{"gene":"PSMG3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2019,"finding":"The PAC3-PAC4 heterodimer functions as a molecular matchmaker, stabilizing the α4-α5-α6 subcomplex during assembly of the proteasomal α-ring. A 0.96-Å crystal structure of the PAC3 homodimer was solved, revealing mobility of the loop comprising residues 51–61. NMR data and structural modeling enabled construction of a PAC3-4/α4/α5/α6 quintet complex model.","method":"X-ray crystallography (0.96-Å resolution), NMR spectroscopy, and 3D complex modeling with biochemical validation","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure combined with NMR and functional modeling; multiple orthogonal methods in a single rigorous study","pmids":["31067643"],"is_preprint":false},{"year":2018,"finding":"Thielocin B1 selectively inhibits the PAC3 homodimer protein-protein interaction. SAR and in silico docking studies showed that the natural product-like bending structure and terminal carboxylic acid groups are essential for activity, and that methyl groups on the diphenyl ether moiety contribute to potent, selective inhibition via hydrophobic interactions with the PAC3 homodimer interface.","method":"Chemical synthesis of analogues, biological evaluation of inhibitory activity against PAC3 homodimer vs. PAC1/PAC2, in silico docking","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro inhibition assay combined with SAR and docking, single lab, two complementary approaches","pmids":["30455074"],"is_preprint":false},{"year":2021,"finding":"The Anaplasma phagocytophilum effector protein AptA directly interacts with host PSMG3 (PAC3). This interaction enhances proteasome activity, increases ubiquitination and autophagy in host cells, promotes UPS-autophagy crosstalk, and reduces host cell apoptosis.","method":"Yeast two-hybrid screening to identify AptA-PSMG3 interaction; functional assays in HEK293T cells measuring proteasome activity, ubiquitination, autophagy, and apoptosis upon AptA expression","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus multiple functional cellular readouts in a single lab study; interaction not confirmed by orthogonal pulldown","pmids":["34126152"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM analysis of endogenous chaperone-tagged complexes (via CRISPR/Cas editing) revealed that PAC1-4 (including PAC3/PSMG3) stabilize an early α-ring intermediate subcomplex. PAC3/PAC4 dissociate upon transition to β-ring assembly, coinciding with rearrangement of the PAC1 N-terminal tail. Completion of the β-ring and dimerization of half-proteasomes repositions lysine K33 to trigger β pro-peptide cleavage, leading to concerted dissociation of POMP and PAC1/PAC2 to yield mature 20S proteasomes.","method":"Cryo-EM of endogenous CRISPR-tagged chaperone-bound complexes; structural analysis of assembly intermediates","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural study with CRISPR-tagged endogenous proteins capturing multiple assembly intermediates; single preprint but highly rigorous structural approach","pmids":["bio_10.1101_2024.08.08.607236"],"is_preprint":true},{"year":2024,"finding":"Overexpression of PSMG3 in liver cancer cell lines promoted proliferation, migration, and invasion, establishing an oncogenic cellular function for PSMG3 protein in hepatocellular carcinoma.","method":"In vitro overexpression in liver cancer cell lines with proliferation, migration, and invasion assays","journal":"Clinical & translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression phenotype assays without pathway placement or mechanistic dissection","pmids":["38967739"],"is_preprint":false}],"current_model":"PSMG3 (PAC3) is a proteasome assembly chaperone that forms a PAC3-PAC4 heterodimer to stabilize the α4-α5-α6 subcomplex during α-ring formation; cryo-EM reveals it is subsequently released upon β-ring assembly, and its homodimer interface can be selectively inhibited by thielocin B1 analogues. Additionally, the bacterial effector AptA exploits PSMG3 by direct interaction to enhance host proteasome activity, autophagy, and suppress apoptosis."},"narrative":{"mechanistic_narrative":"PSMG3 (PAC3) is a proteasome assembly chaperone that acts as a molecular matchmaker during biogenesis of the 20S proteasome α-ring [PMID:31067643]. Functioning as a PAC3-PAC4 heterodimer, it stabilizes the α4-α5-α6 subcomplex during α-ring formation, a role supported by an atomic-resolution crystal structure of the PAC3 homodimer and an NMR-validated PAC3-4/α4/α5/α6 quintet complex model [PMID:31067643]. Cryo-EM of endogenous CRISPR-tagged chaperone complexes places PAC3 within the PAC1-4 chaperone set that stabilizes an early α-ring intermediate, from which PAC3/PAC4 dissociate upon the transition to β-ring assembly, ahead of β pro-peptide cleavage and the concerted release of POMP and PAC1/PAC2 that yields the mature 20S proteasome [PMID:bio_10.1101_2024.08.08.607236]. The PAC3 homodimer interface is a druggable target: thielocin B1 analogues selectively inhibit this protein-protein interaction through hydrophobic contacts and terminal carboxylic acid groups [PMID:30455074]. PSMG3 is also exploited by the Anaplasma phagocytophilum effector AptA, which binds PSMG3 directly to enhance host proteasome activity and autophagy and to suppress apoptosis [PMID:34126152].","teleology":[{"year":2018,"claim":"Before this work the PAC3 homodimer interface was not known to be a tractable small-molecule target; demonstrating selective chemical inhibition established it as a druggable protein-protein interaction distinct from PAC1/PAC2.","evidence":"Synthesis and biological evaluation of thielocin B1 analogues against PAC3 homodimer vs PAC1/PAC2, with SAR and in silico docking","pmids":["30455074"],"confidence":"Medium","gaps":["Cellular consequences of PAC3 dimer inhibition on proteasome assembly not shown","Selectivity validated by docking but without co-crystal structure of inhibitor bound","No demonstration of effect on proteasome maturation in cells"]},{"year":2019,"claim":"Resolved how PAC3 contributes to α-ring assembly by defining it as a matchmaker that, with PAC4, stabilizes the α4-α5-α6 subcomplex, providing atomic-resolution structural grounding for its mechanism.","evidence":"0.96-Å crystal structure of the PAC3 homodimer, NMR, and 3D modeling of a PAC3-4/α4/α5/α6 quintet complex with biochemical validation","pmids":["31067643"],"confidence":"High","gaps":["Timing and trigger of PAC3 release during assembly not resolved by static structure","Function of the mobile 51–61 loop not assigned","Model of the quintet complex not validated by full-complex structure"]},{"year":2021,"claim":"Identified a pathogen route to hijack PSMG3, showing the Anaplasma effector AptA binds PSMG3 to reprogram host proteasome activity, autophagy, and apoptosis — extending PSMG3 relevance to host-pathogen interaction.","evidence":"Yeast two-hybrid identification of AptA-PSMG3 interaction plus functional assays in HEK293T cells (proteasome activity, ubiquitination, autophagy, apoptosis)","pmids":["34126152"],"confidence":"Medium","gaps":["Interaction not confirmed by orthogonal pulldown or in infection context","Whether AptA acts via PSMG3's assembly-chaperone function or an independent activity is unresolved","Mechanism linking PSMG3 binding to UPS-autophagy crosstalk not defined"]},{"year":2024,"claim":"Placed PAC3 within the ordered choreography of 20S assembly, capturing endogenous intermediates and defining the precise transition at which PAC3/PAC4 dissociate during β-ring formation.","evidence":"Cryo-EM of endogenous CRISPR-tagged chaperone-bound assembly intermediates (preprint)","pmids":["bio_10.1101_2024.08.08.607236"],"confidence":"High","gaps":["Preprint not peer-reviewed","Molecular signal triggering PAC3/PAC4 release not mechanistically dissected","Fate of dissociated PAC3 not tracked"]},{"year":2024,"claim":"Raised a candidate disease role by linking PSMG3 overexpression to oncogenic phenotypes in hepatocellular carcinoma cells.","evidence":"Overexpression in liver cancer cell lines with proliferation, migration, and invasion assays","pmids":["38967739"],"confidence":"Low","gaps":["Single-lab overexpression phenotype without mechanistic or pathway placement","No connection drawn to PSMG3's proteasome-assembly function","No in vivo or patient-level validation"]},{"year":null,"claim":"How PSMG3's assembly-chaperone activity mechanistically connects to its reported roles in host-pathogen UPS-autophagy crosstalk and cancer cell phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanistic link between assembly chaperone function and oncogenic phenotype","AptA-PSMG3 functional axis not validated beyond a single study"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3]}],"complexes":["PAC3-PAC4 heterodimer","20S proteasome assembly intermediate (PAC1-4/POMP)"],"partners":["PSMG4","PSMA7","PSMA5","PSMA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BT73","full_name":"Proteasome assembly chaperone 3","aliases":["Proteasome chaperone homolog 3","Pba3"],"length_aa":122,"mass_kda":13.1,"function":"Chaperone protein which promotes assembly of the 20S proteasome. May cooperate with PSMG1-PSMG2 heterodimers to orchestrate the correct assembly of proteasomes","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9BT73/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMG3","classification":"Common Essential","n_dependent_lines":1156,"n_total_lines":1208,"dependency_fraction":0.956953642384106},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000157778","cell_line_id":"CID000129","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMG2","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMA7","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":4.0},{"gene":"PSME3","stoichiometry":4.0},{"gene":"PSMG1","stoichiometry":0.2},{"gene":"PSMF1","stoichiometry":0.2},{"gene":"PSMD6","stoichiometry":0.2},{"gene":"PSME1","stoichiometry":0.2},{"gene":"SLC4A7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000129","total_profiled":1310},"omim":[{"mim_id":"617550","title":"PROTEASOME ASSEMBLY CHAPERONE 4; PSMG4","url":"https://www.omim.org/entry/617550"},{"mim_id":"617528","title":"PROTEASOME ASSEMBLY CHAPERONE 3; PSMG3","url":"https://www.omim.org/entry/617528"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMG3"},"hgnc":{"alias_symbol":["MGC10911","PAC3"],"prev_symbol":["C7orf48"]},"alphafold":{"accession":"Q9BT73","domains":[{"cath_id":"3.30.230.90","chopping":"7-118","consensus_level":"high","plddt":93.6037,"start":7,"end":118}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BT73","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BT73-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BT73-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMG3","jax_strain_url":"https://www.jax.org/strain/search?query=PSMG3"},"sequence":{"accession":"Q9BT73","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BT73.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BT73/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BT73"}},"corpus_meta":[{"pmid":"31661146","id":"PMC_31661146","title":"Novel lncRNA PSMG3‑AS1 functions as a miR‑143‑3p sponge to increase the proliferation and migration of breast cancer cells.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31661146","citation_count":31,"is_preprint":false},{"pmid":"31067643","id":"PMC_31067643","title":"Molecular and Structural Basis of the Proteasome α Subunit Assembly Mechanism Mediated by the Proteasome-Assembling Chaperone PAC3-PAC4 Heterodimer.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31067643","citation_count":23,"is_preprint":false},{"pmid":"32801875","id":"PMC_32801875","title":"miR-143-3p Targets lncRNA PSMG3-AS1 to Inhibit the Proliferation of Hepatocellular Carcinoma Cells.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32801875","citation_count":19,"is_preprint":false},{"pmid":"28107376","id":"PMC_28107376","title":"Deletion of pH Regulator pac-3 Affects Cellulase and Xylanase Activity during Sugarcane Bagasse Degradation by Neurospora crassa.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28107376","citation_count":18,"is_preprint":false},{"pmid":"32471413","id":"PMC_32471413","title":"MiR-449b-5p targets lncRNA PSMG3-AS1 to suppress cancer cell proliferation in lung adenocarcinoma.","date":"2020","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32471413","citation_count":17,"is_preprint":false},{"pmid":"31551996","id":"PMC_31551996","title":"The pH Signaling Transcription Factor PAC-3 Regulates Metabolic and Developmental Processes in Pathogenic Fungi.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31551996","citation_count":12,"is_preprint":false},{"pmid":"32529538","id":"PMC_32529538","title":"Overexpression of LncRNA PSMG3-AS1 Distinguishes Glioblastomas from Sarcoidosis.","date":"2020","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/32529538","citation_count":11,"is_preprint":false},{"pmid":"27557053","id":"PMC_27557053","title":"Molecular Components of the Neurospora crassa pH Signaling Pathway and Their Regulation by pH and the PAC-3 Transcription Factor.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27557053","citation_count":11,"is_preprint":false},{"pmid":"35380741","id":"PMC_35380741","title":"PSMG3-AS1 enhances glioma resistance to temozolomide via stabilizing c-Myc in the nucleus.","date":"2022","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/35380741","citation_count":8,"is_preprint":false},{"pmid":"28567445","id":"PMC_28567445","title":"Unique Features of Aeromonas Plasmid pAC3 and Expression of the Plasmid-Mediated Quinolone Resistance Genes.","date":"2017","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/28567445","citation_count":7,"is_preprint":false},{"pmid":"34539855","id":"PMC_34539855","title":"Expression of oncogenic long noncoding RNA PSMG3-antisense 1 in lung squamous cell carcinoma.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34539855","citation_count":6,"is_preprint":false},{"pmid":"30455074","id":"PMC_30455074","title":"Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer.","date":"2018","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30455074","citation_count":6,"is_preprint":false},{"pmid":"34751795","id":"PMC_34751795","title":"LncRNAs PSMG3-AS1 and MEG3 negatively regulate each other to participate in endometrial carcinoma cell proliferation.","date":"2021","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/34751795","citation_count":5,"is_preprint":false},{"pmid":"33986863","id":"PMC_33986863","title":"miR-4417 targets lncRNA PSMG3-AS1 to suppress cell invasion and migration in cervical squamous cell carcinoma.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33986863","citation_count":5,"is_preprint":false},{"pmid":"34126152","id":"PMC_34126152","title":"Anaplasma phagocytophilum AptA enhances the UPS, autophagy, and anti-apoptosis of host cells by PSMG3.","date":"2021","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/34126152","citation_count":5,"is_preprint":false},{"pmid":"37023254","id":"PMC_37023254","title":"LncRNA PSMG3-AS1 is upregulated in prostate carcinoma and downregulates miR-106b through DNA methylation.","date":"2023","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37023254","citation_count":3,"is_preprint":false},{"pmid":"36777518","id":"PMC_36777518","title":"Long non-coding RNA PSMG3 Antisense RNA 1 is correlated with oral squamous cell carcinoma and regulates cancer cell proliferation by targeting premature microRNA-141.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36777518","citation_count":3,"is_preprint":false},{"pmid":"32584919","id":"PMC_32584919","title":"The PAC-3 transcription factor critically regulates phenotype-associated genes in Neurospora crassa.","date":"2020","source":"Genetics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32584919","citation_count":3,"is_preprint":false},{"pmid":"38967739","id":"PMC_38967739","title":"Comprehensive analysis of PSMG3 in pan-cancer and validation of its role in hepatocellular carcinoma.","date":"2024","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/38967739","citation_count":2,"is_preprint":false},{"pmid":"41020915","id":"PMC_41020915","title":"Unveiling the oncogenic functions of lncRNA PSMG3-AS1: a review of its biological roles in cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41020915","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.08.607236","title":"Structural basis of human 20S proteasome biogenesis","date":"2024-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.08.607236","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12499,"output_tokens":1409,"usd":0.029316,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8165,"output_tokens":2345,"usd":0.049725,"stage2_stop_reason":"end_turn"},"total_usd":0.079041,"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\": 2019,\n      \"finding\": \"The PAC3-PAC4 heterodimer functions as a molecular matchmaker, stabilizing the α4-α5-α6 subcomplex during assembly of the proteasomal α-ring. A 0.96-Å crystal structure of the PAC3 homodimer was solved, revealing mobility of the loop comprising residues 51–61. NMR data and structural modeling enabled construction of a PAC3-4/α4/α5/α6 quintet complex model.\",\n      \"method\": \"X-ray crystallography (0.96-Å resolution), NMR spectroscopy, and 3D complex modeling with biochemical validation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure combined with NMR and functional modeling; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31067643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Thielocin B1 selectively inhibits the PAC3 homodimer protein-protein interaction. SAR and in silico docking studies showed that the natural product-like bending structure and terminal carboxylic acid groups are essential for activity, and that methyl groups on the diphenyl ether moiety contribute to potent, selective inhibition via hydrophobic interactions with the PAC3 homodimer interface.\",\n      \"method\": \"Chemical synthesis of analogues, biological evaluation of inhibitory activity against PAC3 homodimer vs. PAC1/PAC2, in silico docking\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro inhibition assay combined with SAR and docking, single lab, two complementary approaches\",\n      \"pmids\": [\"30455074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Anaplasma phagocytophilum effector protein AptA directly interacts with host PSMG3 (PAC3). This interaction enhances proteasome activity, increases ubiquitination and autophagy in host cells, promotes UPS-autophagy crosstalk, and reduces host cell apoptosis.\",\n      \"method\": \"Yeast two-hybrid screening to identify AptA-PSMG3 interaction; functional assays in HEK293T cells measuring proteasome activity, ubiquitination, autophagy, and apoptosis upon AptA expression\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus multiple functional cellular readouts in a single lab study; interaction not confirmed by orthogonal pulldown\",\n      \"pmids\": [\"34126152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM analysis of endogenous chaperone-tagged complexes (via CRISPR/Cas editing) revealed that PAC1-4 (including PAC3/PSMG3) stabilize an early α-ring intermediate subcomplex. PAC3/PAC4 dissociate upon transition to β-ring assembly, coinciding with rearrangement of the PAC1 N-terminal tail. Completion of the β-ring and dimerization of half-proteasomes repositions lysine K33 to trigger β pro-peptide cleavage, leading to concerted dissociation of POMP and PAC1/PAC2 to yield mature 20S proteasomes.\",\n      \"method\": \"Cryo-EM of endogenous CRISPR-tagged chaperone-bound complexes; structural analysis of assembly intermediates\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural study with CRISPR-tagged endogenous proteins capturing multiple assembly intermediates; single preprint but highly rigorous structural approach\",\n      \"pmids\": [\"bio_10.1101_2024.08.08.607236\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of PSMG3 in liver cancer cell lines promoted proliferation, migration, and invasion, establishing an oncogenic cellular function for PSMG3 protein in hepatocellular carcinoma.\",\n      \"method\": \"In vitro overexpression in liver cancer cell lines with proliferation, migration, and invasion assays\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression phenotype assays without pathway placement or mechanistic dissection\",\n      \"pmids\": [\"38967739\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMG3 (PAC3) is a proteasome assembly chaperone that forms a PAC3-PAC4 heterodimer to stabilize the α4-α5-α6 subcomplex during α-ring formation; cryo-EM reveals it is subsequently released upon β-ring assembly, and its homodimer interface can be selectively inhibited by thielocin B1 analogues. Additionally, the bacterial effector AptA exploits PSMG3 by direct interaction to enhance host proteasome activity, autophagy, and suppress apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMG3 (PAC3) is a proteasome assembly chaperone that acts as a molecular matchmaker during biogenesis of the 20S proteasome α-ring [#0]. Functioning as a PAC3-PAC4 heterodimer, it stabilizes the α4-α5-α6 subcomplex during α-ring formation, a role supported by an atomic-resolution crystal structure of the PAC3 homodimer and an NMR-validated PAC3-4/α4/α5/α6 quintet complex model [#0]. Cryo-EM of endogenous CRISPR-tagged chaperone complexes places PAC3 within the PAC1-4 chaperone set that stabilizes an early α-ring intermediate, from which PAC3/PAC4 dissociate upon the transition to β-ring assembly, ahead of β pro-peptide cleavage and the concerted release of POMP and PAC1/PAC2 that yields the mature 20S proteasome [#3]. The PAC3 homodimer interface is a druggable target: thielocin B1 analogues selectively inhibit this protein-protein interaction through hydrophobic contacts and terminal carboxylic acid groups [#1]. PSMG3 is also exploited by the Anaplasma phagocytophilum effector AptA, which binds PSMG3 directly to enhance host proteasome activity and autophagy and to suppress apoptosis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Before this work the PAC3 homodimer interface was not known to be a tractable small-molecule target; demonstrating selective chemical inhibition established it as a druggable protein-protein interaction distinct from PAC1/PAC2.\",\n      \"evidence\": \"Synthesis and biological evaluation of thielocin B1 analogues against PAC3 homodimer vs PAC1/PAC2, with SAR and in silico docking\",\n      \"pmids\": [\"30455074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequences of PAC3 dimer inhibition on proteasome assembly not shown\", \"Selectivity validated by docking but without co-crystal structure of inhibitor bound\", \"No demonstration of effect on proteasome maturation in cells\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved how PAC3 contributes to α-ring assembly by defining it as a matchmaker that, with PAC4, stabilizes the α4-α5-α6 subcomplex, providing atomic-resolution structural grounding for its mechanism.\",\n      \"evidence\": \"0.96-Å crystal structure of the PAC3 homodimer, NMR, and 3D modeling of a PAC3-4/α4/α5/α6 quintet complex with biochemical validation\",\n      \"pmids\": [\"31067643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing and trigger of PAC3 release during assembly not resolved by static structure\", \"Function of the mobile 51–61 loop not assigned\", \"Model of the quintet complex not validated by full-complex structure\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a pathogen route to hijack PSMG3, showing the Anaplasma effector AptA binds PSMG3 to reprogram host proteasome activity, autophagy, and apoptosis — extending PSMG3 relevance to host-pathogen interaction.\",\n      \"evidence\": \"Yeast two-hybrid identification of AptA-PSMG3 interaction plus functional assays in HEK293T cells (proteasome activity, ubiquitination, autophagy, apoptosis)\",\n      \"pmids\": [\"34126152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not confirmed by orthogonal pulldown or in infection context\", \"Whether AptA acts via PSMG3's assembly-chaperone function or an independent activity is unresolved\", \"Mechanism linking PSMG3 binding to UPS-autophagy crosstalk not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PAC3 within the ordered choreography of 20S assembly, capturing endogenous intermediates and defining the precise transition at which PAC3/PAC4 dissociate during β-ring formation.\",\n      \"evidence\": \"Cryo-EM of endogenous CRISPR-tagged chaperone-bound assembly intermediates (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.08.08.607236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not peer-reviewed\", \"Molecular signal triggering PAC3/PAC4 release not mechanistically dissected\", \"Fate of dissociated PAC3 not tracked\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Raised a candidate disease role by linking PSMG3 overexpression to oncogenic phenotypes in hepatocellular carcinoma cells.\",\n      \"evidence\": \"Overexpression in liver cancer cell lines with proliferation, migration, and invasion assays\",\n      \"pmids\": [\"38967739\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab overexpression phenotype without mechanistic or pathway placement\", \"No connection drawn to PSMG3's proteasome-assembly function\", \"No in vivo or patient-level validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMG3's assembly-chaperone activity mechanistically connects to its reported roles in host-pathogen UPS-autophagy crosstalk and cancer cell phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic link between assembly chaperone function and oncogenic phenotype\", \"AptA-PSMG3 functional axis not validated beyond a single study\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"PAC3-PAC4 heterodimer\", \"20S proteasome assembly intermediate (PAC1-4/POMP)\"],\n    \"partners\": [\"PSMG4\", \"PSMA7\", \"PSMA5\", \"PSMA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}