Affinage

PFDN6

Prefoldin subunit 6 · UniProt O15212

Length
129 aa
Mass
14.6 kDa
Annotated
2026-06-10
46 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 High

    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

    PMID:14634002

    Open questions at the time
    • 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
  2. 2007 Low

    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

    PMID:17257322

    Open questions at the time
    • Single-method IHC without functional follow-up
    • Does not establish causality between PFDN6 level and tumour phenotype
  3. 2011 Medium

    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

    PMID:21478150

    Open questions at the time
    • E3 ligase responsible for monomeric PFDN6 turnover not identified
    • Single lab
  4. 2018 Low

    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

    PMID:30484155

    Open questions at the time
    • Reviews prior Co-IP rather than new direct PFDN6 experiments
    • Functional role of PFDN6 within the URI complex not defined
  5. 2022 Medium

    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

    PMID:36300673

    Open questions at the time
    • Mechanism linking a prefoldin subunit to AKT phosphorylation unresolved
    • Whether the effect requires the chaperone complex is untested
  6. 2024 Medium

    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

    PMID:39944471

    Open questions at the time
    • Direct regulatory relationship between PFDN6 and ZNF575 not mechanistically defined
    • Single lab
  7. 2024 Medium

    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

    PMID:41533771

    Open questions at the time
    • Primary mechanistic focus was Pfdn5, not Pfdn6
    • Molecular basis of Tau suppression not established
  8. 2025 Medium

    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

    PMID:40050397

    Open questions at the time
    • Link between prefoldin-CCT/TRiC function and epithelial integrity not molecularly resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2
Partners
PFDN2PFDN4STAP1URI1
Complex memberships
URI prefoldin-like complexprefoldin complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Reconstitution of PFD from individually expressed recombinant subunits (PFD1–PFD6) in vitro; engineered subunit variants used to map substrate-binding regions The Journal of biological chemistry High 14634002
2011 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. siRNA knockdown of individual PFD subunits; proteasome inhibitor (MG132) treatment; co-transfection experiments in mammalian cells monitoring endogenous and overexpressed subunit levels The Journal of biological chemistry Medium 21478150
2018 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. Immunoprecipitation experiments identifying complex composition (cited from Gstaiger et al. 2003, reviewed here) Advances in experimental medicine and biology Low 30484155
2007 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. Immunohistochemistry with an anti-HKE2 antibody on tissue microarray and tumour specimens Tissue antigens Low 17257322
2022 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. 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 Cell biology international Medium 36300673
2024 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. PFDN6 knockdown in HCT-116 and RKO CRC cell lines; transcriptome sequencing of knockdown cells; bioinformatics pathway analysis identifying ZNF575 as downstream target eGastroenterology Medium 39944471
2024 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. Genetic screen using RNAi knockdown in Drosophila eye model of Tau toxicity; assessment of ommatidial degeneration phenotype as readout eLife / bioRxiv (preprint version also available) Medium 41533771
2025 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. RNAi silencing of PFDN6 in Anopheles mosquitoes; antibody co-feeding transmission-blocking assay; assessment of oocyst loads, epithelial integrity, and immune activation Nature microbiology Medium 40050397

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure. Circulation. Heart failure 128 33356362
2019 Ketone ester supplementation blunts overreaching symptoms during endurance training overload. The Journal of physiology 92 31039280
1999 On the role of kerato-epithelin in the pathogenesis of 5q31-linked corneal dystrophies. Investigative ophthalmology & visual science 74 10476785
1995 Structural hierarchy in the clustering of HLA class I molecules in the plasma membrane of human lymphoblastoid cells. Proceedings of the National Academy of Sciences of the United States of America 73 7862646
1997 Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary delta opioid antagonist activity. Journal of medicinal chemistry 67 9301674
2003 Selective contribution of eukaryotic prefoldin subunits to actin and tubulin binding. The Journal of biological chemistry 56 14634002
1998 TAPASIN, DAXX, RGL2, HKE2 and four new genes (BING 1, 3 to 5) form a dense cluster at the centromeric end of the MHC. Journal of molecular biology 48 9545376
2001 X-ray crystal structures of alpha-KrF(2),[KrF][MF(6)](M=As,Sb,Bi),[Kr(2)F(3)][SbF(6).KrF(2), [Ke(2)F(3)2[SbF(6)]2.KrF(2), and [Kr(2)F(3)][AsF(6)].[KrF][AsF(6)]; synthesis and characterization of [Kr(2)F(3)][PF(6).nKrF(2); and theoretical studies of KrF(2), KrF+, Kr(2)F(3)+, and the [KrF][MF(6)](M=P,As,Sb,Bi) ion pairs. Inorganic chemistry 44 11399167
2017 Adenosine A1 Receptor Antagonism Abolished the Anti-seizure Effects of Exogenous Ketone Supplementation in Wistar Albino Glaxo Rijswijk Rats. Frontiers in molecular neuroscience 43 28790891
2000 Immunohistology of kerato-epithelin in corneal stromal dystrophies associated with R124 mutations of the BIGH3 gene. Current eye research 35 11262611
1992 Search for MHC-associated genes in human: five new genes centromeric to HLA-DP with yet unknown functions. Immunogenetics 33 1541487
1997 Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes. Genomics 26 9205114
2016 Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia. Journal of cell communication and signaling 25 27778231
2017 Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads. BMC pharmacology & toxicology 23 28577368
2015 Low-intensity eccentric contractions of the knee extensors and flexors protect against muscle damage. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 23 26319562
2023 Prediction of zebrafish embryonic developmental toxicity by integrating omics with adverse outcome pathway. Journal of hazardous materials 22 36860045
2021 WGCNA-Based Identification of Hub Genes and Key Pathways Involved in Nonalcoholic Fatty Liver Disease. BioMed research international 22 34938809
2011 Prefoldin subunits are protected from ubiquitin-proteasome system-mediated degradation by forming complex with other constituent subunits. The Journal of biological chemistry 22 21478150
2002 Interaction of the membrane-inserted diphtheria toxin T domain with peptides and its possible implications for chaperone-like T domain behavior. Biochemistry 21 11863463
2019 Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents. Bioorganic chemistry 19 31376783
2019 The 21st Century movement within the area of skin sensitization assessment: From the animal context towards current human-relevant in vitro solutions. Regulatory toxicology and pharmacology : RTP 19 31430506
2011 Biosynthesis of hemiketal eicosanoids by cross-over of the 5-lipoxygenase and cyclooxygenase-2 pathways. Proceedings of the National Academy of Sciences of the United States of America 19 21482803
2017 Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 28096231
2021 Identification of the susceptibility genes for COVID-19 in lung adenocarcinoma with global data and biological computation methods. Computational and structural biotechnology journal 17 34840672
2008 A corneal dystrophy associated with transforming growth factor beta-induced Gly623Asp mutation an amyloidogenic phenotype. Ophthalmology 16 19019446
2020 Inhibition of 5-Lipoxygenase-Derived Leukotrienes and Hemiketals as a Novel Anti-Inflammatory Mechanism of Urolithins. Molecular nutrition & food research 14 32306507
2018 Roles and Functions of the Unconventional Prefoldin URI. Advances in experimental medicine and biology 13 30484155
2018 The Yeast Prefoldin Bud27. Advances in experimental medicine and biology 11 30484156
2007 Characterization of HKE2: an ancient antigen encoded in the major histocompatibility complex. Tissue antigens 11 17257322
2022 Identification of combined biomarkers for predicting the risk of osteoporosis using machine learning. Aging 9 35580864
2020 Proteome alterations associated with the oleic acid and cis-9, trans-11 conjugated linoleic acid content in bovine skeletal muscle. Journal of proteomics 8 32335295
2023 The 5-lipoxygenase/cyclooxygenase-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis. The Journal of biological chemistry 7 36813233
2020 α-Sens: The improved ARE-Nrf2-based sensitization screening assay using normalized transcriptional activity. Toxicology 6 32335162
1989 Electrophysiological interactions between carbachol and class I antiarrhythmic drugs (lidocaine, quinidine)--experimental studies in rabbit atrial myocardium. Basic research in cardiology 5 2923607
2023 AOP Report: Glutathione Conjugation Leading to Reproductive Dysfunction via Oxidative Stress. Environmental toxicology and chemistry 4 37849373
2022 Prefoldin subunit 6 of Plasmodium falciparum binds merozoite surface protein-1. FEBS open bio 4 33145997
1994 [Activity of alanine- and aspartate-aminotransferases in organs of albino rats subjected to whole body gamma-irradiation and physical exercise]. Radiatsionnaia biologiia, radioecologiia 4 7951896
2025 Targeting the mosquito prefoldin-chaperonin complex blocks Plasmodium transmission. Nature microbiology 2 40050397
2022 Prefoldin 6 promotes glioma progression via the AKT signalling pathway. Cell biology international 2 36300673
2024 Assessment of the mode of action of perchloroethylene-induced mouse liver tumors. Toxicology and industrial health 1 38523547
2024 Prefoldins are novel regulators of the unfolded protein response in artemisinin resistant Plasmodium falciparum malaria. The Journal of biological chemistry 1 38925325
2020 An evaluation of the genetic conditioning of evoking pain. Annals of agricultural and environmental medicine : AAEM 1 32588605
2026 Prefoldin 5 is a microtubule-associated protein that suppresses Tau aggregation and neurotoxicity. eLife 0 41533771
2026 Mode-of-Action and Human Relevance Assessment for Diisononyl Phthalate-Induced Liver Tumors in Rodents. Journal of applied toxicology : JAT 0 42086044
2024 PFDN6 contributes to colorectal cancer progression via transcriptional regulation. eGastroenterology 0 39944471
1993 [A case of advanced gastric cancer with liver and lung metastasis effectively treated by combined chemo-immunotherapy of MMC, 5'-DFUR, OK-432]. Gan to kagaku ryoho. Cancer & chemotherapy 0 8333751

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