{"gene":"PSMC6","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2017,"finding":"PSMC6 (19S proteasome regulatory subunit) is required for bortezomib sensitivity in multiple myeloma cells; CRISPR knockout of PSMC6 reproducibly conferred bortezomib resistance, and loss of PSMC6 significantly reduced bortezomib-mediated inhibition of chymotrypsin-like proteasome activity. Deficiency in other PSMC subunits (PSMC1–5) also imparted resistance, indicating the entire PSMC group contributes to bortezomib sensitivity.","method":"Genome-wide CRISPR screen followed by secondary sgRNA library validation and individual gene knockout with proteasome activity assay","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genome-wide screens followed by secondary validation and individual biochemical confirmation of proteasome activity reduction","pmids":["28958990"],"is_preprint":false},{"year":2020,"finding":"PSMC6 promotes osteoblast apoptosis by inhibiting the PI3K/AKT signaling pathway; PSMC6 knockout in an OVX osteoporosis mouse model elevated bone mineral density and increased PI3K phosphorylation, while PSMC6 overexpression in vitro promoted apoptosis (elevated cleaved caspase-3/9) and inhibited cell cycle progression. PI3K activation rescued PSMC6-induced apoptosis and regulated p53, cyclin D1, and cleaved caspase-3/9 protein levels.","method":"In vivo PSMC6 gene knockout in OVX mouse model (bone density, immunoblot for pPI3K, cleaved caspases) combined with in vitro overexpression/inhibition (MTT, BrdU, flow cytometry, PI3K activator rescue experiments)","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO plus in vitro OE/KD with multiple readouts and pathway rescue, single lab","pmids":["32017075"],"is_preprint":false},{"year":2025,"finding":"PSMC6 knockdown in cisplatin-sensitive and -resistant ovarian carcinoma cells reduced cell growth and clonogenicity, caused accumulation of ubiquitinated proteins, and down-regulated ERK1/2 phosphorylation via increased DUSP6. PSMC6 silencing also increased cisplatin sensitivity in resistant cells. Notably, PSMC6 knockdown did not alter sensitivity to 20S or 19S proteasome inhibitors, suggesting a distinct mode of proteasome targeting through interference with a proteasome ATPase subunit.","method":"CRISPR/Cas9 loss-of-function screen, siRNA knockdown, clonogenic assay, 3D spheroids, immunoblot (ubiquitinated proteins, pERK1/2, DUSP6), proteasome inhibitor sensitivity comparison","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus mechanistic follow-up with multiple orthogonal assays, single lab","pmids":["40083690"],"is_preprint":false},{"year":2025,"finding":"SYT4 directly interacts with PSMC6 via the SYT4 C2B domain (amino acids 288–423), as demonstrated by IP-MS, co-immunoprecipitation, and GST pull-down assays. This interaction stabilizes PSMC6 protein and activates Wnt/β-catenin signaling in gastric carcinoma cells.","method":"Immunoprecipitation–mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), GST pull-down, TOP/FOP luciferase reporter assay, in vitro and in vivo tumor models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down identifying direct interaction, plus functional reporter assay, single lab","pmids":["41281742"],"is_preprint":false},{"year":2023,"finding":"In a pSS mouse model, PSMC6 knockdown reduced lymphocytic infiltration in salivary and lacrimal glands, decreased levels of inflammatory factors, and increased the proportion of Treg cells, establishing PSMC6 as a driver of immune cell infiltration and inflammatory responses in primary Sjögren's syndrome.","method":"pSS mouse model with PSMC6 knockdown, histological assessment of lymphocytic infiltration, ELISA/cytokine measurement, flow cytometry for Treg cells","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo knockdown with phenotypic readouts but limited mechanistic detail reported in abstract, single lab","pmids":["36599955"],"is_preprint":false}],"current_model":"PSMC6 is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that is required for full proteasomal chymotrypsin-like activity and bortezomib sensitivity; loss of PSMC6 impairs proteasome function (causing ubiquitinated protein accumulation), modulates downstream signaling (suppressing PI3K/AKT and ERK1/2 via DUSP6), interacts directly with SYT4 to stabilize PSMC6 protein and activate Wnt/β-catenin signaling, and regulates apoptosis and immune cell infiltration in multiple disease contexts."},"narrative":{"mechanistic_narrative":"PSMC6 is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that is required for full proteasomal chymotrypsin-like activity and, consequently, for the protein-degradation function on which cancer cells depend [PMID:28958990]. Genome-wide CRISPR screening in multiple myeloma established that loss of PSMC6 confers resistance to the proteasome inhibitor bortezomib by blunting its inhibition of chymotrypsin-like activity, a property shared across the PSMC ATPase group [PMID:28958990]. In ovarian carcinoma, PSMC6 depletion causes accumulation of ubiquitinated proteins and reduces growth and clonogenicity, and it suppresses ERK1/2 phosphorylation through upregulation of DUSP6 while increasing cisplatin sensitivity—an effect distinct from direct 20S or 19S inhibition, indicating that targeting the ATPase subunit itself perturbs proteasome output through a separable route [PMID:40083690]. PSMC6 also intersects survival and growth signaling beyond the proteasome: it promotes apoptosis by inhibiting PI3K/AKT signaling, with PI3K activation rescuing PSMC6-induced apoptosis and normalizing p53, cyclin D1, and cleaved caspase-3/9 [PMID:32017075], and it is directly bound and stabilized by the SYT4 C2B domain, an interaction that activates Wnt/β-catenin signaling in gastric carcinoma [PMID:41281742]. A lower-confidence study additionally implicates PSMC6 as a driver of lymphocytic infiltration in a Sjögren's syndrome model [PMID:36599955].","teleology":[{"year":2017,"claim":"Established that PSMC6 is functionally required for proteasome chymotrypsin-like activity and therefore for sensitivity to the proteasome inhibitor bortezomib, defining it as a genetic determinant of drug response.","evidence":"Genome-wide CRISPR knockout screen with secondary sgRNA validation and individual knockout plus proteasome activity assay in multiple myeloma cells","pmids":["28958990"],"confidence":"High","gaps":["Does not resolve how PSMC6 ATPase activity mechanistically couples to chymotrypsin-like 20S catalysis","Resistance phenotype shared across PSMC1-6 leaves PSMC6-specific contribution undefined"]},{"year":2020,"claim":"Connected PSMC6 to apoptotic and cell-cycle control by showing it promotes apoptosis through inhibition of PI3K/AKT signaling, linking the proteasome subunit to a survival pathway.","evidence":"In vivo PSMC6 knockout in an OVX osteoporosis mouse model and in vitro overexpression/inhibition with caspase and PI3K-activator rescue readouts","pmids":["32017075"],"confidence":"Medium","gaps":["Mechanism linking proteasome ATPase activity to PI3K suppression not defined","Single-lab findings without independent replication","Whether effect depends on proteasome catalytic function is untested"]},{"year":2023,"claim":"Implicated PSMC6 as a driver of immune cell infiltration and inflammation in autoimmune disease, extending its role beyond cancer cell biology.","evidence":"PSMC6 knockdown in a primary Sjögren's syndrome mouse model with histology, cytokine measurement, and Treg flow cytometry","pmids":["36599955"],"confidence":"Low","gaps":["Limited mechanistic detail reported; molecular pathway connecting PSMC6 to infiltration unknown","Single lab, in vivo knockdown without rescue","No link established to proteasome activity in immune cells"]},{"year":2025,"claim":"Showed that PSMC6 depletion perturbs proteostasis and downstream signaling in a manner distinct from canonical proteasome inhibition, revealing the ATPase subunit as a separable proteasome-targeting node.","evidence":"CRISPR loss-of-function screen and siRNA knockdown in ovarian carcinoma with ubiquitin/pERK1/2/DUSP6 immunoblots, clonogenic and spheroid assays, and proteasome-inhibitor sensitivity comparison","pmids":["40083690"],"confidence":"Medium","gaps":["How loss of an ATPase subunit selectively engages DUSP6/ERK1/2 is unresolved","Single-lab study without orthogonal in vivo confirmation"]},{"year":2025,"claim":"Identified a direct protein partner of PSMC6, demonstrating that SYT4 binds and stabilizes PSMC6 to activate Wnt/β-catenin signaling.","evidence":"IP-MS, reciprocal Co-IP, GST pull-down mapping the SYT4 C2B domain, and TOP/FOP reporter plus tumor models in gastric carcinoma","pmids":["41281742"],"confidence":"Medium","gaps":["Mechanism by which SYT4 binding stabilizes PSMC6 protein not defined","Link between PSMC6 and β-catenin activation downstream of stabilization unclear","Single-lab finding"]},{"year":null,"claim":"How PSMC6's core ATPase function within the 19S particle mechanistically gives rise to its diverse downstream effects on PI3K/AKT, ERK1/2-DUSP6, and Wnt/β-catenin signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking PSMC6 to specific substrate degradation events","No unified mechanism connecting proteasome subunit loss to the multiple signaling pathways reported","Substrate(s) of the PSMC6-containing proteasome relevant to these pathways unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]}],"complexes":["26S proteasome 19S regulatory particle"],"partners":["SYT4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62333","full_name":"26S proteasome regulatory subunit 10B","aliases":["26S proteasome AAA-ATPase subunit RPT4","Proteasome 26S subunit ATPase 6","Proteasome subunit p42"],"length_aa":389,"mass_kda":44.2,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62333/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMC6","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100519","cell_line_id":"CID000128","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMC3","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":10.0},{"gene":"PSMD4","stoichiometry":10.0},{"gene":"PSMC5","stoichiometry":10.0},{"gene":"PSMC1","stoichiometry":10.0},{"gene":"PSMD6","stoichiometry":10.0},{"gene":"PSMD2","stoichiometry":10.0},{"gene":"UCHL5","stoichiometry":10.0},{"gene":"PSMD13","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000128","total_profiled":1310},"omim":[{"mim_id":"606223","title":"PROTEASOME 26S SUBUNIT, NON-ATPASE, 2; PSMD2","url":"https://www.omim.org/entry/606223"},{"mim_id":"603146","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 9; PSMD9","url":"https://www.omim.org/entry/603146"},{"mim_id":"602708","title":"PROTEASOME 26S SUBUNIT, ATPase, 6; PSMC6","url":"https://www.omim.org/entry/602708"},{"mim_id":"602706","title":"PROTEASOME 26S SUBUNIT, ATPase, 1; PSMC1","url":"https://www.omim.org/entry/602706"},{"mim_id":"186852","title":"PROTEASOME 26S SUBUNIT, ATPase, 3; PSMC3","url":"https://www.omim.org/entry/186852"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMC6"},"hgnc":{"alias_symbol":["p42","RPT5"],"prev_symbol":[]},"alphafold":{"accession":"P62333","domains":[{"cath_id":"2.40.50.140","chopping":"54-109","consensus_level":"high","plddt":89.7339,"start":54,"end":109},{"cath_id":"3.40.50.300","chopping":"117-299","consensus_level":"high","plddt":85.4098,"start":117,"end":299},{"cath_id":"1.10.8.60","chopping":"305-379","consensus_level":"high","plddt":90.2547,"start":305,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62333","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62333-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62333-F1-predicted_aligned_error_v6.png","plddt_mean":86.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMC6","jax_strain_url":"https://www.jax.org/strain/search?query=PSMC6"},"sequence":{"accession":"P62333","fasta_url":"https://rest.uniprot.org/uniprotkb/P62333.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62333/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62333"}},"corpus_meta":[{"pmid":"32017075","id":"PMC_32017075","title":"PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy-induced osteoporosis mouse model.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32017075","citation_count":50,"is_preprint":false},{"pmid":"28958990","id":"PMC_28958990","title":"CRISPR Genome-Wide Screening Identifies Dependence on the Proteasome Subunit PSMC6 for Bortezomib Sensitivity in Multiple Myeloma.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28958990","citation_count":49,"is_preprint":false},{"pmid":"34239933","id":"PMC_34239933","title":"The Silence of PSMC6 Inhibits Cell Growth and Metastasis in Lung Adenocarcinoma.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/34239933","citation_count":24,"is_preprint":false},{"pmid":"30559147","id":"PMC_30559147","title":"Identification of candidate biomarkers associated with apoptosis in melanosis coli: GNG5, LPAR3, MAPK8, and PSMC6.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/30559147","citation_count":18,"is_preprint":false},{"pmid":"24875235","id":"PMC_24875235","title":"Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.","date":"2014","source":"Pediatrics and neonatology","url":"https://pubmed.ncbi.nlm.nih.gov/24875235","citation_count":14,"is_preprint":false},{"pmid":"25606411","id":"PMC_25606411","title":"PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity in Latvians, Lithuanians and Taiwanese.","date":"2014","source":"Meta gene","url":"https://pubmed.ncbi.nlm.nih.gov/25606411","citation_count":7,"is_preprint":false},{"pmid":"38357597","id":"PMC_38357597","title":"The coherence between PSMC6 and α-ring in the 26S proteasome is associated with Alzheimer's disease.","date":"2024","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38357597","citation_count":5,"is_preprint":false},{"pmid":"33767773","id":"PMC_33767773","title":"Genetic variations in the PSMA6 and PSMC6 proteasome genes are associated with multiple sclerosis and response to interferon-β therapy in Latvians.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33767773","citation_count":5,"is_preprint":false},{"pmid":"36599955","id":"PMC_36599955","title":"PSMC6 induces immune cell infiltration and inflammatory response to aggravate primary Sjögren's syndrome.","date":"2023","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36599955","citation_count":2,"is_preprint":false},{"pmid":"40083690","id":"PMC_40083690","title":"PSMC6 regulation of ovarian cancer cisplatin resistance unravels a new mode for proteasome targeting.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40083690","citation_count":0,"is_preprint":false},{"pmid":"34187104","id":"PMC_34187104","title":"1,4-dihydropyridine derivatives increase mRNA expression of Psma3, Psmb5, and Psmc6 in rats.","date":"2021","source":"Arhiv za higijenu rada i toksikologiju","url":"https://pubmed.ncbi.nlm.nih.gov/34187104","citation_count":0,"is_preprint":false},{"pmid":"41281742","id":"PMC_41281742","title":"SYT4 Interacts with PSMC6 to Facilitate Malignant Progression in Gastric Carcinoma via Activating Wnt/β-catenin Signaling.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41281742","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9123,"output_tokens":1526,"usd":0.025129,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8342,"output_tokens":2408,"usd":0.050955,"stage2_stop_reason":"end_turn"},"total_usd":0.076084,"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\": 2017,\n      \"finding\": \"PSMC6 (19S proteasome regulatory subunit) is required for bortezomib sensitivity in multiple myeloma cells; CRISPR knockout of PSMC6 reproducibly conferred bortezomib resistance, and loss of PSMC6 significantly reduced bortezomib-mediated inhibition of chymotrypsin-like proteasome activity. Deficiency in other PSMC subunits (PSMC1–5) also imparted resistance, indicating the entire PSMC group contributes to bortezomib sensitivity.\",\n      \"method\": \"Genome-wide CRISPR screen followed by secondary sgRNA library validation and individual gene knockout with proteasome activity assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genome-wide screens followed by secondary validation and individual biochemical confirmation of proteasome activity reduction\",\n      \"pmids\": [\"28958990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSMC6 promotes osteoblast apoptosis by inhibiting the PI3K/AKT signaling pathway; PSMC6 knockout in an OVX osteoporosis mouse model elevated bone mineral density and increased PI3K phosphorylation, while PSMC6 overexpression in vitro promoted apoptosis (elevated cleaved caspase-3/9) and inhibited cell cycle progression. PI3K activation rescued PSMC6-induced apoptosis and regulated p53, cyclin D1, and cleaved caspase-3/9 protein levels.\",\n      \"method\": \"In vivo PSMC6 gene knockout in OVX mouse model (bone density, immunoblot for pPI3K, cleaved caspases) combined with in vitro overexpression/inhibition (MTT, BrdU, flow cytometry, PI3K activator rescue experiments)\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO plus in vitro OE/KD with multiple readouts and pathway rescue, single lab\",\n      \"pmids\": [\"32017075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSMC6 knockdown in cisplatin-sensitive and -resistant ovarian carcinoma cells reduced cell growth and clonogenicity, caused accumulation of ubiquitinated proteins, and down-regulated ERK1/2 phosphorylation via increased DUSP6. PSMC6 silencing also increased cisplatin sensitivity in resistant cells. Notably, PSMC6 knockdown did not alter sensitivity to 20S or 19S proteasome inhibitors, suggesting a distinct mode of proteasome targeting through interference with a proteasome ATPase subunit.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function screen, siRNA knockdown, clonogenic assay, 3D spheroids, immunoblot (ubiquitinated proteins, pERK1/2, DUSP6), proteasome inhibitor sensitivity comparison\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus mechanistic follow-up with multiple orthogonal assays, single lab\",\n      \"pmids\": [\"40083690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SYT4 directly interacts with PSMC6 via the SYT4 C2B domain (amino acids 288–423), as demonstrated by IP-MS, co-immunoprecipitation, and GST pull-down assays. This interaction stabilizes PSMC6 protein and activates Wnt/β-catenin signaling in gastric carcinoma cells.\",\n      \"method\": \"Immunoprecipitation–mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), GST pull-down, TOP/FOP luciferase reporter assay, in vitro and in vivo tumor models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down identifying direct interaction, plus functional reporter assay, single lab\",\n      \"pmids\": [\"41281742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In a pSS mouse model, PSMC6 knockdown reduced lymphocytic infiltration in salivary and lacrimal glands, decreased levels of inflammatory factors, and increased the proportion of Treg cells, establishing PSMC6 as a driver of immune cell infiltration and inflammatory responses in primary Sjögren's syndrome.\",\n      \"method\": \"pSS mouse model with PSMC6 knockdown, histological assessment of lymphocytic infiltration, ELISA/cytokine measurement, flow cytometry for Treg cells\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo knockdown with phenotypic readouts but limited mechanistic detail reported in abstract, single lab\",\n      \"pmids\": [\"36599955\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC6 is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that is required for full proteasomal chymotrypsin-like activity and bortezomib sensitivity; loss of PSMC6 impairs proteasome function (causing ubiquitinated protein accumulation), modulates downstream signaling (suppressing PI3K/AKT and ERK1/2 via DUSP6), interacts directly with SYT4 to stabilize PSMC6 protein and activate Wnt/β-catenin signaling, and regulates apoptosis and immune cell infiltration in multiple disease contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMC6 is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that is required for full proteasomal chymotrypsin-like activity and, consequently, for the protein-degradation function on which cancer cells depend [#0]. Genome-wide CRISPR screening in multiple myeloma established that loss of PSMC6 confers resistance to the proteasome inhibitor bortezomib by blunting its inhibition of chymotrypsin-like activity, a property shared across the PSMC ATPase group [#0]. In ovarian carcinoma, PSMC6 depletion causes accumulation of ubiquitinated proteins and reduces growth and clonogenicity, and it suppresses ERK1/2 phosphorylation through upregulation of DUSP6 while increasing cisplatin sensitivity—an effect distinct from direct 20S or 19S inhibition, indicating that targeting the ATPase subunit itself perturbs proteasome output through a separable route [#2]. PSMC6 also intersects survival and growth signaling beyond the proteasome: it promotes apoptosis by inhibiting PI3K/AKT signaling, with PI3K activation rescuing PSMC6-induced apoptosis and normalizing p53, cyclin D1, and cleaved caspase-3/9 [#1], and it is directly bound and stabilized by the SYT4 C2B domain, an interaction that activates Wnt/β-catenin signaling in gastric carcinoma [#3]. A lower-confidence study additionally implicates PSMC6 as a driver of lymphocytic infiltration in a Sjögren's syndrome model [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that PSMC6 is functionally required for proteasome chymotrypsin-like activity and therefore for sensitivity to the proteasome inhibitor bortezomib, defining it as a genetic determinant of drug response.\",\n      \"evidence\": \"Genome-wide CRISPR knockout screen with secondary sgRNA validation and individual knockout plus proteasome activity assay in multiple myeloma cells\",\n      \"pmids\": [\"28958990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve how PSMC6 ATPase activity mechanistically couples to chymotrypsin-like 20S catalysis\",\n        \"Resistance phenotype shared across PSMC1-6 leaves PSMC6-specific contribution undefined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PSMC6 to apoptotic and cell-cycle control by showing it promotes apoptosis through inhibition of PI3K/AKT signaling, linking the proteasome subunit to a survival pathway.\",\n      \"evidence\": \"In vivo PSMC6 knockout in an OVX osteoporosis mouse model and in vitro overexpression/inhibition with caspase and PI3K-activator rescue readouts\",\n      \"pmids\": [\"32017075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking proteasome ATPase activity to PI3K suppression not defined\",\n        \"Single-lab findings without independent replication\",\n        \"Whether effect depends on proteasome catalytic function is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated PSMC6 as a driver of immune cell infiltration and inflammation in autoimmune disease, extending its role beyond cancer cell biology.\",\n      \"evidence\": \"PSMC6 knockdown in a primary Sjögren's syndrome mouse model with histology, cytokine measurement, and Treg flow cytometry\",\n      \"pmids\": [\"36599955\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Limited mechanistic detail reported; molecular pathway connecting PSMC6 to infiltration unknown\",\n        \"Single lab, in vivo knockdown without rescue\",\n        \"No link established to proteasome activity in immune cells\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that PSMC6 depletion perturbs proteostasis and downstream signaling in a manner distinct from canonical proteasome inhibition, revealing the ATPase subunit as a separable proteasome-targeting node.\",\n      \"evidence\": \"CRISPR loss-of-function screen and siRNA knockdown in ovarian carcinoma with ubiquitin/pERK1/2/DUSP6 immunoblots, clonogenic and spheroid assays, and proteasome-inhibitor sensitivity comparison\",\n      \"pmids\": [\"40083690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How loss of an ATPase subunit selectively engages DUSP6/ERK1/2 is unresolved\",\n        \"Single-lab study without orthogonal in vivo confirmation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a direct protein partner of PSMC6, demonstrating that SYT4 binds and stabilizes PSMC6 to activate Wnt/β-catenin signaling.\",\n      \"evidence\": \"IP-MS, reciprocal Co-IP, GST pull-down mapping the SYT4 C2B domain, and TOP/FOP reporter plus tumor models in gastric carcinoma\",\n      \"pmids\": [\"41281742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which SYT4 binding stabilizes PSMC6 protein not defined\",\n        \"Link between PSMC6 and β-catenin activation downstream of stabilization unclear\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMC6's core ATPase function within the 19S particle mechanistically gives rise to its diverse downstream effects on PI3K/AKT, ERK1/2-DUSP6, and Wnt/β-catenin signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model linking PSMC6 to specific substrate degradation events\",\n        \"No unified mechanism connecting proteasome subunit loss to the multiple signaling pathways reported\",\n        \"Substrate(s) of the PSMC6-containing proteasome relevant to these pathways unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"26S proteasome 19S regulatory particle\"],\n    \"partners\": [\"SYT4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}