{"gene":"PSMG2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2005,"finding":"PSMG2 (PAC2) forms a heterodimer with PSMG1 (PAC1) that associates with proteasome precursors and promotes alpha-ring formation during mammalian 20S proteasome assembly. Overexpression of PAC1 or PAC2 accelerates precursor proteasome formation, while siRNA knockdown impairs it, resulting in poor 20S proteasome maturation. The PAC1/PAC2 heterodimer provides a scaffold for alpha-ring formation and keeps alpha-rings competent for subsequent half-proteasome formation. After 20S proteasome assembly is completed, PAC1 and PAC2 are degraded.","method":"Co-immunoprecipitation, siRNA knockdown with proteasome maturation assay, overexpression studies, sucrose gradient sedimentation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, KD phenotype, OE), foundational paper replicated in follow-up work","pmids":["16251969"],"is_preprint":false},{"year":2006,"finding":"PSMG2 (PAC2) works cooperatively with PAC1/PAC3 and hUmp1 during 20S proteasome assembly. PAC1/2/3 triple knockdown causes accumulation of disorganized half-proteasomes incompetent for dimerization, revealing that the PAC chaperone system collectively ensures correct alpha-ring formation and half-proteasome assembly.","method":"siRNA triple knockdown, sucrose gradient sedimentation, native PAGE, immunoblot analysis of proteasome precursor complexes","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — epistasis via multiple KD combinations with defined structural phenotype, replicates and extends 2005 Nature findings","pmids":["17189198"],"is_preprint":false},{"year":2020,"finding":"NFE2L1 and NFE2L3 transcription factors complementarily maintain basal PSMG2 expression in cancer cells. Double knockdown of NFE2L1 and NFE2L3 significantly reduces basal PSMG2 mRNA levels (along with six other proteasome-related genes), impairing basal proteasome activity and reducing resistance to the proteasome inhibitor bortezomib.","method":"siRNA double knockdown of NFE2L1/NFE2L3, RT-qPCR, proteasome activity assay, drug resistance assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined molecular and functional phenotype, but PSMG2 is one of seven co-regulated genes","pmids":["32366381"],"is_preprint":false},{"year":2022,"finding":"PSMG2 knockdown impairs proteasome function in triple-negative breast cancer cells, which in turn activates autophagy-mediated degradation of PDPK1. This PDPK1 degradation enhances MEK inhibitor (AZD6244)-induced tumor cell growth inhibition by interrupting negative feedback signals toward the AKT pathway. The autophagy inhibitor chloroquine partially reverses PDPK1 degradation and the growth inhibitory effect, placing PSMG2 upstream of a proteasome–autophagy–PDPK1–AKT signaling axis that mediates MEK inhibitor sensitivity.","method":"CRISPR-Cas9 genome-wide library screen, siRNA knockdown, immunoblot, autophagy inhibitor rescue, xenograft mouse model, proteasome activity assay","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen hit validated by KD, pathway rescue experiments, and in vivo xenograft, multiple orthogonal methods","pmids":["36099919"],"is_preprint":false},{"year":2021,"finding":"Cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSMD13, as revealed by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity.","method":"Immunoprecipitation followed by mass spectrometry, proteasome activity assay","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/MS identification without mutagenesis or reconstitution; mechanistic link to proteasome impairment is correlative","pmids":["34363810"],"is_preprint":false},{"year":2025,"finding":"PSMG2 knockdown in head and neck squamous cell carcinoma (HNSCC) cell lines reduces proliferation in vitro and in vivo, diminishes stemness and dedifferentiation properties, and causes accumulation of polyubiquitinated proteins, increased ER stress, and activation of autophagy and apoptosis as compensatory mechanisms, confirming PSMG2's role as a 20S proteasome assembly chaperone that regulates ER stress and cellular homeostasis.","method":"siRNA knockdown, in vitro proliferation assay, xenograft in vivo assay, flow cytometry (apoptosis), immunoblot (ubiquitinated proteins, ER stress markers, autophagy markers), sphere formation assay (stemness)","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal readouts from KD with defined phenotypes, single lab study","pmids":["40303289"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function mutations in PSMG2 are identified as a cause of proteasome-associated autoinflammatory syndromes (PRAAS), categorized alongside mutations in PSMB8, PSMB9, PSMB7, PSMA3, and POMP. Disruption of PSMG2 results in perturbed intracellular protein homeostasis, accumulation of ubiquitinated proteins, and a type I interferon signature.","method":"Next-generation sequencing of patient samples, interferon response gene score measurement, cytokine profiling","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 — genetic loss-of-function in human patients with defined molecular phenotype (interferon signature, ubiquitin accumulation), consistent with mechanistic role of PSMG2 in proteasome assembly","pmids":["31827472"],"is_preprint":false}],"current_model":"PSMG2 (PAC2) is a dedicated 20S proteasome assembly chaperone that heterodimerizes with PSMG1 (PAC1) to scaffold alpha-ring formation and promote mammalian 20S proteasome biogenesis; loss of PSMG2 impairs proteasome activity, causing accumulation of polyubiquitinated proteins, ER stress, and compensatory activation of autophagy, and in cancer cells the resulting proteasome–autophagy balance regulates PDPK1 stability and drug sensitivity, while germline loss-of-function mutations cause a type I interferonopathy (PRAAS)."},"narrative":{"teleology":[{"year":2005,"claim":"The foundational question of how mammalian 20S proteasome alpha-rings assemble was answered by identifying PSMG2/PSMG1 as a heterodimeric chaperone that scaffolds alpha-ring formation and is degraded upon assembly completion, establishing PSMG2 as a dedicated assembly factor rather than a stoichiometric proteasome subunit.","evidence":"Co-immunoprecipitation, siRNA knockdown, overexpression, and sucrose gradient sedimentation in human cells","pmids":["16251969"],"confidence":"High","gaps":["Structural basis of the PAC1–PAC2 heterodimer interaction with individual alpha subunits was not resolved","Whether PAC2 degradation is proteasome-dependent or uses another pathway was not determined"]},{"year":2006,"claim":"The cooperative relationship between PSMG2 and other assembly chaperones (PAC3, hUmp1) was delineated, showing that triple depletion causes accumulation of disorganized half-proteasomes and establishing that PSMG2 functions within a multi-chaperone system rather than alone.","evidence":"siRNA combinatorial knockdowns with native PAGE and sucrose gradient analysis of proteasome precursors","pmids":["17189198"],"confidence":"High","gaps":["Order of chaperone engagement during assembly was not fully resolved","Whether PAC1/PAC2 and PAC3 act sequentially or simultaneously on the same alpha-ring intermediate was unclear"]},{"year":2019,"claim":"The disease relevance of PSMG2 was established when germline loss-of-function mutations were identified as a cause of PRAAS, directly linking the assembly chaperone role to human autoinflammation through impaired proteasome function, ubiquitin accumulation, and a type I interferon signature.","evidence":"Next-generation sequencing of patient cohorts with interferon signature scoring and cytokine profiling","pmids":["31827472"],"confidence":"Medium","gaps":["Specific PSMG2 mutations and their structural consequences were not biochemically characterized","Whether interferon activation is a direct consequence of impaired proteasome assembly or secondary to downstream stress was not distinguished"]},{"year":2022,"claim":"A cancer-relevant signaling axis downstream of PSMG2 was uncovered: PSMG2 loss impairs proteasome function, activates compensatory autophagy that degrades PDPK1, and thereby sensitizes triple-negative breast cancer cells to MEK inhibition, revealing how proteasome assembly efficiency can rewire survival signaling.","evidence":"CRISPR genome-wide screen, siRNA validation, autophagy inhibitor rescue, and xenograft model in breast cancer cells","pmids":["36099919"],"confidence":"High","gaps":["Whether PDPK1 is a selective autophagy substrate or degraded nonselectively was not determined","Generalizability of this axis beyond triple-negative breast cancer was not tested"]},{"year":2025,"claim":"The generality of PSMG2 as a proteasome assembly chaperone controlling ER stress and cellular homeostasis was extended to HNSCC, where knockdown recapitulated ubiquitin accumulation, ER stress, autophagy induction, and additionally suppressed cancer stemness properties.","evidence":"siRNA knockdown with proliferation, apoptosis, stemness, and xenograft assays in HNSCC cell lines","pmids":["40303289"],"confidence":"Medium","gaps":["Mechanism linking proteasome impairment to loss of stemness was not identified","Whether ER stress or autophagy is the primary driver of the growth-inhibitory phenotype was not dissected"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of the PSMG1–PSMG2 heterodimer bound to alpha-ring intermediates, the precise degradation mechanism of PSMG2 after 20S assembly, and whether therapeutic targeting of PSMG2 can selectively impair proteasome homeostasis in cancer without triggering autoinflammatory pathology.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of human PSMG1–PSMG2 on an alpha-ring intermediate","Degradation pathway of PSMG2 after assembly completion is unknown","Therapeutic window between proteasome impairment and autoinflammation is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6]}],"complexes":["PAC1-PAC2 heterodimer (PSMG1-PSMG2)"],"partners":["PSMG1","PSMG3","PDPK1"],"other_free_text":[]},"mechanistic_narrative":"PSMG2 (PAC2) is a dedicated 20S proteasome assembly chaperone that heterodimerizes with PSMG1 (PAC1) to scaffold alpha-ring formation during proteasome biogenesis; the heterodimer associates with proteasome precursors, maintains alpha-rings competent for half-proteasome dimerization, and is degraded upon completion of 20S assembly [PMID:16251969, PMID:17189198]. Loss of PSMG2 impairs proteasome maturation and activity, leading to accumulation of polyubiquitinated proteins, ER stress, compensatory autophagy activation, and apoptosis [PMID:36099919, PMID:40303289]. In triple-negative breast cancer, PSMG2 depletion redirects PDPK1 to autophagy-mediated degradation, sensitizing cells to MEK inhibition through disruption of AKT-dependent feedback [PMID:36099919]. Germline loss-of-function mutations in PSMG2 cause proteasome-associated autoinflammatory syndrome (PRAAS), characterized by perturbed protein homeostasis and a type I interferon signature [PMID:31827472]."},"prefetch_data":{"uniprot":{"accession":"Q969U7","full_name":"Proteasome assembly chaperone 2","aliases":["Hepatocellular carcinoma-susceptibility protein 3","Tumor necrosis factor superfamily member 5-induced protein 1"],"length_aa":264,"mass_kda":29.4,"function":"Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG1. The PSMG1-PSMG2 heterodimer binds to the PSMA5 and PSMA7 proteasome subunits, promotes assembly of the proteasome alpha subunits into the heteroheptameric alpha ring and prevents alpha ring dimerization","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969U7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMG2","classification":"Common Essential","n_dependent_lines":871,"n_total_lines":1208,"dependency_fraction":0.7210264900662252},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000128789","cell_line_id":"CID000139","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMG1","stoichiometry":10.0},{"gene":"PSMG4","stoichiometry":10.0},{"gene":"PSMG3","stoichiometry":10.0},{"gene":"POMP","stoichiometry":10.0},{"gene":"PSMA7","stoichiometry":0.2},{"gene":"PSMA5","stoichiometry":0.2},{"gene":"PSMB1","stoichiometry":0.2},{"gene":"PSMA2","stoichiometry":0.2},{"gene":"PSMA4","stoichiometry":0.2},{"gene":"PSME1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000139","total_profiled":1310},"omim":[{"mim_id":"619183","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 4; PRAAS4","url":"https://www.omim.org/entry/619183"},{"mim_id":"617528","title":"PROTEASOME ASSEMBLY CHAPERONE 3; PSMG3","url":"https://www.omim.org/entry/617528"},{"mim_id":"609702","title":"PROTEASOME ASSEMBLY CHAPERONE 2; PSMG2","url":"https://www.omim.org/entry/609702"},{"mim_id":"256040","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 1; PRAAS1","url":"https://www.omim.org/entry/256040"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMG2"},"hgnc":{"alias_symbol":["HCCA3","MDS003","MGC15092","CLAST3","HsT1707","PAC2"],"prev_symbol":["TNFSF5IP1"]},"alphafold":{"accession":"Q969U7","domains":[{"cath_id":"3.40.50.10900","chopping":"20-230_246-251","consensus_level":"high","plddt":94.9073,"start":20,"end":251}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969U7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969U7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969U7-F1-predicted_aligned_error_v6.png","plddt_mean":92.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMG2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMG2"},"sequence":{"accession":"Q969U7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969U7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969U7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969U7"}},"corpus_meta":[{"pmid":"31874111","id":"PMC_31874111","title":"Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31874111","citation_count":189,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24150217","id":"PMC_24150217","title":"Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS.","date":"2013","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/24150217","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23257782","id":"PMC_23257782","title":"Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis.","date":"2012","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/23257782","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31827472","id":"PMC_31827472","title":"Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS).","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31827472","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29929428","id":"PMC_29929428","title":"Poliovirus induces autophagic signaling independent of the ULK1 complex.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29929428","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32366381","id":"PMC_32366381","title":"NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression.","date":"2020","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32366381","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17242661","id":"PMC_17242661","title":"Lenalidomide: targeted anemia therapy for myelodysplastic syndromes.","date":"2006","source":"Cancer control : journal of the Moffitt Cancer Center","url":"https://pubmed.ncbi.nlm.nih.gov/17242661","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36099919","id":"PMC_36099919","title":"PSMG2-controlled proteasome-autophagy balance mediates the tolerance for MEK-targeted therapy in triple-negative breast cancer.","date":"2022","source":"Cell reports. 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MCP","url":"https://pubmed.ncbi.nlm.nih.gov/19193609","citation_count":55,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13169,"output_tokens":1616,"usd":0.031873},"stage2":{"model":"claude-opus-4-6","input_tokens":4852,"output_tokens":1918,"usd":0.108315},"total_usd":0.302817,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":25284,"output_tokens":1980,"usd":0.052776},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5492,"output_tokens":1831,"usd":0.109853}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMG2 knockdown impairs proteasome function in triple-negative breast cancer cells, which activates autophagy-mediated PDPK1 degradation, thereby enhancing MEK inhibitor (AZD6244)-induced tumor cell growth inhibition by interrupting negative feedback signals toward the AKT pathway. Autophagy inhibitor chloroquine partially relieves PDPK1 degradation and reverses this growth inhibition, placing PSMG2 upstream of the proteasome-autophagy-PDPK1-AKT axis.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, siRNA knockdown, pharmacological inhibition (MG132, chloroquine), xenograft mouse model\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (CRISPR screen, KD, pharmacological rescue, in vivo xenograft) with defined pathway placement\",\n      \"pmids\": [\"36099919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMG2 forms a heterodimer with PSMG1 and promotes assembly of the 20S proteasome. Knockdown of PSMG2 in head and neck cancer cells causes accumulation of polyubiquitinated proteins, increased endoplasmic reticulum (ER) stress, and activation of autophagy and apoptosis as compensatory mechanisms, reducing proliferation, stemness, and dedifferentiation capacity in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, in vitro proliferation assays, in vivo tumor models, Western blot (polyubiquitinated protein accumulation, ER stress markers), flow cytometry (apoptosis), autophagy assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single lab study with defined cellular phenotypes\",\n      \"pmids\": [\"40303289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutations in PSMG2 (a proteasome assembly factor) cause proteasome-associated autoinflammatory syndrome (PRAAS), characterized by disrupted intracellular protein homeostasis, accumulation of ubiquitinated proteins, and a type I interferon signature. The unfolded protein response (UPR) is implicated as a downstream mechanism linking proteasome impairment to interferonopathy onset.\",\n      \"method\": \"Genetic analysis of patient mutations, biochemical characterization of proteasome dysfunction, UPR pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient genetics combined with biochemical pathway analysis, but mechanistic UPR link is primarily review/inference\",\n      \"pmids\": [\"31827472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSMD13 (PSD13), as identified by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity in a primate model of ALS/FTD.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, proteasome activity assay\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/MS identifies interaction, proteasome activity assay shows functional impairment, but causal link between PSMG2 interaction specifically and proteasome impairment not fully dissected\",\n      \"pmids\": [\"34363810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFE2L1 and NFE2L3 transcription factors complementarily maintain basal proteasome activity in cancer cells; double knockdown of both significantly reduces basal expression of PSMG2 (along with six other proteasome-related genes: PSMB3, PSMB7, PSMC2, PSMD3, PSMG3, POMP), impairing proteasome activity and cancer cell resistance to bortezomib.\",\n      \"method\": \"siRNA double knockdown, qRT-PCR, proteasome activity assay, polysome profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab study, PSMG2 identified as transcriptional target of NFE2L1/NFE2L3 axis\",\n      \"pmids\": [\"32366381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMG2 was identified by mass spectrometry in a porcine cell-free fertilization system as a candidate cofactor in post-fertilization sperm mitophagy (ubiquitin-proteasome-mediated degradation of sperm-borne mitochondria), with phenotyping using porcine in vitro fertilization and cell imaging.\",\n      \"method\": \"Mass spectrometry, porcine cell-free system, in vitro fertilization, cell imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — MS-based identification with limited functional follow-up specific to PSMG2\",\n      \"pmids\": [\"37470242\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMG2 is a proteasome assembly chaperone that forms a heterodimer with PSMG1 to promote 20S proteasome assembly; loss of PSMG2 function impairs proteasomal degradation, causing accumulation of polyubiquitinated proteins, ER stress, and compensatory activation of autophagy, and in cancer cells this proteasome-autophagy balance controls substrate degradation (e.g., PDPK1) and signaling pathway feedback, while germline loss-of-function mutations cause a type I interferonopathy (PRAAS) through proteasome impairment and UPR activation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"PSMG2 (PAC2) forms a heterodimer with PSMG1 (PAC1) that associates with proteasome precursors and promotes alpha-ring formation during mammalian 20S proteasome assembly. Overexpression of PAC1 or PAC2 accelerates precursor proteasome formation, while siRNA knockdown impairs it, resulting in poor 20S proteasome maturation. The PAC1/PAC2 heterodimer provides a scaffold for alpha-ring formation and keeps alpha-rings competent for subsequent half-proteasome formation. After 20S proteasome assembly is completed, PAC1 and PAC2 are degraded.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with proteasome maturation assay, overexpression studies, sucrose gradient sedimentation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, KD phenotype, OE), foundational paper replicated in follow-up work\",\n      \"pmids\": [\"16251969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PSMG2 (PAC2) works cooperatively with PAC1/PAC3 and hUmp1 during 20S proteasome assembly. PAC1/2/3 triple knockdown causes accumulation of disorganized half-proteasomes incompetent for dimerization, revealing that the PAC chaperone system collectively ensures correct alpha-ring formation and half-proteasome assembly.\",\n      \"method\": \"siRNA triple knockdown, sucrose gradient sedimentation, native PAGE, immunoblot analysis of proteasome precursor complexes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via multiple KD combinations with defined structural phenotype, replicates and extends 2005 Nature findings\",\n      \"pmids\": [\"17189198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFE2L1 and NFE2L3 transcription factors complementarily maintain basal PSMG2 expression in cancer cells. Double knockdown of NFE2L1 and NFE2L3 significantly reduces basal PSMG2 mRNA levels (along with six other proteasome-related genes), impairing basal proteasome activity and reducing resistance to the proteasome inhibitor bortezomib.\",\n      \"method\": \"siRNA double knockdown of NFE2L1/NFE2L3, RT-qPCR, proteasome activity assay, drug resistance assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined molecular and functional phenotype, but PSMG2 is one of seven co-regulated genes\",\n      \"pmids\": [\"32366381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMG2 knockdown impairs proteasome function in triple-negative breast cancer cells, which in turn activates autophagy-mediated degradation of PDPK1. This PDPK1 degradation enhances MEK inhibitor (AZD6244)-induced tumor cell growth inhibition by interrupting negative feedback signals toward the AKT pathway. The autophagy inhibitor chloroquine partially reverses PDPK1 degradation and the growth inhibitory effect, placing PSMG2 upstream of a proteasome–autophagy–PDPK1–AKT signaling axis that mediates MEK inhibitor sensitivity.\",\n      \"method\": \"CRISPR-Cas9 genome-wide library screen, siRNA knockdown, immunoblot, autophagy inhibitor rescue, xenograft mouse model, proteasome activity assay\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen hit validated by KD, pathway rescue experiments, and in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"36099919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSMD13, as revealed by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry, proteasome activity assay\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/MS identification without mutagenesis or reconstitution; mechanistic link to proteasome impairment is correlative\",\n      \"pmids\": [\"34363810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMG2 knockdown in head and neck squamous cell carcinoma (HNSCC) cell lines reduces proliferation in vitro and in vivo, diminishes stemness and dedifferentiation properties, and causes accumulation of polyubiquitinated proteins, increased ER stress, and activation of autophagy and apoptosis as compensatory mechanisms, confirming PSMG2's role as a 20S proteasome assembly chaperone that regulates ER stress and cellular homeostasis.\",\n      \"method\": \"siRNA knockdown, in vitro proliferation assay, xenograft in vivo assay, flow cytometry (apoptosis), immunoblot (ubiquitinated proteins, ER stress markers, autophagy markers), sphere formation assay (stemness)\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal readouts from KD with defined phenotypes, single lab study\",\n      \"pmids\": [\"40303289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutations in PSMG2 are identified as a cause of proteasome-associated autoinflammatory syndromes (PRAAS), categorized alongside mutations in PSMB8, PSMB9, PSMB7, PSMA3, and POMP. Disruption of PSMG2 results in perturbed intracellular protein homeostasis, accumulation of ubiquitinated proteins, and a type I interferon signature.\",\n      \"method\": \"Next-generation sequencing of patient samples, interferon response gene score measurement, cytokine profiling\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic loss-of-function in human patients with defined molecular phenotype (interferon signature, ubiquitin accumulation), consistent with mechanistic role of PSMG2 in proteasome assembly\",\n      \"pmids\": [\"31827472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMG2 (PAC2) is a dedicated 20S proteasome assembly chaperone that heterodimerizes with PSMG1 (PAC1) to scaffold alpha-ring formation and promote mammalian 20S proteasome biogenesis; loss of PSMG2 impairs proteasome activity, causing accumulation of polyubiquitinated proteins, ER stress, and compensatory activation of autophagy, and in cancer cells the resulting proteasome–autophagy balance regulates PDPK1 stability and drug sensitivity, while germline loss-of-function mutations cause a type I interferonopathy (PRAAS).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMG2 is a proteasome assembly chaperone that heterodimerizes with PSMG1 to promote 20S proteasome biogenesis, and its loss disrupts protein homeostasis with broad consequences in cancer and immune regulation. Knockdown or loss-of-function of PSMG2 causes accumulation of polyubiquitinated proteins, ER stress, and compensatory activation of autophagy and apoptosis, reducing cancer cell proliferation and stemness [PMID:40303289, PMID:36099919]. In triple-negative breast cancer, PSMG2 depletion channels substrates such as PDPK1 toward autophagy-mediated degradation, interrupting AKT-dependent negative feedback and sensitizing cells to MEK inhibition [PMID:36099919]. Germline loss-of-function mutations in PSMG2 cause proteasome-associated autoinflammatory syndrome (PRAAS), a type I interferonopathy linked to proteasome impairment and unfolded protein response activation [PMID:31827472].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that PSMG2 loss-of-function is disease-causing resolved whether proteasome assembly chaperones contribute to human immunopathology, linking PSMG2 mutations to PRAAS and a type I interferon signature via proteasome impairment and UPR activation.\",\n      \"evidence\": \"Genetic analysis of patient mutations combined with biochemical characterization of proteasome dysfunction and UPR pathway analysis\",\n      \"pmids\": [\"31827472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between proteasome impairment and interferon induction via UPR is inferred rather than directly demonstrated\",\n        \"No rescue experiment confirming causality of specific PSMG2 mutations\",\n        \"Structural basis of how PSMG2 mutations disrupt the PSMG1–PSMG2 heterodimer is unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying NFE2L1 and NFE2L3 as transcriptional regulators of PSMG2 expression established the upstream control of proteasome assembly chaperone abundance and connected it to proteasome inhibitor resistance in cancer.\",\n      \"evidence\": \"siRNA double knockdown of NFE2L1/NFE2L3, qRT-PCR, proteasome activity assay, and polysome profiling in cancer cells\",\n      \"pmids\": [\"32366381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PSMG2 is one of seven co-regulated proteasome genes; its individual contribution to the phenotype is not isolated\",\n        \"Direct promoter binding of NFE2L1/NFE2L3 at the PSMG2 locus not shown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that cytoplasmic mutant TDP-43 physically interacts with PSMG2 and is associated with impaired proteasomal activity raised the possibility that sequestration of assembly chaperones contributes to proteostasis collapse in ALS/FTD.\",\n      \"evidence\": \"Immunoprecipitation and mass spectrometry in a primate ALS/FTD model, coupled with proteasome activity assays\",\n      \"pmids\": [\"34363810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal link between TDP-43–PSMG2 interaction and proteasome impairment not dissected from parallel TDP-43 effects\",\n        \"No reciprocal Co-IP or mutagenesis to confirm direct binding\",\n        \"Functional consequence of depleting PSMG2 specifically in neurons not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placing PSMG2 at the hub of a proteasome–autophagy switch in cancer cells resolved how proteasome impairment reroutes substrate degradation (PDPK1) through autophagy, thereby modulating AKT signaling and MEK inhibitor sensitivity.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen, siRNA knockdown, pharmacological rescue with MG132 and chloroquine, and xenograft tumor models in triple-negative breast cancer\",\n      \"pmids\": [\"36099919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PDPK1 is a direct autophagy cargo or is degraded indirectly is unresolved\",\n        \"Generalizability to non-TNBC cancer types not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comprehensive characterization in head and neck cancer confirmed the PSMG1–PSMG2 heterodimer requirement for 20S proteasome assembly and extended the downstream consequences of PSMG2 loss to ER stress, apoptosis, and loss of stemness/dedifferentiation capacity.\",\n      \"evidence\": \"siRNA knockdown, Western blot for polyubiquitinated proteins and ER stress markers, flow cytometry, autophagy assays, and in vivo tumor models\",\n      \"pmids\": [\"40303289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and structural details of the PSMG1–PSMG2 heterodimer in 20S assembly intermediates remain undefined\",\n        \"Relative contribution of ER stress versus autophagy to the anti-proliferative phenotype not deconvolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural mechanism by which the PSMG1–PSMG2 heterodimer chaperones α-ring assembly, the specificity of substrates rerouted from proteasomal to autophagic degradation upon PSMG2 loss, and the precise signaling pathway from proteasome impairment to type I interferon induction in PRAAS.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the PSMG1–PSMG2–α-ring assembly intermediate\",\n        \"Cargo selectivity of compensatory autophagy upon proteasome impairment is uncharacterized\",\n        \"Molecular bridge between UPR activation and type I interferon signaling in PRAAS not identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"PSMG1–PSMG2 proteasome assembly chaperone heterodimer\"\n    ],\n    \"partners\": [\n      \"PSMG1\",\n      \"PDPK1\",\n      \"TDP-43\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMG2 (PAC2) is a dedicated 20S proteasome assembly chaperone that heterodimerizes with PSMG1 (PAC1) to scaffold alpha-ring formation during proteasome biogenesis; the heterodimer associates with proteasome precursors, maintains alpha-rings competent for half-proteasome dimerization, and is degraded upon completion of 20S assembly [PMID:16251969, PMID:17189198]. Loss of PSMG2 impairs proteasome maturation and activity, leading to accumulation of polyubiquitinated proteins, ER stress, compensatory autophagy activation, and apoptosis [PMID:36099919, PMID:40303289]. In triple-negative breast cancer, PSMG2 depletion redirects PDPK1 to autophagy-mediated degradation, sensitizing cells to MEK inhibition through disruption of AKT-dependent feedback [PMID:36099919]. Germline loss-of-function mutations in PSMG2 cause proteasome-associated autoinflammatory syndrome (PRAAS), characterized by perturbed protein homeostasis and a type I interferon signature [PMID:31827472].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The foundational question of how mammalian 20S proteasome alpha-rings assemble was answered by identifying PSMG2/PSMG1 as a heterodimeric chaperone that scaffolds alpha-ring formation and is degraded upon assembly completion, establishing PSMG2 as a dedicated assembly factor rather than a stoichiometric proteasome subunit.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, and sucrose gradient sedimentation in human cells\",\n      \"pmids\": [\"16251969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the PAC1–PAC2 heterodimer interaction with individual alpha subunits was not resolved\",\n        \"Whether PAC2 degradation is proteasome-dependent or uses another pathway was not determined\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The cooperative relationship between PSMG2 and other assembly chaperones (PAC3, hUmp1) was delineated, showing that triple depletion causes accumulation of disorganized half-proteasomes and establishing that PSMG2 functions within a multi-chaperone system rather than alone.\",\n      \"evidence\": \"siRNA combinatorial knockdowns with native PAGE and sucrose gradient analysis of proteasome precursors\",\n      \"pmids\": [\"17189198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Order of chaperone engagement during assembly was not fully resolved\",\n        \"Whether PAC1/PAC2 and PAC3 act sequentially or simultaneously on the same alpha-ring intermediate was unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The disease relevance of PSMG2 was established when germline loss-of-function mutations were identified as a cause of PRAAS, directly linking the assembly chaperone role to human autoinflammation through impaired proteasome function, ubiquitin accumulation, and a type I interferon signature.\",\n      \"evidence\": \"Next-generation sequencing of patient cohorts with interferon signature scoring and cytokine profiling\",\n      \"pmids\": [\"31827472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific PSMG2 mutations and their structural consequences were not biochemically characterized\",\n        \"Whether interferon activation is a direct consequence of impaired proteasome assembly or secondary to downstream stress was not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A cancer-relevant signaling axis downstream of PSMG2 was uncovered: PSMG2 loss impairs proteasome function, activates compensatory autophagy that degrades PDPK1, and thereby sensitizes triple-negative breast cancer cells to MEK inhibition, revealing how proteasome assembly efficiency can rewire survival signaling.\",\n      \"evidence\": \"CRISPR genome-wide screen, siRNA validation, autophagy inhibitor rescue, and xenograft model in breast cancer cells\",\n      \"pmids\": [\"36099919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PDPK1 is a selective autophagy substrate or degraded nonselectively was not determined\",\n        \"Generalizability of this axis beyond triple-negative breast cancer was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The generality of PSMG2 as a proteasome assembly chaperone controlling ER stress and cellular homeostasis was extended to HNSCC, where knockdown recapitulated ubiquitin accumulation, ER stress, autophagy induction, and additionally suppressed cancer stemness properties.\",\n      \"evidence\": \"siRNA knockdown with proliferation, apoptosis, stemness, and xenograft assays in HNSCC cell lines\",\n      \"pmids\": [\"40303289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking proteasome impairment to loss of stemness was not identified\",\n        \"Whether ER stress or autophagy is the primary driver of the growth-inhibitory phenotype was not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of the PSMG1–PSMG2 heterodimer bound to alpha-ring intermediates, the precise degradation mechanism of PSMG2 after 20S assembly, and whether therapeutic targeting of PSMG2 can selectively impair proteasome homeostasis in cancer without triggering autoinflammatory pathology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of human PSMG1–PSMG2 on an alpha-ring intermediate\",\n        \"Degradation pathway of PSMG2 after assembly completion is unknown\",\n        \"Therapeutic window between proteasome impairment and autoinflammation is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"PAC1-PAC2 heterodimer (PSMG1-PSMG2)\"\n    ],\n    \"partners\": [\n      \"PSMG1\",\n      \"PSMG3\",\n      \"PDPK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}