Affinage

EPN1

Epsin-1 · UniProt Q9Y6I3

Length
576 aa
Mass
60.3 kDa
Annotated
2026-06-09
24 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPN1 (epsin 1) is a specialized endocytic adaptor that couples membrane deformation to the selective internalization of ubiquitinated and clustered cell-surface cargo (PMID:19666558, PMID:39324332). Its ENTH domain drives membrane vesiculation, generating the curvature required for endocytic budding (PMID:39324332). EPN1 operates within clathrin-mediated endocytosis adaptor networks: intersectin1 (ITSN1) recruits EPN1 together with AP2, EPS15, FCHO2, and dynamin2 into organized endocytic puncta (PMID:39580802), and EPN1 itself recruits clathrin to specific cargo, including ubiquitinated TCR microclusters at the immunological synapse to enable trans-endocytosis of pMHC-TCR conjugates (PMID:36730202). Functionally, EPN1 (acting redundantly with EPN2/EPN3) mediates internalization and degradation of activated VEGFR2 to downregulate angiogenic signaling (PMID:24311377), internalizes ubiquitinated SNAT2 to control its membrane abundance (PMID:38949026), and is specifically required for Notch signaling activation during development, distinct from housekeeping endocytosis (PMID:19666558). In podocytes, epsins sustain cell function through the Cdc42-SRF-β1 integrin signaling axis (PMID:33051360). A conserved role is seen in C. elegans, where the epsin homolog EPN-1 promotes actin-dependent pseudopod extension during apoptotic cell engulfment downstream of CED-1 signaling (PMID:23861060).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 High

    Established that epsins are not merely generic endocytic adaptors but are specifically required for a defined signaling pathway, answering whether their function is dispensable or cargo-selective.

    Evidence Genetic EPN1/EPN2 double knockout in mice with Notch target gene readouts and housekeeping endocytosis controls

    PMID:19666558

    Open questions at the time
    • Does not define the molecular step (ligand vs receptor side) at which epsins enable Notch activation
    • Redundancy between EPN1 and EPN2 not separated
  2. 2013 High

    Placed epsin function at a specific cargo, showing it controls receptor signaling output by mediating activated receptor internalization and degradation.

    Evidence Endothelial-specific DKO mice with genetic epistasis to VEGFR2 heterozygosity plus in vitro and in vivo angiogenesis assays

    PMID:24311377

    Open questions at the time
    • Direct physical EPN1-VEGFR2 interaction and ubiquitin-dependence not biochemically resolved here
    • Role of individual epsin paralogs not separated
  3. 2013 Medium

    Revealed a conserved, actin-linked role for epsin beyond classical clathrin endocytosis, in apoptotic cell engulfment downstream of corpse-recognition signaling.

    Evidence RNAi inactivation, genetic epistasis, and live imaging of pseudopod localization in C. elegans

    PMID:23861060

    Open questions at the time
    • Molecular link between EPN-1 and the actin machinery not defined
    • C. elegans ortholog; mammalian conservation of this engulfment role not tested
  4. 2020 High

    Connected epsin loss to a tissue-level homeostatic phenotype and a defined downstream signaling axis, broadening epsin function from cargo trafficking to cytoskeletal/adhesion signaling.

    Evidence Podocyte-specific triple KO mice with Cdc42/SRF activity assays, β1 integrin expression, and adhesion/spreading assays

    PMID:33051360

    Open questions at the time
    • Mechanism linking epsin endocytic activity to Cdc42-SRF activation not resolved
    • Requires triple knockout, leaving paralog-specific contributions unclear
  5. 2021 Low

    Indicated cargo-selective endocytic regulation of neurotransmitter receptors, showing epsin differentially controls surface abundance of distinct receptor subtypes.

    Evidence Genome-wide RNAi screen with levamisole pharmacology and receptor abundance measurements in C. elegans

    PMID:33713125

    Open questions at the time
    • RNAi knockdown with abundance readouts only; no direct mechanistic dissection
    • Opposing effects on L-AChR vs GABAA receptors are unexplained
    • Single lab, single method
  6. 2023 Medium

    Resolved how EPN1 directs cargo fate, showing it recruits clathrin to ubiquitinated TCR microclusters to specify endocytosis within a sequence of adaptor handoffs.

    Evidence Live-cell imaging at the immunological synapse with sequential recruitment analysis and functional perturbation distinguishing ecto- vs endocytic fates

    PMID:36730202

    Open questions at the time
    • Direct EPN1 ubiquitin-binding requirement at TCR not biochemically isolated
    • Single lab; generality beyond TCR not addressed
  7. 2024 Medium

    Defined the architectural context of EPN1 recruitment, showing ITSN1 organizes an EPN1-containing CME adaptor network and can recruit it de novo.

    Evidence Genome-edited live-cell imaging with ectopic mitochondrial targeting reconstitution and ITSN1 knockdown

    PMID:39580802

    Open questions at the time
    • Direct ITSN1-EPN1 binding interface not mapped
    • Functional consequence of ITSN1-dependent EPN1 recruitment for cargo not tested
  8. 2024 Medium

    Provided direct biophysical confirmation that the ENTH domain itself deforms membranes, grounding the cell-biological adaptor role in an intrinsic membrane-shaping activity.

    Evidence In vitro single-particle liposome vesiculation assay with the isolated ENTH domain at physiological concentrations

    PMID:39324332

    Open questions at the time
    • Single in vitro method; in-cell contribution relative to other curvature drivers not quantified
  9. 2024 Medium

    Linked EPN1-mediated endocytosis to metabolic and tumor phenotypes via ubiquitin-code crosstalk controlling cargo surface levels.

    Evidence Ubiquitination site mutagenesis, co-IP, membrane fractionation, EPN1 siRNA, and in vivo/PDX bladder cancer tumor models

    PMID:38949026

    Open questions at the time
    • Direct EPN1 recognition of K63-polyubiquitinated SNAT2 not demonstrated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EPN1 achieves cargo selectivity and is partitioned among its paralogs (EPN2/EPN3) across tissues and pathways remains unresolved.
  • No isolated EPN1-specific (paralog-resolved) loss-of-function across the characterized pathways
  • Structural basis for selective ubiquitinated-cargo recognition not established in this corpus
  • Mechanistic link between endocytic activity and downstream signaling axes (Cdc42-SRF, Notch) not bridged

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
AP2CLTCDNM2EPS15FCHO2ITSN1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Epsin 1 (EPN1) and epsin 2 (EPN2) together act as specialized endocytic adaptors required for Notch signaling activation in mammals; combined loss of both genes causes embryonic lethality at E9.5-E10 with severe reduction of Notch primary target gene expression, recapitulating global Notch signaling impairment, while housekeeping clathrin-mediated endocytosis remains intact in double-knockout cells. Genetic double knockout in mice, embryo phenotyping, Notch target gene expression analysis, endocytosis assays in derived cells Proceedings of the National Academy of Sciences of the United States of America High 19666558
2013 Endothelial epsins (EPN1/EPN2) function to downregulate VEGFR2 by mediating activated VEGFR2 internalization and degradation; genetic reduction of VEGFR2 in endothelial epsin-deleted mice rescues aberrant angiogenesis, restoring normal VEGF signaling, EC proliferation, EC migration, and EC network formation. Conditional endothelial-specific DKO mice, genetic epistasis with VEGFR2 heterozygosity, in vitro angiogenesis assays with primary endothelial cells, in vivo wound healing and tumor angiogenesis assays Arteriosclerosis, thrombosis, and vascular biology High 24311377
2013 In C. elegans, epsin (EPN-1) plays a role in apoptotic cell engulfment by promoting actin polymerization during pseudopod extension; CHC-1 is recruited to extending pseudopods in an EPN-1-dependent manner, and epistasis analysis places epn-1 and chc-1 in the same engulfment pathway as ced-1, ced-6, and dyn-1. CED-1 signaling is required for pseudopod enrichment of EPN-1 and CHC-1. RNAi inactivation in C. elegans, genetic epistasis, live imaging of pseudopod localization, cofilin partial suppression assay Development (Cambridge, England) Medium 23861060
2020 Podocyte-specific triple knockout of Epn1, Epn2, and Epn3 in mice causes increased albuminuria and foot process effacement, with reduced activation of Cdc42 and SRF, resulting in diminished β1 integrin expression; epsins maintain podocyte function through the Cdc42–SRF–β1 integrin signaling axis. Podocyte-specific triple KO mice, albuminuria measurements, primary podocyte isolation, cell adhesion/spreading assays, Cdc42 and SRF activity assays, β1 integrin expression analysis Journal of the American Society of Nephrology : JASN High 33051360
2023 EPN1 recruits clathrin to ubiquitinated TCR microclusters at the immunological synapse to enable trans-endocytosis of pMHC-TCR conjugates from the antigen-presenting cell; this occurs after an earlier HRS/STAM2-mediated clathrin recruitment step that drives ectocytic vesicle release, demonstrating that EPN1 coordinates the endocytic fate of TCR through sequential adaptor recruitment. Live-cell imaging at immunological synapse, sequential recruitment analysis, functional perturbation experiments distinguishing ecto- and endocytic fates Proceedings of the National Academy of Sciences of the United States of America Medium 36730202
2024 ITSN1 (intersectin1) recruits epsin1 (EPN1) as part of a CME adaptor protein interaction network; artificially targeting ITSN1 to the mitochondrial surface was sufficient to assemble puncta containing EPN1, AP2, EPS15, FCHO2, and dynamin2, demonstrating that ITSN1 organizes EPN1-containing endocytic protein complexes. ITSN1 can form puncta and recruit dynamin2 independently of EPN1. Genome-edited live-cell imaging, mitochondrial targeting assay, ITSN1 knockdown with endocytic protein recruitment analysis Cell reports Medium 39580802
2024 The ENTH domain of epsin-1 (EPN1) has membrane vesiculation activity, demonstrated using a single-particle analysis assay with free-floating liposomes at physiologically relevant protein concentrations, consistent with its established role in membrane curvature generation during endocytosis. In vitro liposome vesiculation assay (single-particle fluorescence), biophysical reconstitution Journal of cell science Medium 39324332
2024 UBE2C-mediated monoubiquitination of SNAT2 at K59 inhibits K63-linked polyubiquitination at K33, increasing SNAT2 membrane protein levels by suppressing EPN1-mediated endocytosis of SNAT2; this crosstalk promotes glutamine uptake, VEGFC secretion, and lymphangiogenesis in bladder cancer. Ubiquitination mutagenesis, co-IP, membrane fractionation, siRNA knockdown of EPN1, in vitro and in vivo tumor models, patient-derived xenograft The Journal of clinical investigation Medium 38949026
2021 In C. elegans, loss of the epsin homolog epn-1 causes levamisole hypersensitivity and has opposing effects on postsynaptic receptor levels: increased abundance of L-type acetylcholine receptors (L-AChRs) and decreased abundance of GABAA receptors at the neuromuscular junction, indicating that EPN-1 mediates endocytosis of these receptor subtypes differentially. C. elegans genome-wide RNAi screen, pharmacological levamisole assay, receptor abundance measurements G3 (Bethesda, Md.) Low 33713125

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proceedings of the National Academy of Sciences of the United States of America 96 19666558
2013 Mosquito cellular factors and functions in mediating the infectious entry of chikungunya virus. PLoS neglected tropical diseases 58 23409203
2013 Genetic reduction of vascular endothelial growth factor receptor 2 rescues aberrant angiogenesis caused by epsin deficiency. Arteriosclerosis, thrombosis, and vascular biology 42 24311377
2013 Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans. Development (Cambridge, England) 33 23861060
2023 Clathrin mediates both internalization and vesicular release of triggered T cell receptor at the immunological synapse. Proceedings of the National Academy of Sciences of the United States of America 28 36730202
1993 Molecular analysis and overexpression of the gene encoding endothiapepsin, an aspartic protease from Cryphonectria parasitica. Gene 27 8462868
2004 Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases. Genes, chromosomes & cancer 20 15287029
2024 UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer. The Journal of clinical investigation 16 38949026
2023 Methylome and proteome integration in human skeletal muscle uncover group and individual responses to high-intensity interval training. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 37698381
2021 A C. elegans genome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function. G3 (Bethesda, Md.) 10 33713125
2022 Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods. Frontiers in genetics 6 35991579
2020 Novel Nasal Epithelial Cell Markers of Parkinson's Disease Identified Using Cells Treated with α-Synuclein Preformed Fibrils. Journal of clinical medicine 6 32640699
2010 Epimorphin-derived peptide antagonists remedy epidermal parakeratosis triggered by unsaturated fatty acid. Journal of dermatological science 6 20688483
2021 m6A Regulator Expression Segregates Meningiomas Into Biologically Distinct Subtypes. Frontiers in oncology 4 35004283
2020 Murine Epsins Play an Integral Role in Podocyte Function. Journal of the American Society of Nephrology : JASN 4 33051360
2024 Synaptic Vesicle-Related Proteins and Ubiquilin 2 in Cortical Synaptosomes Mediate Cognitive Impairment in Vascular Dementia Rats. Molecular neurobiology 3 38990251
2005 A refined radiation hybrid map of the telomeric region of bovine chromosome 18q25-q26 compared with human chromosome 19q13. Animal genetics 3 15771725
2025 Genome-wide association and functional annotation analyses reveal candidate genes and pathways associated with various ewe longevity indicators in U.S. Katahdin sheep. Frontiers in genetics 2 40678382
2024 Intersectin1 promotes clathrin-mediated endocytosis by organizing and stabilizing endocytic protein interaction networks. Cell reports 2 39580802
2024 Intersectin1 promotes clathrin-mediated endocytosis by organizing and stabilizing endocytic protein interaction networks. bioRxiv : the preprint server for biology 1 38712149
2024 A single-particle analysis method for detecting membrane remodelling and curvature sensing. Journal of cell science 1 39324332
2010 Establishment of a neonate cell line from Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae) that supports replication of E. postvittana nucleopolyhedrovirus. Journal of invertebrate pathology 1 20167219
2026 The binding mechanism of an iron-chelating peptide from duck plasma and insights into its absorption-enhancing effect in Caco-2 cells. Food research international (Ottawa, Ont.) 0 42083210
2026 Intracellular Vesicle Transport Impairment as a Candidate Systems-Level Bottleneck in Chronic Diabetic Foot Ulcers: Network Medicine Identifies KIF13A as a Potential Therapeutic Vulnerability. Biomedicines 0 42193464

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