{"gene":"PSMG2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2002,"finding":"CLAST3 (PSMG2) is a cell cycle-regulated protein that localizes to discrete nuclear foci; forced overexpression induces growth retardation, polyploidy, and multinucleated cells by interfering with the mitotic spindle checkpoint, while antisense-mediated knockdown decreases G2/M cells and increases apoptosis.","method":"Immunofluorescence localization, forced overexpression with nocodazole treatment, antisense oligonucleotide knockdown with cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression and knockdown experiments with specific phenotypic readouts (polyploidy, G2/M changes, apoptosis) and localization, single lab with multiple orthogonal methods","pmids":["12147697"],"is_preprint":false},{"year":2022,"finding":"PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation, significantly enhancing MEK inhibitor (AZD6244)-induced tumor growth inhibition in TNBC cells; the autophagy inhibitor chloroquine partially reverses PDPK1 degradation and the growth inhibition phenotype, placing PSMG2 upstream of proteasome-autophagy balance and PDPK1-AKT negative feedback signaling.","method":"Genome-wide CRISPR-Cas9 screen, PSMG2 knockdown, autophagy inhibitor rescue, proteasome activity assays, xenograft mouse model","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen discovery followed by mechanistic validation with KD, rescue experiments, proteasome assays, and in vivo xenograft, multiple orthogonal methods in one study","pmids":["36099919"],"is_preprint":false},{"year":2025,"finding":"PSMG2 forms a heterodimer with PSMG1 and promotes assembly of the 20S proteasome; knockdown of PSMG2 in HNSCC cells causes accumulation of polyubiquitinated proteins, triggers ER stress, activates autophagy and apoptosis as compensatory mechanisms, and reduces stemness and dedifferentiation properties in vitro and in vivo.","method":"PSMG2 knockdown in cancer cell lines, polyubiquitinated protein accumulation assay, ER stress markers, autophagy/apoptosis assays, in vitro and in vivo proliferation/stemness assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct KD with multiple orthogonal mechanistic readouts (UPS impairment, ER stress, autophagy, stemness) in a single lab study","pmids":["40303289"],"is_preprint":false},{"year":2021,"finding":"Cytoplasmic mutant TDP-43 interacts with proteasome assembly protein PSMG2 (and PSD13) as identified by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity.","method":"Immunoprecipitation and mass spectrometry from rhesus monkey model expressing mutant TDP-43(M337V)","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS experiment identifying interaction, no direct mutagenesis or reconstitution to confirm functional consequence for PSMG2 specifically","pmids":["34363810"],"is_preprint":false},{"year":2020,"finding":"NFE2L1 and NFE2L3 double knockdown significantly reduces basal expression of PSMG2 (along with six other proteasome-related genes), impairs basal proteasome activity in cancer cells, and reduces resistance to the proteasome inhibitor bortezomib, placing PSMG2 expression under transcriptional control of the NFE2L1/NFE2L3 axis.","method":"Double siRNA knockdown of NFE2L1 and NFE2L3, proteasome activity assay, bortezomib resistance assay, gene expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean double KD with functional proteasome activity readout and drug resistance phenotype, but PSMG2 is one of seven genes affected, so specificity is moderate","pmids":["32366381"],"is_preprint":false},{"year":2001,"finding":"HCCA3 (PSMG2) was cloned as a novel full-length cDNA identified by differential display PCR between hepatocellular carcinoma and surrounding liver tissue; it is widely distributed in human normal tissues with high expression in lung, brain, and colon and low expression in liver.","method":"mRNA differential display PCR, cDNA library screening, Northern blot","journal":"World journal of gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene cloning and expression characterization with no functional mechanistic experiment","pmids":["11854909"],"is_preprint":false},{"year":2019,"finding":"PSMG2 is identified as a proteasome assembly factor whose loss-of-function mutations cause PRAAS (proteasome-associated autoinflammatory syndrome) with a type I interferon signature, placing PSMG2 in the pathway of proteasome assembly alongside PSMB8, PSMB9, PSMB7, PSMA3, and POMP; disruption leads to accumulation of ubiquitinated proteins.","method":"Review synthesizing genetic and functional data from PRAAS patient mutations and cellular studies","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper synthesizing existing findings; no new direct experiment on PSMG2 mechanism reported in this abstract","pmids":["31827472"],"is_preprint":false}],"current_model":"PSMG2 (CLAST3/HCCA3) is a proteasome assembly chaperone that heterodimerizes with PSMG1 to promote 20S proteasome assembly; loss of PSMG2 impairs proteasome function, causing polyubiquitinated protein accumulation, ER stress, and compensatory activation of autophagy and apoptosis, while PSMG2-controlled proteasome-autophagy balance regulates PDPK1 stability and downstream AKT signaling; PSMG2 expression is transcriptionally maintained by NFE2L1/NFE2L3, and its mutations cause proteasome-associated autoinflammatory syndrome (PRAAS) with type I interferon signatures."},"narrative":{"mechanistic_narrative":"PSMG2 (CLAST3/HCCA3) is a proteasome assembly chaperone that heterodimerizes with PSMG1 to drive maturation of the 20S proteasome [PMID:40303289]. Loss of PSMG2 impairs proteasomal activity and causes accumulation of polyubiquitinated proteins, which triggers ER stress and engages autophagy and apoptosis as compensatory responses [PMID:40303289]. This proteasome-autophagy balance governed by PSMG2 has downstream signaling consequences: PSMG2 knockdown activates autophagy-mediated degradation of PDPK1, sensitizing triple-negative breast cancer cells to MEK inhibition through the PDPK1-AKT axis, an effect reversed by autophagy blockade [PMID:36099919]. PSMG2 expression is transcriptionally maintained by the NFE2L1/NFE2L3 axis, and its depletion impairs basal proteasome activity and reduces resistance to proteasome inhibitors [PMID:32366381]. An earlier characterization linked PSMG2 to cell cycle progression, with overexpression causing polyploidy and mitotic spindle checkpoint interference and knockdown reducing G2/M cells and increasing apoptosis [PMID:12147697]. Loss-of-function PSMG2 mutations are associated with proteasome-associated autoinflammatory syndrome (PRAAS) bearing a type I interferon signature [PMID:31827472].","teleology":[{"year":2001,"claim":"Established PSMG2/HCCA3 as a distinct gene by cloning it from a hepatocellular carcinoma differential-display screen, providing the molecular entity and its tissue expression profile before any function was known.","evidence":"mRNA differential display PCR, cDNA library screening, and Northern blot across human tissues","pmids":["11854909"],"confidence":"Low","gaps":["No functional or mechanistic experiment","Differential expression in HCC does not establish a causal role","Subcellular localization and molecular activity undefined"]},{"year":2002,"claim":"First functional readout linked PSMG2/CLAST3 to cell cycle control, showing it localizes to nuclear foci and that altering its level perturbs mitotic progression and viability.","evidence":"Immunofluorescence, forced overexpression with nocodazole, and antisense knockdown with cell cycle analysis","pmids":["12147697"],"confidence":"Medium","gaps":["Mechanistic link between PSMG2 and the spindle checkpoint not defined","Predates the proteasome-chaperone model and is not reconciled with it","No molecular partners identified"]},{"year":2020,"claim":"Defined the upstream transcriptional control of PSMG2, placing it under the NFE2L1/NFE2L3 axis that maintains basal proteasome capacity and drug resistance.","evidence":"Double siRNA knockdown of NFE2L1/NFE2L3 with proteasome activity assays and bortezomib resistance readouts","pmids":["32366381"],"confidence":"Medium","gaps":["PSMG2 is one of seven co-regulated genes, limiting specificity","Direct promoter binding not demonstrated","Contribution of PSMG2 alone to the proteasome phenotype not isolated"]},{"year":2021,"claim":"Connected PSMG2 to neurodegeneration-associated proteostasis by identifying it as an interactor of cytoplasmic mutant TDP-43 in a context of proteasomal impairment.","evidence":"Immunoprecipitation and mass spectrometry from a rhesus model expressing mutant TDP-43(M337V)","pmids":["34363810"],"confidence":"Low","gaps":["Single Co-IP/MS without reciprocal validation or mutagenesis","Functional consequence for PSMG2 specifically not established","Direct versus indirect interaction unresolved"]},{"year":2022,"claim":"Positioned PSMG2 upstream of a proteasome-autophagy balance that controls PDPK1-AKT signaling, revealing how proteasome assembly failure reshapes oncogenic signaling and drug response.","evidence":"Genome-wide CRISPR-Cas9 screen, knockdown, autophagy-inhibitor rescue, proteasome assays, and xenograft model in TNBC","pmids":["36099919"],"confidence":"High","gaps":["Mechanism by which autophagy selectively targets PDPK1 not defined","Generalizability beyond TNBC and MEK-inhibitor context unclear","Direct biochemical demonstration of PSMG2 in proteasome assembly not shown here"]},{"year":2025,"claim":"Provided the core mechanistic model that PSMG2 heterodimerizes with PSMG1 to assemble the 20S proteasome, linking its loss to polyubiquitin accumulation, ER stress, and compensatory autophagy/apoptosis.","evidence":"Knockdown in HNSCC cells with polyubiquitin, ER stress, autophagy/apoptosis, and stemness assays in vitro and in vivo","pmids":["40303289"],"confidence":"Medium","gaps":["Structural details of the PSMG1-PSMG2 heterodimer not resolved","Direct reconstitution of assembly chaperone activity not shown","Single-lab study"]},{"year":null,"claim":"How PSMG2's earlier cell-cycle/spindle-checkpoint phenotype mechanistically relates to its role as a 20S proteasome assembly chaperone remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PSMG1-PSMG2 acting on 20S intermediates","Direct biochemical demonstration of chaperone-mediated assembly in human cells absent","Reconciliation of nuclear-foci localization with cytoplasmic proteasome assembly function unaddressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2]}],"complexes":["PSMG1-PSMG2 proteasome assembly chaperone heterodimer"],"partners":["PSMG1","TDP-43"],"other_free_text":[]}},"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":190,"is_preprint":false},{"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},{"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":64,"is_preprint":false},{"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},{"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":49,"is_preprint":false},{"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},{"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},{"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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forced overexpression induces growth retardation, polyploidy, and multinucleated cells by interfering with the mitotic spindle checkpoint, while antisense-mediated knockdown decreases G2/M cells and increases apoptosis.\",\n      \"method\": \"Immunofluorescence localization, forced overexpression with nocodazole treatment, antisense oligonucleotide knockdown with cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression and knockdown experiments with specific phenotypic readouts (polyploidy, G2/M changes, apoptosis) and localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12147697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMG2 knockdown impairs proteasome function, which in turn activates autophagy-mediated PDPK1 degradation, significantly enhancing MEK inhibitor (AZD6244)-induced tumor growth inhibition in TNBC cells; the autophagy inhibitor chloroquine partially reverses PDPK1 degradation and the growth inhibition phenotype, placing PSMG2 upstream of proteasome-autophagy balance and PDPK1-AKT negative feedback signaling.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, PSMG2 knockdown, autophagy inhibitor rescue, proteasome activity assays, xenograft mouse model\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen discovery followed by mechanistic validation with KD, rescue experiments, proteasome assays, and in vivo xenograft, multiple orthogonal methods in one study\",\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 HNSCC cells causes accumulation of polyubiquitinated proteins, triggers ER stress, activates autophagy and apoptosis as compensatory mechanisms, and reduces stemness and dedifferentiation properties in vitro and in vivo.\",\n      \"method\": \"PSMG2 knockdown in cancer cell lines, polyubiquitinated protein accumulation assay, ER stress markers, autophagy/apoptosis assays, in vitro and in vivo proliferation/stemness assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct KD with multiple orthogonal mechanistic readouts (UPS impairment, ER stress, autophagy, stemness) in a single lab study\",\n      \"pmids\": [\"40303289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cytoplasmic mutant TDP-43 interacts with proteasome assembly protein PSMG2 (and PSD13) as identified by immunoprecipitation and mass spectrometry, and this interaction is associated with impairment of proteasomal activity.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry from rhesus monkey model expressing mutant TDP-43(M337V)\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS experiment identifying interaction, no direct mutagenesis or reconstitution to confirm functional consequence for PSMG2 specifically\",\n      \"pmids\": [\"34363810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFE2L1 and NFE2L3 double knockdown significantly reduces basal expression of PSMG2 (along with six other proteasome-related genes), impairs basal proteasome activity in cancer cells, and reduces resistance to the proteasome inhibitor bortezomib, placing PSMG2 expression under transcriptional control of the NFE2L1/NFE2L3 axis.\",\n      \"method\": \"Double siRNA knockdown of NFE2L1 and NFE2L3, proteasome activity assay, bortezomib resistance assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean double KD with functional proteasome activity readout and drug resistance phenotype, but PSMG2 is one of seven genes affected, so specificity is moderate\",\n      \"pmids\": [\"32366381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HCCA3 (PSMG2) was cloned as a novel full-length cDNA identified by differential display PCR between hepatocellular carcinoma and surrounding liver tissue; it is widely distributed in human normal tissues with high expression in lung, brain, and colon and low expression in liver.\",\n      \"method\": \"mRNA differential display PCR, cDNA library screening, Northern blot\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene cloning and expression characterization with no functional mechanistic experiment\",\n      \"pmids\": [\"11854909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMG2 is identified as a proteasome assembly factor whose loss-of-function mutations cause PRAAS (proteasome-associated autoinflammatory syndrome) with a type I interferon signature, placing PSMG2 in the pathway of proteasome assembly alongside PSMB8, PSMB9, PSMB7, PSMA3, and POMP; disruption leads to accumulation of ubiquitinated proteins.\",\n      \"method\": \"Review synthesizing genetic and functional data from PRAAS patient mutations and cellular studies\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper synthesizing existing findings; no new direct experiment on PSMG2 mechanism reported in this abstract\",\n      \"pmids\": [\"31827472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMG2 (CLAST3/HCCA3) is a proteasome assembly chaperone that heterodimerizes with PSMG1 to promote 20S proteasome assembly; loss of PSMG2 impairs proteasome function, causing polyubiquitinated protein accumulation, ER stress, and compensatory activation of autophagy and apoptosis, while PSMG2-controlled proteasome-autophagy balance regulates PDPK1 stability and downstream AKT signaling; PSMG2 expression is transcriptionally maintained by NFE2L1/NFE2L3, and its mutations cause proteasome-associated autoinflammatory syndrome (PRAAS) with type I interferon signatures.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMG2 (CLAST3/HCCA3) is a proteasome assembly chaperone that heterodimerizes with PSMG1 to drive maturation of the 20S proteasome [#2]. Loss of PSMG2 impairs proteasomal activity and causes accumulation of polyubiquitinated proteins, which triggers ER stress and engages autophagy and apoptosis as compensatory responses [#2]. This proteasome-autophagy balance governed by PSMG2 has downstream signaling consequences: PSMG2 knockdown activates autophagy-mediated degradation of PDPK1, sensitizing triple-negative breast cancer cells to MEK inhibition through the PDPK1-AKT axis, an effect reversed by autophagy blockade [#1]. PSMG2 expression is transcriptionally maintained by the NFE2L1/NFE2L3 axis, and its depletion impairs basal proteasome activity and reduces resistance to proteasome inhibitors [#4]. An earlier characterization linked PSMG2 to cell cycle progression, with overexpression causing polyploidy and mitotic spindle checkpoint interference and knockdown reducing G2/M cells and increasing apoptosis [#0]. Loss-of-function PSMG2 mutations are associated with proteasome-associated autoinflammatory syndrome (PRAAS) bearing a type I interferon signature [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PSMG2/HCCA3 as a distinct gene by cloning it from a hepatocellular carcinoma differential-display screen, providing the molecular entity and its tissue expression profile before any function was known.\",\n      \"evidence\": \"mRNA differential display PCR, cDNA library screening, and Northern blot across human tissues\",\n      \"pmids\": [\"11854909\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional or mechanistic experiment\", \"Differential expression in HCC does not establish a causal role\", \"Subcellular localization and molecular activity undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First functional readout linked PSMG2/CLAST3 to cell cycle control, showing it localizes to nuclear foci and that altering its level perturbs mitotic progression and viability.\",\n      \"evidence\": \"Immunofluorescence, forced overexpression with nocodazole, and antisense knockdown with cell cycle analysis\",\n      \"pmids\": [\"12147697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between PSMG2 and the spindle checkpoint not defined\", \"Predates the proteasome-chaperone model and is not reconciled with it\", \"No molecular partners identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the upstream transcriptional control of PSMG2, placing it under the NFE2L1/NFE2L3 axis that maintains basal proteasome capacity and drug resistance.\",\n      \"evidence\": \"Double siRNA knockdown of NFE2L1/NFE2L3 with proteasome activity assays and bortezomib resistance readouts\",\n      \"pmids\": [\"32366381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PSMG2 is one of seven co-regulated genes, limiting specificity\", \"Direct promoter binding not demonstrated\", \"Contribution of PSMG2 alone to the proteasome phenotype not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PSMG2 to neurodegeneration-associated proteostasis by identifying it as an interactor of cytoplasmic mutant TDP-43 in a context of proteasomal impairment.\",\n      \"evidence\": \"Immunoprecipitation and mass spectrometry from a rhesus model expressing mutant TDP-43(M337V)\",\n      \"pmids\": [\"34363810\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/MS without reciprocal validation or mutagenesis\", \"Functional consequence for PSMG2 specifically not established\", \"Direct versus indirect interaction unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned PSMG2 upstream of a proteasome-autophagy balance that controls PDPK1-AKT signaling, revealing how proteasome assembly failure reshapes oncogenic signaling and drug response.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen, knockdown, autophagy-inhibitor rescue, proteasome assays, and xenograft model in TNBC\",\n      \"pmids\": [\"36099919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which autophagy selectively targets PDPK1 not defined\", \"Generalizability beyond TNBC and MEK-inhibitor context unclear\", \"Direct biochemical demonstration of PSMG2 in proteasome assembly not shown here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the core mechanistic model that PSMG2 heterodimerizes with PSMG1 to assemble the 20S proteasome, linking its loss to polyubiquitin accumulation, ER stress, and compensatory autophagy/apoptosis.\",\n      \"evidence\": \"Knockdown in HNSCC cells with polyubiquitin, ER stress, autophagy/apoptosis, and stemness assays in vitro and in vivo\",\n      \"pmids\": [\"40303289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural details of the PSMG1-PSMG2 heterodimer not resolved\", \"Direct reconstitution of assembly chaperone activity not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMG2's earlier cell-cycle/spindle-checkpoint phenotype mechanistically relates to its role as a 20S proteasome assembly chaperone remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PSMG1-PSMG2 acting on 20S intermediates\", \"Direct biochemical demonstration of chaperone-mediated assembly in human cells absent\", \"Reconciliation of nuclear-foci localization with cytoplasmic proteasome assembly function unaddressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"PSMG1-PSMG2 proteasome assembly chaperone heterodimer\"],\n    \"partners\": [\"PSMG1\", \"TDP-43\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}