{"gene":"PFDN6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2003,"finding":"PFDN6 (PFD6) is one of six subunits that spontaneously assemble into the heterohexameric eukaryotic prefoldin (PFD) complex; the tips of the PFD tentacles (including PFD6) are required to form binary complexes with target proteins actin and tubulin, with different but overlapping sets of subunits contacting different substrates.","method":"Reconstitution of PFD from individually expressed recombinant subunits (PFD1–PFD6) in vitro; engineered subunit variants used to map substrate-binding regions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis/engineering of individual subunits, directly establishing PFDN6's role in complex assembly and substrate binding","pmids":["14634002"],"is_preprint":false},{"year":2011,"finding":"PFDN6 protein stability is regulated by the ubiquitin-proteasome system (UPS): monomeric PFDN6 is degraded by the UPS, but incorporation into the prefoldin hexameric complex protects it from degradation. Knockdown of any one prefoldin subunit reduces protein levels of the others, and co-expression of other subunits stabilises PFDN6.","method":"siRNA knockdown of individual PFD subunits; proteasome inhibitor (MG132) treatment; co-transfection experiments in mammalian cells monitoring endogenous and overexpressed subunit levels","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown and proteasome inhibition experiments in mammalian cells with multiple orthogonal approaches, single lab","pmids":["21478150"],"is_preprint":false},{"year":2018,"finding":"PFDN6 is a β-subunit of the URI prefoldin-like complex, a heterohexameric chaperone complex (α2β4) comprising URI and STAP1 (α subunits) and PFDN2, PFDN6, and PFDN4r (β subunits), distinct from the canonical PFD complex.","method":"Immunoprecipitation experiments identifying complex composition (cited from Gstaiger et al. 2003, reviewed here)","journal":"Advances in experimental medicine and biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article citing original Co-IP data; abstract does not describe new direct experiments on PFDN6 specifically","pmids":["30484155"],"is_preprint":false},{"year":2007,"finding":"HKE2/PFDN6 protein is expressed in the cytoplasm and is upregulated upon cellular activation; in a tissue microarray, HKE2 protein was overexpressed in certain cancers relative to normal counterparts.","method":"Immunohistochemistry with an anti-HKE2 antibody on tissue microarray and tumour specimens","journal":"Tissue antigens","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method immunohistochemistry, single lab, no functional mechanistic follow-up","pmids":["17257322"],"is_preprint":false},{"year":2022,"finding":"PFDN6 knockdown in glioma cell lines attenuates cell proliferation and migration, induces apoptosis, and blocks cell cycle progression at G2; these effects are mediated through the AKT signalling pathway, as shown by a human phospho-kinase array demonstrating reduced AKT phosphorylation upon PFDN6 knockdown.","method":"siRNA knockdown in glioma cell lines; CCK-8 and Celigo viability assays; flow cytometry for apoptosis/cell cycle; wound-healing and transwell migration assays; xenograft mouse model; human phospho-kinase array","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts plus in vivo validation and pathway identification, single lab","pmids":["36300673"],"is_preprint":false},{"year":2024,"finding":"PFDN6 knockdown in colorectal cancer (CRC) cell lines reduces tumour cell number, promotes apoptosis, and inhibits migration and invasion; transcriptome sequencing after PFDN6 knockdown identified ZNF575 as a transcriptional target through which PFDN6 regulates CRC progression.","method":"PFDN6 knockdown in HCT-116 and RKO CRC cell lines; transcriptome sequencing of knockdown cells; bioinformatics pathway analysis identifying ZNF575 as downstream target","journal":"eGastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with transcriptome sequencing and identification of downstream target, single lab","pmids":["39944471"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, Pfdn6 RNAi-mediated knockdown modifies hTauV337M-induced eye-ommatidial degeneration, identifying Pfdn6 as a genetic modifier of Tau cytotoxicity; this epistatic relationship places Pfdn6 in a pathway that suppresses Tau aggregation and neurotoxicity.","method":"Genetic screen using RNAi knockdown in Drosophila eye model of Tau toxicity; assessment of ommatidial degeneration phenotype as readout","journal":"eLife / bioRxiv (preprint version also available)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis screen in Drosophila model with defined phenotypic readout; Pfdn6 identified as modifier but primary mechanistic focus is Pfdn5; single study","pmids":["41533771"],"is_preprint":false},{"year":2025,"finding":"In Anopheles mosquitoes, silencing PFDN6 via RNA interference reduces Plasmodium falciparum oocyst loads in the midgut; co-feeding with PFDN6-specific antibody and gametocytes also reduces infection, establishing that the mosquito PFDN6 subunit is required for Plasmodium transmission and that disruption of the PFDN-CCT/TRiC complex impairs epithelial and extracellular matrix integrity, triggering anti-Plasmodium immune priming.","method":"RNAi silencing of PFDN6 in Anopheles mosquitoes; antibody co-feeding transmission-blocking assay; assessment of oocyst loads, epithelial integrity, and immune activation","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with antibody co-feeding, multiple orthogonal readouts in vivo; single lab but rigorous design","pmids":["40050397"],"is_preprint":false}],"current_model":"PFDN6 is a β-subunit of the eukaryotic heterohexameric prefoldin (PFD) chaperone complex that uses the distal tips of its tentacle-like structure to form binary complexes with unfolded actin and tubulin substrates for delivery to the cytosolic chaperonin TRiC/CCT; as a monomer it is degraded by the ubiquitin-proteasome system but is stabilised by incorporation into the hexamer; it also participates in a distinct URI prefoldin-like complex, contributes to AKT-mediated signalling in cancer cells, genetically suppresses Tau toxicity in Drosophila, and its inhibition in mosquitoes blocks Plasmodium transmission by disrupting epithelial integrity and immune evasion."},"narrative":{"mechanistic_narrative":"PFDN6 is a β-subunit of the eukaryotic heterohexameric prefoldin (PFD) chaperone complex, which spontaneously assembles from six subunits and uses the distal tips of its tentacle-like coiled-coil arms to form binary complexes with unfolded actin and tubulin for delivery to the cytosolic chaperonin [PMID:14634002]. As a monomer PFDN6 is degraded by the ubiquitin-proteasome system, but incorporation into the hexamer protects it, such that the steady-state level of each subunit depends on the others — knockdown of any one subunit lowers the levels of the rest [PMID:21478150]. Beyond its assembly and substrate-handoff role, PFDN6 loss-of-function impairs tumour cell proliferation, migration and survival in glioma, acting through reduced AKT phosphorylation [PMID:36300673], and in colorectal cancer cells it regulates progression via the downstream transcriptional target ZNF575 [PMID:39944471]. In organismal models PFDN6 functions as a genetic modifier of Tau cytotoxicity in Drosophila [PMID:41533771] and is required in Anopheles mosquitoes for Plasmodium transmission, where its silencing disrupts midgut epithelial and extracellular matrix integrity and triggers anti-Plasmodium immune priming [PMID:40050397].","teleology":[{"year":2003,"claim":"Established that PFDN6 is a bona fide subunit of the assembled prefoldin hexamer and directly contributes to substrate capture, answering how the complex engages its clients.","evidence":"In vitro reconstitution of prefoldin from individually expressed recombinant subunits with engineered tip variants mapping actin/tubulin binding","pmids":["14634002"],"confidence":"High","gaps":["Does not define PFDN6-specific contacts versus shared subunit contacts on each substrate","No structural model of the PFDN6-containing complex bound to a folding intermediate"]},{"year":2007,"claim":"First placed PFDN6 protein in the cytoplasm and linked its abundance to cellular activation and tumour overexpression, raising the possibility of a disease-relevant role.","evidence":"Immunohistochemistry with anti-HKE2 antibody on tissue microarray and tumour specimens","pmids":["17257322"],"confidence":"Low","gaps":["Single-method IHC without functional follow-up","Does not establish causality between PFDN6 level and tumour phenotype"]},{"year":2011,"claim":"Resolved how PFDN6 levels are controlled, showing that complex incorporation rather than free monomer governs its stability and coupling its abundance to that of the other subunits.","evidence":"siRNA knockdown of individual subunits, MG132 proteasome inhibition, and co-transfection stabilization assays in mammalian cells","pmids":["21478150"],"confidence":"Medium","gaps":["E3 ligase responsible for monomeric PFDN6 turnover not identified","Single lab"]},{"year":2018,"claim":"Assigned PFDN6 to a second, URI prefoldin-like complex distinct from canonical PFD, indicating it operates in more than one chaperone assembly.","evidence":"Review citing immunoprecipitation data defining the URI/STAP1/PFDN2/PFDN6/PFDN4r composition","pmids":["30484155"],"confidence":"Low","gaps":["Reviews prior Co-IP rather than new direct PFDN6 experiments","Functional role of PFDN6 within the URI complex not defined"]},{"year":2022,"claim":"Connected PFDN6 to a cancer signalling output, showing its depletion suppresses glioma growth and migration via reduced AKT phosphorylation.","evidence":"siRNA knockdown in glioma lines with viability, apoptosis, cell-cycle, migration assays, xenografts, and phospho-kinase array","pmids":["36300673"],"confidence":"Medium","gaps":["Mechanism linking a prefoldin subunit to AKT phosphorylation unresolved","Whether the effect requires the chaperone complex is untested"]},{"year":2024,"claim":"Identified a transcriptional axis (ZNF575) through which PFDN6 drives colorectal cancer progression, broadening its oncogenic relevance beyond glioma.","evidence":"PFDN6 knockdown in HCT-116 and RKO cells with transcriptome sequencing and pathway analysis","pmids":["39944471"],"confidence":"Medium","gaps":["Direct regulatory relationship between PFDN6 and ZNF575 not mechanistically defined","Single lab"]},{"year":2024,"claim":"Placed PFDN6 in a genetic pathway that suppresses Tau neurotoxicity, implicating prefoldin chaperone function in proteostasis of an aggregation-prone protein.","evidence":"RNAi knockdown in a Drosophila eye model of hTauV337M-induced ommatidial degeneration","pmids":["41533771"],"confidence":"Medium","gaps":["Primary mechanistic focus was Pfdn5, not Pfdn6","Molecular basis of Tau suppression not established"]},{"year":2025,"claim":"Demonstrated an organismal requirement for PFDN6 in disease transmission, showing its silencing disrupts mosquito midgut epithelial/ECM integrity and blocks Plasmodium infection.","evidence":"RNAi silencing and antibody co-feeding transmission-blocking assays in Anopheles with oocyst, epithelial, and immune readouts","pmids":["40050397"],"confidence":"Medium","gaps":["Link between prefoldin-CCT/TRiC function and epithelial integrity not molecularly resolved","Single lab"]},{"year":null,"claim":"How PFDN6's chaperone activity within the PFD and URI complexes mechanistically connects to AKT signalling, ZNF575 regulation, Tau proteostasis, and epithelial integrity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a PFDN6-containing complex with substrate","Whether oncogenic and host-pathogen phenotypes depend on canonical chaperone function is untested","E3 ligase and regulatory inputs controlling PFDN6 turnover unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["prefoldin complex","URI prefoldin-like complex"],"partners":["PFDN2","PFDN4","URI1","STAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15212","full_name":"Prefoldin subunit 6","aliases":["Protein Ke2"],"length_aa":129,"mass_kda":14.6,"function":"Binds specifically to cytosolic chaperonin (c-CPN) and transfers target proteins to it. Binds to nascent polypeptide chain and promotes folding in an environment in which there are many competing pathways for nonnative proteins","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O15212/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PFDN6","classification":"Common Essential","n_dependent_lines":1194,"n_total_lines":1208,"dependency_fraction":0.9884105960264901},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000204220","cell_line_id":"CID000797","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"VBP1","stoichiometry":10.0},{"gene":"PFDN2","stoichiometry":10.0},{"gene":"PFDN5","stoichiometry":10.0},{"gene":"PFDN1","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"RUVBL2","stoichiometry":4.0},{"gene":"RUVBL1","stoichiometry":4.0},{"gene":"PFDN4","stoichiometry":4.0},{"gene":"POLR2E","stoichiometry":4.0},{"gene":"POLR2B","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000797","total_profiled":1310},"omim":[{"mim_id":"611479","title":"GPN-LOOP GTPase 1; GPN1","url":"https://www.omim.org/entry/611479"},{"mim_id":"611477","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 3; RPAP3","url":"https://www.omim.org/entry/611477"},{"mim_id":"611476","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 2; RPAP2","url":"https://www.omim.org/entry/611476"},{"mim_id":"611475","title":"RNA POLYMERASE II-ASSOCIATED PROTEIN 1; RPAP1","url":"https://www.omim.org/entry/611475"},{"mim_id":"605660","title":"PREFOLDIN 6; PFDN6","url":"https://www.omim.org/entry/605660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PFDN6"},"hgnc":{"alias_symbol":["KE-2","H2-KE2","PFD6"],"prev_symbol":["HKE2"]},"alphafold":{"accession":"O15212","domains":[{"cath_id":"1.10.287.370","chopping":"31-111","consensus_level":"medium","plddt":97.7556,"start":31,"end":111}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15212","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15212-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15212-F1-predicted_aligned_error_v6.png","plddt_mean":94.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PFDN6","jax_strain_url":"https://www.jax.org/strain/search?query=PFDN6"},"sequence":{"accession":"O15212","fasta_url":"https://rest.uniprot.org/uniprotkb/O15212.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15212/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15212"}},"corpus_meta":[{"pmid":"33356362","id":"PMC_33356362","title":"Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.","date":"2020","source":"Circulation. 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microtubule-associated protein that suppresses Tau aggregation and neurotoxicity.","date":"2026","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41533771","citation_count":0,"is_preprint":false},{"pmid":"42086044","id":"PMC_42086044","title":"Mode-of-Action and Human Relevance Assessment for Diisononyl Phthalate-Induced Liver Tumors in Rodents.","date":"2026","source":"Journal of applied toxicology : JAT","url":"https://pubmed.ncbi.nlm.nih.gov/42086044","citation_count":0,"is_preprint":false},{"pmid":"8333751","id":"PMC_8333751","title":"[A case of advanced gastric cancer with liver and lung metastasis effectively treated by combined chemo-immunotherapy of MMC, 5'-DFUR, OK-432].","date":"1993","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8333751","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.14.618171","title":"Prefoldin 5 is a microtubule-associated protein that suppresses Tau-aggregation and neurotoxicity","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618171","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28190,"output_tokens":2148,"usd":0.058395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9170,"output_tokens":2660,"usd":0.056175,"stage2_stop_reason":"end_turn"},"total_usd":0.11457,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PFDN6 (PFD6) is one of six subunits that spontaneously assemble into the heterohexameric eukaryotic prefoldin (PFD) complex; the tips of the PFD tentacles (including PFD6) are required to form binary complexes with target proteins actin and tubulin, with different but overlapping sets of subunits contacting different substrates.\",\n      \"method\": \"Reconstitution of PFD from individually expressed recombinant subunits (PFD1–PFD6) in vitro; engineered subunit variants used to map substrate-binding regions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis/engineering of individual subunits, directly establishing PFDN6's role in complex assembly and substrate binding\",\n      \"pmids\": [\"14634002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PFDN6 protein stability is regulated by the ubiquitin-proteasome system (UPS): monomeric PFDN6 is degraded by the UPS, but incorporation into the prefoldin hexameric complex protects it from degradation. Knockdown of any one prefoldin subunit reduces protein levels of the others, and co-expression of other subunits stabilises PFDN6.\",\n      \"method\": \"siRNA knockdown of individual PFD subunits; proteasome inhibitor (MG132) treatment; co-transfection experiments in mammalian cells monitoring endogenous and overexpressed subunit levels\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown and proteasome inhibition experiments in mammalian cells with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"21478150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PFDN6 is a β-subunit of the URI prefoldin-like complex, a heterohexameric chaperone complex (α2β4) comprising URI and STAP1 (α subunits) and PFDN2, PFDN6, and PFDN4r (β subunits), distinct from the canonical PFD complex.\",\n      \"method\": \"Immunoprecipitation experiments identifying complex composition (cited from Gstaiger et al. 2003, reviewed here)\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article citing original Co-IP data; abstract does not describe new direct experiments on PFDN6 specifically\",\n      \"pmids\": [\"30484155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HKE2/PFDN6 protein is expressed in the cytoplasm and is upregulated upon cellular activation; in a tissue microarray, HKE2 protein was overexpressed in certain cancers relative to normal counterparts.\",\n      \"method\": \"Immunohistochemistry with an anti-HKE2 antibody on tissue microarray and tumour specimens\",\n      \"journal\": \"Tissue antigens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method immunohistochemistry, single lab, no functional mechanistic follow-up\",\n      \"pmids\": [\"17257322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PFDN6 knockdown in glioma cell lines attenuates cell proliferation and migration, induces apoptosis, and blocks cell cycle progression at G2; these effects are mediated through the AKT signalling pathway, as shown by a human phospho-kinase array demonstrating reduced AKT phosphorylation upon PFDN6 knockdown.\",\n      \"method\": \"siRNA knockdown in glioma cell lines; CCK-8 and Celigo viability assays; flow cytometry for apoptosis/cell cycle; wound-healing and transwell migration assays; xenograft mouse model; human phospho-kinase array\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular readouts plus in vivo validation and pathway identification, single lab\",\n      \"pmids\": [\"36300673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PFDN6 knockdown in colorectal cancer (CRC) cell lines reduces tumour cell number, promotes apoptosis, and inhibits migration and invasion; transcriptome sequencing after PFDN6 knockdown identified ZNF575 as a transcriptional target through which PFDN6 regulates CRC progression.\",\n      \"method\": \"PFDN6 knockdown in HCT-116 and RKO CRC cell lines; transcriptome sequencing of knockdown cells; bioinformatics pathway analysis identifying ZNF575 as downstream target\",\n      \"journal\": \"eGastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with transcriptome sequencing and identification of downstream target, single lab\",\n      \"pmids\": [\"39944471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, Pfdn6 RNAi-mediated knockdown modifies hTauV337M-induced eye-ommatidial degeneration, identifying Pfdn6 as a genetic modifier of Tau cytotoxicity; this epistatic relationship places Pfdn6 in a pathway that suppresses Tau aggregation and neurotoxicity.\",\n      \"method\": \"Genetic screen using RNAi knockdown in Drosophila eye model of Tau toxicity; assessment of ommatidial degeneration phenotype as readout\",\n      \"journal\": \"eLife / bioRxiv (preprint version also available)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis screen in Drosophila model with defined phenotypic readout; Pfdn6 identified as modifier but primary mechanistic focus is Pfdn5; single study\",\n      \"pmids\": [\"41533771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Anopheles mosquitoes, silencing PFDN6 via RNA interference reduces Plasmodium falciparum oocyst loads in the midgut; co-feeding with PFDN6-specific antibody and gametocytes also reduces infection, establishing that the mosquito PFDN6 subunit is required for Plasmodium transmission and that disruption of the PFDN-CCT/TRiC complex impairs epithelial and extracellular matrix integrity, triggering anti-Plasmodium immune priming.\",\n      \"method\": \"RNAi silencing of PFDN6 in Anopheles mosquitoes; antibody co-feeding transmission-blocking assay; assessment of oocyst loads, epithelial integrity, and immune activation\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with antibody co-feeding, multiple orthogonal readouts in vivo; single lab but rigorous design\",\n      \"pmids\": [\"40050397\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PFDN6 is a β-subunit of the eukaryotic heterohexameric prefoldin (PFD) chaperone complex that uses the distal tips of its tentacle-like structure to form binary complexes with unfolded actin and tubulin substrates for delivery to the cytosolic chaperonin TRiC/CCT; as a monomer it is degraded by the ubiquitin-proteasome system but is stabilised by incorporation into the hexamer; it also participates in a distinct URI prefoldin-like complex, contributes to AKT-mediated signalling in cancer cells, genetically suppresses Tau toxicity in Drosophila, and its inhibition in mosquitoes blocks Plasmodium transmission by disrupting epithelial integrity and immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PFDN6 is a β-subunit of the eukaryotic heterohexameric prefoldin (PFD) chaperone complex, which spontaneously assembles from six subunits and uses the distal tips of its tentacle-like coiled-coil arms to form binary complexes with unfolded actin and tubulin for delivery to the cytosolic chaperonin [#0]. As a monomer PFDN6 is degraded by the ubiquitin-proteasome system, but incorporation into the hexamer protects it, such that the steady-state level of each subunit depends on the others — knockdown of any one subunit lowers the levels of the rest [#1]. Beyond its assembly and substrate-handoff role, PFDN6 loss-of-function impairs tumour cell proliferation, migration and survival in glioma, acting through reduced AKT phosphorylation [#4], and in colorectal cancer cells it regulates progression via the downstream transcriptional target ZNF575 [#5]. In organismal models PFDN6 functions as a genetic modifier of Tau cytotoxicity in Drosophila [#6] and is required in Anopheles mosquitoes for Plasmodium transmission, where its silencing disrupts midgut epithelial and extracellular matrix integrity and triggers anti-Plasmodium immune priming [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that PFDN6 is a bona fide subunit of the assembled prefoldin hexamer and directly contributes to substrate capture, answering how the complex engages its clients.\",\n      \"evidence\": \"In vitro reconstitution of prefoldin from individually expressed recombinant subunits with engineered tip variants mapping actin/tubulin binding\",\n      \"pmids\": [\"14634002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define PFDN6-specific contacts versus shared subunit contacts on each substrate\", \"No structural model of the PFDN6-containing complex bound to a folding intermediate\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"First placed PFDN6 protein in the cytoplasm and linked its abundance to cellular activation and tumour overexpression, raising the possibility of a disease-relevant role.\",\n      \"evidence\": \"Immunohistochemistry with anti-HKE2 antibody on tissue microarray and tumour specimens\",\n      \"pmids\": [\"17257322\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method IHC without functional follow-up\", \"Does not establish causality between PFDN6 level and tumour phenotype\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how PFDN6 levels are controlled, showing that complex incorporation rather than free monomer governs its stability and coupling its abundance to that of the other subunits.\",\n      \"evidence\": \"siRNA knockdown of individual subunits, MG132 proteasome inhibition, and co-transfection stabilization assays in mammalian cells\",\n      \"pmids\": [\"21478150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for monomeric PFDN6 turnover not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Assigned PFDN6 to a second, URI prefoldin-like complex distinct from canonical PFD, indicating it operates in more than one chaperone assembly.\",\n      \"evidence\": \"Review citing immunoprecipitation data defining the URI/STAP1/PFDN2/PFDN6/PFDN4r composition\",\n      \"pmids\": [\"30484155\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Reviews prior Co-IP rather than new direct PFDN6 experiments\", \"Functional role of PFDN6 within the URI complex not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PFDN6 to a cancer signalling output, showing its depletion suppresses glioma growth and migration via reduced AKT phosphorylation.\",\n      \"evidence\": \"siRNA knockdown in glioma lines with viability, apoptosis, cell-cycle, migration assays, xenografts, and phospho-kinase array\",\n      \"pmids\": [\"36300673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking a prefoldin subunit to AKT phosphorylation unresolved\", \"Whether the effect requires the chaperone complex is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a transcriptional axis (ZNF575) through which PFDN6 drives colorectal cancer progression, broadening its oncogenic relevance beyond glioma.\",\n      \"evidence\": \"PFDN6 knockdown in HCT-116 and RKO cells with transcriptome sequencing and pathway analysis\",\n      \"pmids\": [\"39944471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct regulatory relationship between PFDN6 and ZNF575 not mechanistically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PFDN6 in a genetic pathway that suppresses Tau neurotoxicity, implicating prefoldin chaperone function in proteostasis of an aggregation-prone protein.\",\n      \"evidence\": \"RNAi knockdown in a Drosophila eye model of hTauV337M-induced ommatidial degeneration\",\n      \"pmids\": [\"41533771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary mechanistic focus was Pfdn5, not Pfdn6\", \"Molecular basis of Tau suppression not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated an organismal requirement for PFDN6 in disease transmission, showing its silencing disrupts mosquito midgut epithelial/ECM integrity and blocks Plasmodium infection.\",\n      \"evidence\": \"RNAi silencing and antibody co-feeding transmission-blocking assays in Anopheles with oocyst, epithelial, and immune readouts\",\n      \"pmids\": [\"40050397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between prefoldin-CCT/TRiC function and epithelial integrity not molecularly resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PFDN6's chaperone activity within the PFD and URI complexes mechanistically connects to AKT signalling, ZNF575 regulation, Tau proteostasis, and epithelial integrity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a PFDN6-containing complex with substrate\", \"Whether oncogenic and host-pathogen phenotypes depend on canonical chaperone function is untested\", \"E3 ligase and regulatory inputs controlling PFDN6 turnover unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"prefoldin complex\", \"URI prefoldin-like complex\"],\n    \"partners\": [\"PFDN2\", \"PFDN4\", \"URI1\", \"STAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}