Affinage

SNX3

Sorting nexin-3 · UniProt O60493

Length
162 aa
Mass
18.8 kDa
Annotated
2026-04-28
26 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX3 is a phosphatidylinositol-3-phosphate (PI3P)-binding sorting nexin that functions as a cargo-specific adapter on early endosomes, directing retrograde recycling of transmembrane cargos through the retromer pathway and organizing endosomal membrane identity. Its PX domain anchors it to PI3P-enriched endosomal membranes, where it directly engages the VPS26/VPS29/VPS35 cargo-selective retromer subcomplex—independently of SNX-BAR proteins—to sort Wntless (required for Wnt secretion), the transferrin receptor (required for iron uptake), and yeast iron transporters (Fet3–Ftr1) into tubular retrieval carriers destined for the Golgi or plasma membrane (PMID:21725319, PMID:23416069, PMID:17420293). SNX3 also competes with EEA1 for PI3P binding, thereby controlling the balance between recycling and ESCRT-mediated lysosomal degradation of clathrin-independent endocytic cargos, contributes to multivesicular body biogenesis, and promotes phagosome maturation by recruiting Rab5a vesicles and galectin-9 via its C-terminal region (PMID:34081703, PMID:18767904, PMID:31337623). Loss of SNX3 in mice causes fully penetrant cranial neural tube defects due to failed Wntless recycling and impaired Wnt signaling, and a human SNX3 variant associated with neural tube defects is functionally impaired (PMID:33214242).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Establishing SNX3 as a PI3P-binding early endosomal protein resolved how a minimal PX-domain-only sorting nexin achieves membrane targeting and revealed its requirement for endosomal sorting and morphology.

    Evidence PX domain–PI3P binding assay, overexpression morphology analysis, and antibody microinjection blocking recycling endosome transport in mammalian cells

    PMID:11433298

    Open questions at the time
    • No cargo identified at this stage
    • Mechanism of endosomal morphology alteration undefined
    • Relationship to retromer unknown
  2. 2007 High

    Identification of yeast Snx3/Grd19 as a cargo-specific adapter for retromer answered how retromer recognizes cargo lacking canonical sorting signals, establishing a new mode of retromer engagement distinct from SNX-BAR-dependent sorting.

    Evidence Direct binding of Snx3 to the Ftr1p recycling signal, co-IP with retromer, colocalization on tubular endosomes, and genetic epistasis with retromer mutants in S. cerevisiae

    PMID:17420293

    Open questions at the time
    • Adapter function not yet confirmed in metazoans
    • Structural basis of SNX3–retromer–cargo ternary complex unknown
  3. 2008 High

    Demonstrating that SNX3 is required for MVB biogenesis independently of Hrs-mediated cargo sorting revealed that PI3P effectors partition complementary endosomal functions—SNX3 for intraluminal vesicle formation, Hrs for receptor degradation.

    Evidence RNAi knockdown with electron microscopy of MVB morphology and EGF receptor degradation assays in mammalian cells; parallel epistasis in yeast showing recycling–degradation pathway divergence at a common endosome

    PMID:18767904 PMID:18768754

    Open questions at the time
    • Molecular mechanism by which SNX3 promotes MVB biogenesis unresolved
    • Whether SNX3's MVB role is retromer-dependent or independent unclear
  4. 2011 High

    Showing that SNX3 directly binds the VPS26/VPS29/VPS35 cargo-selective subcomplex to sort Wntless into a morphologically distinct retrieval pathway—independent of SNX1/SNX2/SNX5/SNX6—established SNX3-retromer as a dedicated Wnt-secretion-enabling sorting machine conserved across metazoa.

    Evidence Direct pulldown of SNX3 with retromer subcomplex, C. elegans and Drosophila genetic epistasis, mammalian cell knockdown with Wntless trafficking readout, Drosophila co-IP of DSNX3–Vps35 with genetic rescue by Wls overexpression

    PMID:21725319 PMID:22041890

    Open questions at the time
    • How membrane curvature is generated without SNX-BAR proteins remained unclear
    • Identity of the membrane-remodeling machinery cooperating with SNX3-retromer unknown
  5. 2013 High

    Extension of SNX3-retromer cargo repertoire to the transferrin receptor linked endosomal sorting to systemic iron homeostasis, explaining how Snx3 loss causes anemia, and revealed SNX3's competition with EEA1 for PI3P on phagosomes as a mechanism regulating phagocytic uptake.

    Evidence Co-IP of Snx3/Vps35/Tfrc, zebrafish and mouse knockout with iron uptake assays and hemoglobin defects; live imaging and siRNA in dendritic cells showing SNX3–EEA1 competition on phagosomes

    PMID:23237080 PMID:23416069

    Open questions at the time
    • Competition mechanism not reconstituted with purified components
    • Whether SNX3 directly contacts Tfrc cytosolic tail or requires VPS26 adaptations unresolved
  6. 2018 High

    Discovery that SNX3 associates with a MON2–DOPEY2–ATP9A membrane-remodeling complex resolved the long-standing question of how SNX3-retromer generates membrane tubules without SNX-BAR proteins, linking aminophospholipid flipping to retrograde carrier formation.

    Evidence Co-IP of SNX3 with MON2/DOPEY2/ATP9A, C. elegans genetic epistasis phenocopying SNX3-retromer loss, dominant-negative ATPase mutant validation

    PMID:30213940

    Open questions at the time
    • Direct reconstitution of tubule formation by SNX3–MON2–DOPEY2–ATP9A not achieved
    • Structural organization of the complex undefined
  7. 2018 Medium

    Demonstration that alpha-synuclein inhibits SNX3 endosomal membrane association provided a mechanistic link between Parkinson's disease-associated protein aggregation and defective retromer-mediated iron transporter recycling.

    Evidence Fluorescence microscopy of Snx3-mCherry vesicle association in yeast α-synuclein model, C. elegans dopaminergic neuron degeneration assay, iron chelator rescue

    PMID:29452354

    Open questions at the time
    • Direct α-synuclein–SNX3 molecular contact not demonstrated
    • PI3P competition between α-synuclein and SNX3 inferred but not reconstituted in vitro
    • Relevance to mammalian dopaminergic neurons not established
  8. 2019 High

    Identification of SNX3 as a bifunctional hub on phagosomes—recruiting Rab5a vesicles via its PX domain and galectin-9 via its C-terminal region—revealed how a minimal sorting nexin coordinates two distinct vesicle populations to drive phagosome compaction and maturation.

    Evidence Live cell imaging of SNX3/Rab5a vesicle trafficking to Borrelia-containing phagosomes, co-IP of SNX3 with galectin-9, phagosome compaction assay

    PMID:31337623

    Open questions at the time
    • Whether galectin-9 recruitment is retromer-dependent or independent unclear
    • Structural basis of C-terminal region–galectin-9 interaction unknown
  9. 2020 High

    Mouse knockout establishing that Snx3 loss causes fully penetrant cranial neural tube defects through failed Wntless recycling and impaired Wnt secretion provided the first in vivo mammalian demonstration that SNX3-retromer is essential for embryonic development, with a human NTD-associated SNX3 variant shown to be functionally impaired.

    Evidence Mouse Snx3 knockout with NTD phenotype, live cell imaging of WLS mis-trafficking to lysosomes, WNT agonist rescue, human variant functional assay

    PMID:33214242

    Open questions at the time
    • Whether other SNX3-retromer cargos contribute to the NTD phenotype unknown
    • Penetrance and spectrum of human SNX3 mutations in NTD populations not established
  10. 2021 High

    Discovery that SNX3 generates ARF-6-associated recycling tubules for clathrin-independent endocytic cargos independently of retromer expanded SNX3 function beyond retromer-dependent sorting and formalized the SNX3–EEA1 competition model as a general endosomal fate-determination mechanism.

    Evidence C. elegans genetic screen and loss-of-function, CIE cargo (hTAC) trafficking assays, SNX3–EEA1 PI3P competition in HeLa cells, retromer epistasis showing independence

    PMID:34081703

    Open questions at the time
    • Molecular mechanism of SNX3-driven tubule formation without retromer not defined
    • Whether ARF-6-dependent and retromer-dependent functions of SNX3 occur on distinct membrane domains unknown
  11. 2022 Medium

    Demonstration that alpha-synuclein's membrane-binding activity is specifically required to disrupt SNX3-retromer trafficking of Kex2 and Ste13 cargos refined the pathological mechanism, distinguishing it from aggregation-dependent toxicity.

    Evidence Fluorescence microscopy and western blotting of Kex2/Ste13 trafficking in yeast expressing α-syn variants (A53T, A30P, ΔC), yeast mating assay for α-factor processing

    PMID:34570221

    Open questions at the time
    • Direct molecular contact between membrane-bound α-synuclein and SNX3 or retromer not identified
    • Validation in mammalian neuronal cells lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the SNX3–retromer–cargo ternary complex at atomic resolution, how SNX3 generates membrane tubules in retromer-independent contexts, whether hybrid SNX3/SNX-BAR coats operate in vivo in mammalian cells, and the full spectrum of human disease caused by SNX3 mutations.
  • No high-resolution structure of SNX3–retromer–cargo complex published in the timeline
  • Retromer-independent tubulation mechanism undefined
  • In vivo relevance of hybrid SNX3/SNX-BAR coats in mammals not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 7 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
ATP9ALGALS9MON2TFRCVPS26VPS29VPS35WLS
Complex memberships
SNX3-MON2-DOPEY2-ATP9ASNX3-retromer (VPS26/VPS29/VPS35)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SNX3 is associated with early endosomes through its PX domain, which directly binds phosphatidylinositol-3-phosphate (PtdIns(3)P). Overexpression of SNX3 alters endosomal morphology and delays transport to the lysosome; microinjection of SNX3 antibodies impairs transport from the early to the recycling endosome. PX domain-PtdIns(3)P binding assay, overexpression studies, antibody microinjection, endosomal morphology analysis Nature cell biology High 11433298
2007 Yeast Grd19/Snx3p functions as a cargo-specific adapter for the retromer complex by directly binding a recycling signal in the iron transporter Ftr1p cytosolic tail. Snx3p and retromer partially colocalize on tubular endosomes and are physically associated; this complex mediates endosome-to-plasma membrane recycling of Fet3p-Ftr1p. Direct binding assay (recycling signal in Ftr1p binds Grd19/Snx3p), co-immunoprecipitation, colocalization microscopy, genetic epistasis with retromer mutants and Ypt6p Golgi Rab GTPase module The Journal of cell biology High 17420293
2008 SNX3 is required for multivesicular body (MVB) formation but not for EGF receptor degradation, whereas Hrs is essential for lysosomal targeting but dispensable for MVB biogenesis. PtdIns(3)P thus controls complementary functions of Hrs and SNX3 in sorting and MVB biogenesis. RNAi knockdown of SNX3 and Hrs with electron microscopy of MVB morphology, EGF receptor degradation assays, epistasis analysis PLoS biology High 18767904
2008 In yeast, Snx3/Grd19 and retromer sort Fet3-Ftr1 into a recycling pathway at a common endosome where Vps27 (ESCRT component) also localizes; the recycling (Snx3-retromer) and degradative (ESCRT/MVB) pathways diverge at this compartment. Iron-induced degradation requires ESCRT machinery and Rsp5 ubiquitin ligase-mediated ubiquitylation, while Snx3-retromer-dependent recycling is constitutive when ESCRT or ubiquitylation is absent. Genetic epistasis (ESCRT and Rsp5 mutants), fluorescence microscopy colocalization, ubiquitylation site mutagenesis of Fet3-Ftr1 Molecular biology of the cell High 18768754
2011 SNX3 interacts directly with the cargo-selective subcomplex (VPS26/VPS29/VPS35) of the retromer to sort Wntless (Wls) into a morphologically distinct endosome-to-Golgi retrieval pathway that is independent of SNX1-SNX2 and SNX5-SNX6. This SNX3-retromer pathway is evolutionarily conserved and required for Wls recycling and Wnt secretion. Direct protein interaction assays (pulldown of SNX3 with retromer cargo-selective subcomplex), C. elegans genetic epistasis, Drosophila and mammalian cell knockdown with Wls trafficking readout Nature cell biology High 21725319
2011 Drosophila SNX3 (DSNX3) colocalizes with the retromer component Vps35 in early endosomes and interacts with Vps35. Loss of DSNX3 causes reduction of Wls levels and impairs Wingless secretion; overexpression of Wls rescues the Wg secretion defect, placing SNX3 upstream of Wls in the Wnt secretion pathway. Co-immunoprecipitation (DSNX3-Vps35), colocalization microscopy, Drosophila loss-of-function clonal analysis, dsRNA knockdown in S2 cells, genetic rescue by Wls overexpression Cell research High 22041890
2013 Snx3 and Vps35 (retromer component) interact with the transferrin receptor (Tfrc) to sort it to recycling endosomes. Loss of Snx3 in vertebrates causes Tfrc accumulation in early endosomes, impaired transferrin-mediated iron uptake, and anemia/hemoglobin defects in erythroid progenitors. Co-immunoprecipitation (Snx3, Vps35, and Tfrc), Snx3 knockdown/knockout in zebrafish and mouse with iron uptake assays, rescue with non-Tf iron chelates Cell metabolism High 23416069
2013 SNX3 recruits to nascent phagosomes via its PI3P-binding PX domain and negatively regulates phagocytic uptake of bacteria by dendritic cells. SNX3 competes with EEA1 for binding to PI3P on phagosomal membranes, reducing EEA1 recruitment and thereby dampening phagocytosis. Live cell imaging of SNX3-phagosome recruitment, siRNA silencing with phagocytosis uptake assay, competition assay between SNX3 and EEA1 for PI3P binding Immunology Medium 23237080
2018 SNX3-retromer assembly is essential for Wntless endosome-to-Golgi transport, and SNX3 associates with an evolutionarily conserved endosomal membrane-remodeling complex composed of MON2, DOPEY2, and the putative aminophospholipid translocase ATP9A. In vivo suppression of MON2, DOPEY2, or ATP9A orthologues in C. elegans phenocopies loss of SNX3-retromer, leading to lysosomal degradation of Wntless and Wnt phenotype. Co-immunoprecipitation (SNX3 with MON2/DOPEY2/ATP9A), C. elegans genetic knockdown epistasis, dominant-negative ATPase mutant (TAT-5 E246Q) expression Nature communications High 30213940
2018 Alpha-synuclein inhibits Snx3-retromer-mediated recycling of iron transporters (Fet3/Ftr1) in yeast by blocking the association of Snx3 with endocytic vesicles, possibly by interfering with Snx3 binding to PI3P on endosomal membranes. Fluorescence microscopy of Snx3-mCherry vesicle association, yeast genetic model of Parkinson's disease, C. elegans dopaminergic neuron degeneration assay, iron chelator rescue Human molecular genetics Medium 29452354
2019 SNX3's PX domain binds PI(3)P in the phagosomal coat of Borrelia-containing phagosomes, enabling vesicle-phagosome contact via Rab5a vesicles. The C-terminal region of SNX3 recruits galectin-9, making SNX3 a hub for two distinct vesicle populations that contribute to phagosome compaction and maturation. Live cell imaging of SNX3 and Rab5a vesicle trafficking, PI(3)P binding assay (PX domain), co-immunoprecipitation/interaction assay of SNX3 with galectin-9, phagosome compaction assay The Journal of cell biology High 31337623
2020 Snx3 is required for neural tube closure in mice via its role in recycling WLS (Wnt ligand-binding protein) to support WNT secretion. Loss of Snx3 causes mis-trafficking of WLS to the lysosome. A human NTD-associated point mutation in SNX3 results in functionally impaired SNX3 that fails to colocalize with WLS and leads to WLS degradation. Mouse knockout (fully penetrant cranial NTD), live cell imaging of WLS recycling, WNT agonist rescue of NT closure, human variant functional assay Development (Cambridge, England) High 33214242
2021 SNX3 interacts with EGFR upon EGF stimulation (detected by proximity labeling) and colocalizes with early endosomes and endocytosed EGF. SNX3 loss affects EGFR protein levels; long-term SNX3 silencing leads to compensatory EGFR overexpression, increased proliferation, migration, invasion, and tumor metastasis in TNBC models. Proximity labeling (BioID), colocalization microscopy, RNAi knockdown (transient and long-term), EGFR protein level assay, syngeneic mouse tumor model Oncogene Medium 34718348
2021 In C. elegans, SNX-3 is essential for generation of ARF-6-associated recycling endosomal tubules and retrieval of clathrin-independent endocytic (CIE) cargoes back to the plasma membrane. This function is independent of the retromer trimer (VPS-26/-29/-35). SNX3 and EEA1 compete for binding to PI3P on early endosomes, and loss of SNX-3 allows increased EEA1 recruitment and ESCRT-mediated lysosomal degradation of CIE cargo. C. elegans genetic screen and loss-of-function, fluorescence microscopy of tubule formation, hTAC CIE cargo trafficking assay, competition assay between SNX3 and EEA1 for PI3P in HeLa cells, retromer component epistasis PLoS genetics High 34081703
2022 Alpha-synuclein disrupts Snx3-retromer retrograde trafficking of the proprotein convertase Kex2 and dipeptidyl aminopeptidase Ste13 from late endosomes to the trans-Golgi network in yeast, causing their default transit to the vacuole. The membrane-binding ability of α-syn is necessary for this inhibition, as the A30P membrane-binding-defective variant does not inhibit Snx3-retromer recycling. Fluorescence microscopy of Kex2-GFP/GFP-Ste13 trafficking, western blotting, yeast mating assay (α-factor processing), α-syn variant analysis (A53T, A30P, αsynΔC) Human molecular genetics Medium 34570221
2025 SNX3-retromer mediates retrograde trafficking of the AAV receptor AAVR; in vitro reconstitution demonstrates that AAVR's cytosolic tail directly engages the SNX3-retromer complex and drives membrane tubulation, a hallmark of retrograde trafficking. In vitro reconstitution assay (AAVR cytosolic tail with SNX3-retromer), membrane tubulation assay, AAVR-knockout cell trafficking studies bioRxivpreprint Medium bio_10.1101_2025.11.22.689972
2025 SNX3 directly interacts with HMGB1 (identified by immunoprecipitation-mass spectrometry and localized surface plasmon resonance), and the SNX3-retromer complex mediates the efflux of nuclear HMGB1 to the cytoplasm, promoting pathological cardiac hypertrophy and heart failure. Immunoprecipitation-mass spectrometry, localized surface plasmon resonance (direct binding), cardiac-specific SNX3 knockout (TAC mouse), adenoviral overexpression (Ad-SNX3), AAC rat model, HMGB1 overexpression/knockdown epistasis Acta pharmacologica Sinica Medium 39753981
2025 Snx3 and SNX-BAR proteins (Vps5-Vps17) can form hybrid endosomal coats at variable subunit ratios, assembled on tubular carriers with greater membrane scaffolding activity than homogeneous coats. In vivo, Snx3 and SNX-BARs colocalize and mutually impact sorting of their respective cargos, linked through retromer oligomerization rather than simultaneous direct retromer binding. In vitro reconstitution with purified SNX-BARs and Snx3, membrane scaffolding assay, in vivo colocalization, cargo sorting epistasis bioRxivpreprint Medium bio_10.1101_2025.07.29.667382

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature cell biology 276 21725319
2001 SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nature cell biology 252 11433298
2007 Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling. The Journal of cell biology 144 17420293
2011 SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless. Cell research 104 22041890
2013 Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell metabolism 103 23416069
2008 Hrs and SNX3 functions in sorting and membrane invagination within multivesicular bodies. PLoS biology 84 18767904
2018 SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nature communications 69 30213940
2008 Opposing activities of the Snx3-retromer complex and ESCRT proteins mediate regulated cargo sorting at a common endosome. Molecular biology of the cell 57 18768754
2021 Defect Study and Modelling of SnX3-Based Perovskite Solar Cells with SCAPS-1D. Nanomaterials (Basel, Switzerland) 37 34063020
2018 Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease. Human molecular genetics 31 29452354
2002 Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype. Journal of medical genetics 29 12471201
2021 LINC01614 promotes osteosarcoma progression via miR-520a-3p/SNX3 axis. Cellular signalling 27 33753211
2013 SNX3 recruits to phagosomes and negatively regulates phagocytosis in dendritic cells. Immunology 19 23237080
2021 EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers. Oncogene 17 34718348
2021 SNX-3 mediates retromer-independent tubular endosomal recycling by opposing EEA-1-facilitated trafficking. PLoS genetics 16 34081703
2007 Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes. BMC medical genetics 13 17655765
2020 Snx3 is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling. Development (Cambridge, England) 11 33214242
2019 SNX3 suppresses the migration and invasion of colorectal cancer cells by reversing epithelial-to-mesenchymal transition via the β-catenin pathway. Oncology letters 10 31612043
2019 SNX3 drives maturation of Borrelia phagosomes by forming a hub for PI(3)P, Rab5a, and galectin-9. The Journal of cell biology 9 31337623
2011 SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells. Cellular and molecular life sciences : CMLS 9 22159558
2018 Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein. Neuro-degenerative diseases 8 29414832
2024 Honokiol enhances the sensitivity of cetuximab in KRASG13D mutant colorectal cancer through destroying SNX3-retromer complex. Theranostics 7 39310106
2022 α-synuclein inhibits Snx3-retromer retrograde trafficking of the conserved membrane-bound proprotein convertase Kex2 in the secretory pathway of Saccharomyces cerevisiae. Human molecular genetics 5 34570221
2024 SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis. International journal of medical sciences 2 39006843
2025 SNX3 mediates heart failure by interacting with HMGB1 and subsequently facilitating its nuclear-cytoplasmic translocation. Acta pharmacologica Sinica 1 39753981
2026 SNX-3 confers lysosomal fusion-competence to sustain basal autophagy. Cellular and molecular life sciences : CMLS 0 41537964