose mesangial cells with MALDI-TOF identification and Western blot validation in two diabetic rat models\",\n      \"pmids\": [\"20651835\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely descriptive — no functional mechanism established\", \"Correlation between PSMA6 loss and renal pathology not demonstrated causally\", \"Single lab, model-organism observation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that PSMA6 is a survival-essential gene across cancer types, establishing it as a vulnerability whose loss triggers apoptosis/cell-cycle arrest and sensitizes cells to proteasome inhibition.\",\n      \"evidence\": \"Semi-genome-wide shRNA screen in lung cancer with apoptosis/cell-cycle readouts; genome-wide CRISPR negative-selection screen in PDAC with siRNA deconvolution, spheroid assays, and bortezomib cytotoxicity\",\n      \"pmids\": [\"28165654\", \"30898113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity over normal cells shown in limited models\", \"Whether essentiality reflects general proteasome dependence or a PSMA6-specific function is unresolved\", \"No mechanistic link between essentiality and the NF-κB/RNA-binding activities\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical role of PSMA6's RNA-binding activity and its precise contribution to substrate selection within the 20S core remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified physiological RNA ligand or its function\", \"No structural model of PSMA6 within the assembled proteasome from the corpus\", \"Mechanism connecting subunit-level perturbation to NF-κB and cancer-cell phenotypes not directly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"20S proteasome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}