Affinage

ZFYVE16

Zinc finger FYVE domain-containing protein 16 · UniProt Q7Z3T8

Round 2 corrected
Length
1539 aa
Mass
168.9 kDa
Annotated
2026-04-28
43 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZFYVE16 (endofin) is a FYVE-domain protein that localizes to early endosomes through direct binding of phosphatidylinositol 3-phosphate (PtdIns(3)P), dependent on an intact FYVE zinc finger (C753) and PI3-kinase activity; overexpression induces endosome fusion and accumulation of endocytosed cargo (PMID:11546807). In vivo, Zfyve16 is required for normal B-lymphoid cell proliferation and participates in TGF-β signaling through its interaction with Smad4, influencing Smad2/3–Smad4 complex formation and T-cell homeostasis (PMID:29247407). ZFYVE16 also associates with LAMP1- and LAMP2A-positive late endosomal/lysosomal compartments in human iPSC-derived cortical neuron axons, indicating roles beyond early endosome biology (PMID:41537223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2001 High

    The fundamental question of how ZFYVE16 reaches endosomes was resolved: its FYVE domain binds PtdIns(3)P directly, and a single cysteine mutation (C753S) or PI3-kinase inhibition abolishes endosomal targeting, establishing ZFYVE16 as a PtdIns(3)P effector on early endosomes.

    Evidence Point mutagenesis, liposome binding assay, wortmannin treatment, and immunofluorescence in cultured cells

    PMID:11546807

    Open questions at the time
    • Endogenous regulation of ZFYVE16 endosomal recruitment (post-translational modifications, binding partners) was not addressed
    • The overexpression-induced endosome fusion phenotype was not linked to a specific downstream pathway
    • Despite co-localization with SARA, no direct interaction was found—how the two FYVE-domain proteins partition on endosomes remains unknown
  2. 2017 Medium

    The in vivo requirement for Zfyve16 was established: knockout mice revealed that Zfyve16 is needed for B-cell proliferation and contributes to TGF-β-mediated T-cell suppression through Smad4 interaction, placing the endosomal protein in an immunological signaling context.

    Evidence Zfyve16 knockout mouse, flow cytometry of hematopoietic compartments, in vitro B-cell proliferation assay

    PMID:29247407

    Open questions at the time
    • The molecular mechanism by which ZFYVE16 promotes Smad4-dependent signaling on endosomes is not defined
    • Whether the B-cell proliferation defect is cell-autonomous or secondary to altered cytokine milieu was not resolved
    • Findings are from a single laboratory and have not been independently replicated
  3. 2020 Low

    Phosphoproteomic profiling linked ZFYVE16 phosphorylation status to phagosomal maturation in neutrophils, suggesting that post-translational modification of ZFYVE16 may regulate endosomal/phagosomal dynamics downstream of VPS34.

    Evidence Quantitative phosphoproteomics in C5a-treated human neutrophils challenged with S. aureus, VPS34 inhibition

    PMID:32634128

    Open questions at the time
    • ZFYVE16 was identified in a broad screen without direct functional manipulation—causality is not established
    • The specific phosphorylation site(s) and their functional consequences were not characterized
    • No link to the previously described Smad4 interaction or B-cell phenotype
  4. 2026 Medium

    ZFYVE16 was shown to reside on LAMP1/LAMP2A-positive late endosomal/lysosomal compartments in neuronal axons, expanding its localization beyond classical early endosomes and implicating it in late endosome/lysosome biology in the nervous system.

    Evidence Proximity biotinylation (LOV-Turbo BioID) with LAMP1/LAMP2A baits in hiPSC-derived cortical neurons, validated by orthogonal methods

    PMID:41537223

    Open questions at the time
    • Whether ZFYVE16 functions on late endosomes/lysosomes or simply transits through these compartments is unknown
    • The binding partner or lipid signal mediating ZFYVE16 association with LAMP1/LAMP2A-positive membranes has not been identified
    • Functional consequences of ZFYVE16 loss in neurons remain untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ZFYVE16's interaction with Smad4, how ZFYVE16 transitions between early and late endosomal compartments, the identity of its phosphorylation-dependent regulators, and whether its neuronal and immune functions share a common endosomal trafficking mechanism.
  • No structural data exist for ZFYVE16 or the ZFYVE16–Smad4 complex
  • Substrate or cargo specificity on late endosomes is unknown
  • Cell-type-specific functions (neurons vs. lymphocytes) have not been compared mechanistically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-162582 Signal Transduction 1
Partners
LAMP1LAMP2ASMAD4

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ZFYVE16 (endofin/KIAA0305) localizes to early endosomes via its FYVE domain, which binds preferentially to phosphatidylinositol 3-phosphate (PtdIns(3)P). A single point mutation C753S in the FYVE finger abolishes both PtdIns(3)P binding and endosomal association. Endosomal localization is also sensitive to the PI3-kinase inhibitor wortmannin. At high expression levels, endofin causes endosome aggregation/fusion and accumulation of endocytosed EGF. Although endofin co-localizes with SARA, the two proteins do not co-immunoprecipitate and endofin does not associate with Smad2 nor replicate SARA's effect on TGF-β signaling. Indirect immunofluorescence microscopy, deletion mutagenesis, point mutagenesis (C753S), in vitro liposome binding assay, co-immunoprecipitation, wortmannin treatment The Journal of biological chemistry High 11546807
2017 In vivo knockout of Zfyve16 in mice reveals that Zfyve16 is required for normal B-lymphoid cell proliferation: Zfyve16KO mice show significantly reduced B cell proportions and Zfyve16KO B-lymphoid cells have decreased proliferation potential in vitro. Conversely, T cell proportions increase in KO mice, consistent with Zfyve16 facilitating TGF-β-mediated T cell suppression through its interaction with Smad4 (which affects Smad2/3–Smad4 complex formation in TGF-β signaling). Knockout mouse generation, flow cytometric analysis of hematopoietic compartments, in vitro B-cell proliferation assay Frontiers of medicine Medium 29247407
2020 Phosphoproteomic profiling of C5a-treated human neutrophils identifies ZFYVE16 as an early endosomal marker whose phosphorylation is selectively impaired upon phagosomal challenge with S. aureus in the presence of C5a, linking ZFYVE16 phosphorylation status to phagosomal maturation and acidification downstream of PI3K VPS34. Quantitative phosphoproteomic profiling (2712 phosphoproteins), phagosomal acidification assay, VPS34 inhibition JCI insight Low 32634128
2008 In an mRNA-display selection with a mixed human cDNA library against an anti-p53 antibody, ZFYVE16 was identified as a cross-reactive antigen candidate sharing the consensus epitope motif -S-D-L-( )-K-L- with p53. Pull-down assay confirmed ZFYVE16 binds the antibody with affinity comparable to p53 itself. mRNA-display selection, in vitro transcription/translation, pull-down assay Biotechnology letters Low 18633578
2026 Proximity labelling using LOV-Turbo fused to full-length LAMP1 or LAMP2A in human iPSC-derived cortical neurons identified ZFYVE16 as a novel interactor of both LAMP1- and LAMP2A-positive late endosomal/lysosomal compartments in axons, which was subsequently validated experimentally. Proximity biotinylation (LOV-Turbo BioID), mass spectrometry interactome mapping, experimental validation in hiPSC-derived cortical neurons Journal of cell science Medium 41537223

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Bone morphogenetic proteins. Growth factors (Chur, Switzerland) 1639 15621726
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2001 SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nature cell biology 252 11433298
2004 Functional proteomics mapping of a human signaling pathway. Genome research 247 15231748
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
1997 Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 187 9205841
2004 Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Analytical chemistry 174 15144186
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2010 The influence of surface microroughness and hydrophilicity of titanium on the up-regulation of TGFβ/BMP signalling in osteoblasts. Biomaterials 137 20933273
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2015 Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. Nature communications 116 25854761
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2023 ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling. Nature communications 104 36739287
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2001 Endofin, an endosomal FYVE domain protein. The Journal of biological chemistry 62 11546807
2018 Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM). Journal of medical genetics 60 30120215
2020 C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling. JCI insight 28 32634128
2020 Investigating the Transition of Pre-Symptomatic to Symptomatic Huntington's Disease Status Based on Omics Data. International journal of molecular sciences 26 33049985
2016 Whole-exome sequencing to identify somatic mutations in peritoneal metastatic gastric adenocarcinoma: A preliminary study. Oncotarget 24 27270314
2024 Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance. British journal of cancer 8 38594370
2017 Zfyve16 regulates the proliferation of B-lymphoid cells. Frontiers of medicine 5 29247407
2008 Isolation of cross-reacting antigen candidates by mRNA-display using a mixed cDNA library. Biotechnology letters 4 18633578
2023 Genomic insights into the genetic basis of eagle-beak jaw, large head, and long tail in the big-headed turtle. Ecology and evolution 2 37502307
2026 LAMP1 and LAMP2A localise to axonal organelles with distinct motility dynamics and partially overlapping molecular signatures in human neurons. Journal of cell science 0 41537223
2016 Genetic Mutation that May Contribute to Failure of Prolapse Surgery in White Women: A Case-Control Study. Journal of minimally invasive gynecology 0 26944198