WDFY3 Gene

HGNC Family	WD repeat domain containing (WDR), Zinc fingers
Name	WD repeat and FYVE domain containing 3
Description	This gene encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of these aggregated proteins. However, it is not necessary for starvation-induced macroautophagy. [provided by RefSeq, May 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWDFY3 (also known as ALFY) is a large phosphatidylinositol 3‐phosphate–binding scaffold protein that is essential for selective macroautophagy. It mediates the targeting and degradation of misfolded and aggregated proteins by linking ubiquitinated cargo—often bound by receptors such as p62—to core autophagic effectors (e.g., Atg5/Atg12/Atg16L, LC3, and GABARAP proteins). Through its ability to bind phosphatidylinositol 3‐phosphate and by harboring specialized domains such as the FYVE and LC3‐interacting region (LIR), WDFY3 localizes to both autophagic structures and intracellular inclusions, thereby facilitating the formation of protein bodies that are destined for lysosomal degradation. This adaptor function is critical for clearing aggregates in cells undergoing stress or proteasome inhibition, and its overexpression confers neuroprotection in disease models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in autophagy, WDFY3 is emerging as a key regulator in neurodevelopment and cellular differentiation. In neural tissues, it is required not only for the proper division of neural progenitors but also for the organization of axonal tracts and the guidance of axon outgrowth. In humans, loss‐of‐function variants or haploinsufficiency in WDFY3 are linked to neurodevelopmental delay and altered brain size—with defects ranging from macrocephaly to microcephaly—via dysregulation of pathways such as canonical Wnt signaling. Furthermore, by promoting autophagy‐dependent clearance processes, WDFY3 supports retinoid‐triggered differentiation in acute myeloid leukemia cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn additional cellular contexts, WDFY3 contributes to the regulation of endocytic trafficking and cell motility. It is involved in the phagocytic clearance of apoptotic cells (efferocytosis), where its interaction with GABARAP promotes LC3 lipidation and lysosomal acidification, and is crucial for proper actin disassembly during particle uptake. Moreover, distinct features of its FYVE domain underlie specific membrane targeting, while its dynamic localization to early endosomes in migrating cells influences integrin glycosylation and cell adhesion, thereby affecting directional motility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anne Simonsen, Hanne C G Birkeland, David J Gillooly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01287"}], "href": "https://doi.org/10.1242/jcs.01287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15292400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15292400"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Terje Høyvarde Clausen, Trond Lamark, Pauline Isakson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/auto.6.3.11226"}], "href": "https://doi.org/10.4161/auto.6.3.11226"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20168092"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20168092"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maria Filimonenko, Pauline Isakson, Kim D Finley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.04.007"}], "href": "https://doi.org/10.1016/j.molcel.2010.04.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20417604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20417604"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ai Yamamoto, Anne Simonsen "}, {"type": "b", "children": [{"type": "t", "text": "Alfy-dependent elimination of aggregated proteins by macroautophagy: can there be too much of a good thing?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/auto.7.3.14234"}], "href": "https://doi.org/10.4161/auto.7.3.14234"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21150266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21150266"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Alf Håkon Lystad, Yoshinobu Ichimura, Kenji Takagi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/embr.201338003"}], "href": "https://doi.org/10.1002/embr.201338003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24668264"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24668264"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rotem Kadir, Tamar Harel, Barak Markus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1005919"}], "href": "https://doi.org/10.1371/journal.pgen.1005919"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27008544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27008544"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Joanna M Dragich, Takaaki Kuwajima, Megumi Hirose-Ikeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.14810"}], "href": "https://doi.org/10.7554/eLife.14810"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27648578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27648578"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Anna M Schläfli, Pauline Isakson, E Garattini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-12734-4"}], "href": "https://doi.org/10.1038/s41598-017-12734-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29021535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29021535"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Diana Le Duc, Cecilia Giulivi, Susan M Hiatt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awz198"}], "href": "https://doi.org/10.1093/brain/awz198"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31327001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31327001"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Erin F Reinhart, Nicole A Litt, Sarah Katzenell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A highly conserved glutamic acid in ALFY inhibits membrane binding to aid in aggregate clearance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/tra.12771"}], "href": "https://doi.org/10.1111/tra.12771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33225481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33225481"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kristiane Søreng, Serhiy Pankiv, Camilla Bergsmark, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.259138"}], "href": "https://doi.org/10.1242/jcs.259138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35099014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35099014"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jianting Shi, Xun Wu, Ziyi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-022-35604-8"}], "href": "https://doi.org/10.1038/s41467-022-35604-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36566259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36566259"}]}]}]}
Synonyms	ALFY, BCHS, ZFYVE25, MCPH18
Proteins	WDFY3_HUMAN
NCBI Gene ID	23001
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

WDFY3 has 8,173 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 118 datasets.

Click the + buttons to view associations for WDFY3 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

WDFY3 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of WDFY3 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of WDFY3 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of WDFY3 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of WDFY3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of WDFY3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of WDFY3 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of WDFY3 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of WDFY3 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of WDFY3 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of WDFY3 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of WDFY3 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of WDFY3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with WDFY3 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of WDFY3 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of WDFY3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of WDFY3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with WDFY3 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing WDFY3 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of WDFY3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing WDFY3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing WDFY3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing WDFY3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing WDFY3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with WDFY3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with WDFY3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with WDFY3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with WDFY3 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with WDFY3 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of WDFY3 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by WDFY3 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving WDFY3 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with WDFY3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with WDFY3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with WDFY3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at WDFY3 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of WDFY3 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of WDFY3 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing WDFY3 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with WDFY3 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with WDFY3 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.