Affinage

ANKFY1

Ankyrin repeat and FYVE domain-containing protein 1 · UniProt Q9P2R3

Length
1169 aa
Mass
128.4 kDa
Annotated
2026-06-09
14 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANKFY1 (Rabankyrin-5/Ankhzn) is an endosome-associated protein that integrates phosphoinositide-dependent membrane recognition with ubiquitin signaling and lipid transfer to control endosomal trafficking, receptor surface display, and autophagosome biogenesis (PMID:10092534, PMID:38622126). It localizes to endosomal membranes via a FYVE domain that binds PI3P and is found in both membrane and soluble pools (PMID:10092534, PMID:10940552, PMID:38622126). ANKFY1 functions as a BTB/adaptor for the CUL3 E3 ubiquitin ligase, with CUL3 required for its early endosomal localization; this CUL3–ANKFY1 module sustains cell-surface levels of integrin β1 and supports angiogenesis (PMID:29038302), and ANKFY1 likewise maintains surface VEGFR2 and downstream Akt/eNOS signaling in endothelial cells without affecting receptor transcription (PMID:33092793). In a parallel trafficking role, ANKFY1 binds active GTP-bound RAB5 and interacts with GAPVD1 to govern RAB5-dependent endosomal regulation in podocytes (PMID:29959197). Beyond receptor trafficking, ANKFY1 directly interacts with ATG2A and promotes ATG2A-mediated lipid transfer from PI3P-containing membranes, operating within a UVRAG–PI3P–ATG2A pathway that delivers lipid from endosomes to growing phagophores; its loss impairs autophagosome growth and autophagy flux (PMID:38622126). ANKFY1 can also recruit CUL3 to ubiquitinate a viral substrate (PDCoV nsp8) for p62-dependent selective autophagic degradation, restricting viral replication (PMID:41763084). In vivo, loss of ANKFY1 causes background-dependent embryonic lethality, progressive cerebellar Purkinje cell degeneration with motor defects, and bi-allelic loss-of-function variants are associated with a neuro-renal syndrome of proteinuria and movement disorder (PMID:33796010, PMID:28123425, PMID:38915441).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 Medium

    Established the basic identity and subcellular home of ANKFY1, defining it as an endosomal ankyrin-repeat/FYVE protein and setting the structural basis for membrane recognition.

    Evidence Immunoelectron microscopy and in vitro transcription/translation with antibody detection

    PMID:10092534

    Open questions at the time
    • FYVE-PI3P binding not yet functionally demonstrated
    • no molecular partners or activity defined
  2. 2000 Medium

    Refined biochemical distribution and genomic mapping, showing ANKFY1 partitions between membrane and soluble fractions consistent with dynamic membrane association.

    Evidence Subcellular fractionation/Western blot and radiation hybrid/FISH mapping to 17p13

    PMID:10940552

    Open questions at the time
    • determinants of membrane vs soluble partitioning unknown
    • no functional role assigned
  3. 2003 Low

    Linked ANKFY1 to endocytic and starvation-responsive vesicular compartments, hinting at roles in endocytosis and autophagy.

    Evidence Immunofluorescence co-localization with transferrin and dextran plus serum-starvation in macrophages

    PMID:12833855

    Open questions at the time
    • localization-only, no genetic manipulation
    • autophagy involvement not mechanistically tested
  4. 2017 High

    Identified ANKFY1 as a CUL3 E3 ligase adaptor controlling surface receptor trafficking, providing the first mechanistic activity and a physiological angiogenesis output.

    Evidence BTBP siRNA screen, reciprocal Co-IP, surface integrin β1 flow cytometry in endothelial cells

    PMID:29038302

    Open questions at the time
    • ubiquitination substrates in this pathway not identified
    • how CUL3 directs endosomal localization unresolved
  5. 2018 High

    Connected ANKFY1 to RAB5/GAPVD1-dependent endosomal regulation and to human disease, showing patient mutations impair RAB5 binding and podocyte function.

    Evidence Co-IP, co-localization, podocyte migration rescue with patient mutants, Drosophila nephrocyte assay

    PMID:29959197

    Open questions at the time
    • structural basis of active-RAB5 recognition not resolved
    • relationship between RAB5 and CUL3 functions unclear
  6. 2020 Medium

    Extended the receptor-trafficking role to VEGFR2, showing ANKFY1 maintains surface receptor levels and downstream Akt/eNOS signaling post-transcriptionally.

    Evidence siRNA knockdown with surface VEGFR2 Western blot, signaling and migration/proliferation assays in HRMECs

    PMID:33092793

    Open questions at the time
    • whether CUL3 ubiquitination drives VEGFR2 trafficking untested
    • trafficking step affected (recycling vs degradation) undefined
  7. 2021 Medium

    Demonstrated a cell-type-specific in vivo requirement, with Purkinje cell loss and motor defects upon ANKFY1 knockout.

    Evidence Whole-body knockout mouse histology, immunofluorescence, motor behavior

    PMID:33796010

    Open questions at the time
    • molecular cause of Purkinje cell vulnerability unknown
    • endosomal vs autophagy contribution to phenotype not separated
  8. 2016 Medium

    Revealed an essential but genetic-background-dependent role in early embryogenesis, complicating interpretation of organismal requirement.

    Evidence Knockout mice in mixed vs pure C57BL/6 backgrounds with developmental analysis

    PMID:28123425

    Open questions at the time
    • modifier loci explaining background dependence unidentified
    • molecular pathway underlying lethality unknown
  9. 2024 High

    Defined a direct biochemical mechanism in autophagy: ANKFY1 binds PI3P and ATG2A and promotes ATG2A-mediated lipid transfer from endosomes to phagophores.

    Evidence In vitro lipid transfer with purified proteins and PI3P liposomes, FYVE mutagenesis, autophagy flux assays, UVRAG/ANKFY1/ATG2A epistasis

    PMID:38622126

    Open questions at the time
    • how ANKFY1 tethers ATG2A to phagophores structurally undefined
    • relationship between autophagy and CUL3/RAB5 roles unresolved
  10. 2024 Low

    Strengthened the human disease link by associating bi-allelic loss-of-function ANKFY1 variants with a neuro-renal syndrome.

    Evidence Whole-exome sequencing with in vitro protein-expression assay of patient variants

    PMID:38915441

    Open questions at the time
    • single in vitro expression readout, no rescue or animal model
    • genotype-phenotype causality not formally established
  11. 2026 Medium

    Showed ANKFY1 couples CUL3-mediated ubiquitination to selective autophagy of a substrate, recruiting CUL3 to ubiquitinate viral nsp8 for p62-dependent degradation.

    Evidence Co-IP, ubiquitination assay with K58 mutagenesis, p62 interaction, viral replication quantification

    PMID:41763084

    Open questions at the time
    • endogenous (non-viral) ubiquitination substrates not identified
    • generality of CUL3-to-p62 axis beyond this pathogen untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ANKFY1's distinct activities — CUL3 adaptor, RAB5/GAPVD1 endosomal regulator, and ATG2A lipid-transfer cofactor — are coordinated on a single endosomal platform, and which is responsible for each in vivo phenotype, remains unresolved.
  • no integrated model linking trafficking, ubiquitination, and lipid transfer
  • endogenous ubiquitination substrates unknown
  • structural basis of multivalent partner engagement undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Complex memberships
CUL3 E3 ubiquitin ligase complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 ANKFY1 (Ankhzn) protein localizes to endosomal membranes, as determined by immunoelectron microscopy. The protein contains 17 ankyrin repeats hooked to a zinc finger (FYVE) motif, and was confirmed at ~130 kDa by in vitro transcription/translation and antibody detection on SDS-PAGE. Immunoelectron microscopy, in vitro transcription/translation, SDS-PAGE/Western blot Biochemical and biophysical research communications Medium 10092534
2000 Human ANKFY1 (ANKHZN) protein is present in both membrane and soluble fractions on subcellular fractionation, confirming partial membrane association. The gene maps to chromosome 17p13. Subcellular fractionation, Western blot, radiation hybrid panel, FISH Gene Medium 10940552
2003 ANKFY1 (Ankhzn) co-localizes with phagocytosed dextran particles and transferrin-labeled endocytotic structures in macrophages, and its immunoreactivity is markedly increased in serum-starved cells, suggesting involvement in endocytosis and autophagy vesicle formation. Immunohistochemistry, immunofluorescence co-localization with transferrin and dextran, serum starvation assay Kaibogaku zasshi. Journal of anatomy Low 12833855
2017 ANKFY1 acts as a BTB-domain adaptor protein for the CUL3 E3 ubiquitin ligase complex and is required for early endosomal localization of integrin β1 on the cell surface of endothelial cells. CUL3 physically interacts with ANKFY1 and is required for ANKFY1's early endosomal localization. Depletion of either CUL3 or ANKFY1 by siRNA reduces surface integrin β1 levels and impairs angiogenesis. siRNA knockdown, co-immunoprecipitation, immunofluorescence/confocal localization, flow cytometry for surface integrin β1, siRNA screen of 175 BTBPs Biology open High 29038302
2018 ANKFY1 physically interacts with GAPVD1 (co-immunoprecipitation) and both proteins co-localize in HEK293T cells. Both proteins interact with active RAB5 (GTP-bound form). Patient-derived missense mutations in ANKFY1 alter binding affinity for active RAB5 and reduce ability to rescue knockout-induced podocyte migration defects, implicating ANKFY1 in RAB5-dependent endosomal regulation in podocytes. Co-immunoprecipitation, co-localization in HEK293T, siRNA silencing, podocyte migration assay, ectopic expression of patient-derived mutant proteins, Drosophila nephrocyte endocytosis assay Journal of the American Society of Nephrology : JASN High 29959197
2020 ANKFY1 knockdown in human retinal microvascular endothelial cells (HRMECs) reduces cell-surface VEGFR2 protein levels (without affecting VEGFR2 mRNA) and attenuates downstream Akt/eNOS signaling, thereby impairing VEGF-dependent and -independent endothelial cell proliferation and migration. siRNA knockdown, Western blot for surface VEGFR2 and Akt/eNOS phosphorylation, qRT-PCR, cell proliferation and migration assays Biochemical and biophysical research communications Medium 33092793
2021 Ankfy1 knockout mice develop normally but at 9 months show progressive loss of cerebellar Purkinje cells (with other cerebellar cell types largely unaffected) and defective motor function, establishing a cell-type-specific role for ANKFY1 in Purkinje cell maintenance in vivo. Whole-body knockout mouse model, histology, immunofluorescence, motor behavior tests Frontiers in cellular neuroscience Medium 33796010
2024 ANKFY1 is an endosome-localized protein that binds PI3P through its FYVE domain, directly interacts with ATG2A, and promotes ATG2A-mediated lipid transfer from PI3P-containing liposomes. A pool of ANKFY1 co-localizes with ATG2A between endosomes and phagophores. Depletion of ANKFY1 impairs autophagosome growth and reduces autophagy flux, phenocopying ATG2A/B depletion. Depletion of UVRAG, ANKFY1, or ATG2A/B reduces PI3P on phagophores, placing ANKFY1 in the UVRAG–PI3P–ATG2A lipid transfer pathway from endosomes to phagophores. Co-immunoprecipitation/pulldown, in vitro lipid transfer assay with purified recombinant proteins and PI3P-containing liposomes, siRNA/shRNA depletion, autophagy flux assays, confocal co-localization, genetic epistasis (UVRAG/ANKFY1/ATG2A/B depletion) Cell discovery High 38622126
2016 Ankfy1 is dispensable for neural stem/precursor cell development in mice with a mixed genetic background, but Ankfy1 knockout is lethal by embryonic day 11.5 in a pure C57BL/6 inbred background, indicating an essential but genetically background-dependent role in early embryonic development. Knockout mouse generation, immunofluorescence, in situ hybridization, genotyping by PCR Neural regeneration research Medium 28123425
2024 Compound heterozygous ANKFY1 variants (p.Ser918Ter and a splice-site deletion) found in a patient with proteinuria and movement disorder lead to reduced ANKFY1 protein expression in vitro, supporting a loss-of-function mechanism for bi-allelic ANKFY1 variants in a neuro-renal syndrome. Whole-exome sequencing, in vitro functional study (Western blot for protein expression of patient variants) Clinical kidney journal Low 38915441
2026 ANKFY1 interacts with PDCoV nonstructural protein nsp8, recruits the E3 ubiquitin ligase Cullin3 to catalyze K63/K33-linked ubiquitination of nsp8 at lysine 58, and the ubiquitinated nsp8 is subsequently recognized by selective autophagy receptor p62 and delivered to autolysosomes for degradation, thereby suppressing viral replication. Co-immunoprecipitation, gain/loss-of-function (overexpression and siRNA depletion), ubiquitination assay with site-directed mutagenesis (K58 site), p62 interaction assay, viral replication and RNA synthesis quantification Veterinary microbiology Medium 41763084
2023 miR-760 directly targets the ANKFY1 3'UTR (validated by luciferase reporter assay) and suppresses ANKFY1 protein expression. ANKFY1 participates in APS-mediated promotion of osteogenic differentiation and proliferation of human bone marrow mesenchymal stem cells. Luciferase reporter assay, Western blot, qRT-PCR, miR-760 overexpression/knockdown, osteogenic differentiation assays Bone & joint research Low 37532241

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome. Journal of the American Society of Nephrology : JASN 50 29959197
2017 Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin β1 in endothelial cells. Biology open 33 29038302
1999 Molecular cloning of a novel 130-kDa cytoplasmic protein, Ankhzn, containing Ankyrin repeats hooked to a zinc finger motif. Biochemical and biophysical research communications 18 10092534
2023 Astragalus polysaccharide promotes osteogenic differentiation of human bone marrow derived mesenchymal stem cells by facilitating ANKFY1 expression through miR-760 inhibition. Bone & joint research 12 37532241
2024 ANKFY1 bridges ATG2A-mediated lipid transfer from endosomes to phagophores. Cell discovery 10 38622126
2020 ANKFY1 is essential for retinal endothelial cell proliferation and migration via VEGFR2/Akt/eNOS pathway. Biochemical and biophysical research communications 8 33092793
2000 Characterization and chromosomal mapping of a novel human gene, ANKHZN. Gene 8 10940552
2021 Ankfy1 Is Involved in the Maintenance of Cerebellar Purkinje Cells. Frontiers in cellular neuroscience 7 33796010
2016 Ankfy1 is dispensable for neural stem/precursor cell development. Neural regeneration research 5 28123425
2022 The relationship of maternal rank, 5-HTTLPR genotype, and MAOA-LPR genotype to temperament in infant rhesus monkeys (Macaca mulatta). American journal of primatology 3 35322905
2003 [Possible involvement of Ankhzn, a novel protein possessing FYVE domain, in cellular endocytosis and autophagocytosis in vitro]. Kaibogaku zasshi. Journal of anatomy 1 12833855
2026 ANKFY1 suppresses PDCoV replication by degrading viral nsp8 protein via p62-dependent selective autophagy. Veterinary microbiology 0 41763084
2025 Identification of spastic ataxia-related proteins via comparative proteomic analysis of the cerebellum of conditional Ankfy1 knockout mice. Scientific reports 0 40594855
2024 Compound heterozygous variants of ANKFY1 in a child with infantile-onset proteinuria and movement disorder. Clinical kidney journal 0 38915441

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