{"gene":"SNX3","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2001,"finding":"SNX3 associates with early endosomes through its PX domain by directly binding 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 early to recycling endosomes.","method":"PX domain-PtdIns(3)P binding assay, overexpression morphology analysis, antibody microinjection with transport assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct lipid-binding interaction demonstrated, functional consequences shown with two orthogonal perturbation methods (overexpression and antibody microinjection), independently cited and replicated across the field","pmids":["11433298"],"is_preprint":false},{"year":2007,"finding":"Yeast Grd19/Snx3p functions as a cargo-specific adaptor for the retromer complex. A recycling signal in the iron transporter subunit Ftr1p binds directly to Grd19/Snx3p, and Grd19/Snx3p physically associates with retromer on tubular endosomes to sort Fet3p-Ftr1p into an endocytic recycling pathway that returns the transporter to the plasma membrane via the Golgi (Ypt6p Rab GTPase module).","method":"Direct binding assay (recycling signal in Ftr1p to Grd19/Snx3p), co-localization on tubular endosomes, genetic epistasis with retromer and Ypt6p module, yeast deletion mutants with cargo trafficking readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding of cargo tail to SNX3 demonstrated, genetic epistasis established pathway position, replicated by independent studies","pmids":["17420293"],"is_preprint":false},{"year":2008,"finding":"Snx3/Grd19p-retromer recycling pathway and the ESCRT-dependent MVB sorting pathway act in opposition at a common endosome (marked by Vps27, Snx3, and retromer). Iron-induced ubiquitylation of Fet3-Ftr1 by Rsp5 at this endosome diverts cargo from the Snx3-retromer recycling route to the MVB/degradative route; loss of ESCRT components or ubiquitin-acceptor lysines constitutively shunts Fet3-Ftr1 into the Snx3-retromer recycling pathway.","method":"Yeast genetics (ESCRT deletion, ubiquitylation site mutants, rsp5 mutants), co-localization of Vps27/Snx3/retromer on endosomes, cargo trafficking assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple ESCRT components, ubiquitylation site mutagenesis, co-localization, replicated/consistent with companion paper","pmids":["18768754"],"is_preprint":false},{"year":2008,"finding":"SNX3 is required for multivesicular body (MVB) formation but is dispensable for EGF receptor degradation. PtdIns(3)P controls complementary functions: Hrs mediates lysosomal targeting while SNX3 mediates MVB biogenesis.","method":"siRNA knockdown of SNX3 with morphological analysis of MVB formation and EGF receptor degradation assay","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (MVB biogenesis vs. degradation), single lab but two distinct readouts separating the two functions","pmids":["18767904"],"is_preprint":false},{"year":2011,"finding":"SNX3 mediates retrograde endosome-to-Golgi recycling of the Wnt sorting receptor Wntless (Wls) through a retromer pathway that is independent of SNX1/SNX2 and SNX5/SNX6. SNX3 interacts directly with the cargo-selective VPS26/VPS29/VPS35 subcomplex of retromer to sort Wls into a morphologically distinct retrieval pathway required for efficient Wnt secretion.","method":"C. elegans and mammalian cell genetics (RNAi/knockdown), direct interaction assay of SNX3 with retromer cargo-selective subcomplex, epistasis showing SNX1/2/5/6 independence, Wls recycling and Wnt secretion assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding to retromer subcomplex demonstrated, epistasis in multiple organisms, functional readout (Wnt secretion), replicated by companion Drosophila paper","pmids":["21725319"],"is_preprint":false},{"year":2011,"finding":"Drosophila SNX3 (DSNX3) is required for retromer-mediated Wls recycling and Wingless secretion. DSNX3 interacts with retromer component Vps35 and co-localizes with Vps35 on early endosomes. SNX1 and SNX6 cannot substitute for SNX3 in Wls recycling, establishing SNX3 specificity in this pathway.","method":"Drosophila genetic mutants (all 8 snx members), S2 cell RNAi, Wg secretion assay (medium levels), Wls overexpression rescue, co-immunoprecipitation with Vps35, co-localization imaging","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mutants, reciprocal Co-IP, rescue experiments, confirmed by companion mammalian paper (PMID 21725319)","pmids":["22041890"],"is_preprint":false},{"year":2013,"finding":"SNX3 and retromer component VPS35 interact with the transferrin receptor (Tfrc) to sort it to recycling endosomes. Loss of Snx3 impairs Tfrc recycling, causing iron to accumulate in early endosomes, leading to impaired transferrin-mediated iron uptake and anemia in vertebrates.","method":"Zebrafish/vertebrate morpholino knockdown with hematological phenotype, co-immunoprecipitation of SNX3, VPS35, and Tfrc, endosomal accumulation assay, rescue with non-Tf iron chelates","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of tripartite complex, in vivo loss-of-function with specific mechanistic rescue, functional iron assimilation readout","pmids":["23416069"],"is_preprint":false},{"year":2013,"finding":"SNX3 recruits to nascent phagosomes via its PI3P-binding PX domain and negatively regulates phagocytic uptake of bacteria in dendritic cells. SNX3 competes with EEA1 for PI3P-binding at phagosomal membranes, suggesting it modulates recruitment of essential PI3P effectors during phagocytosis.","method":"Live cell imaging of SNX3 recruitment to phagosomes, siRNA knockdown with phagocytosis assay (bacterial uptake), competition assay with EEA1 for membrane recruitment","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — localization directly tied to functional consequence (phagocytosis), competition mechanism supported by imaging, single lab","pmids":["23237080"],"is_preprint":false},{"year":2018,"finding":"SNX3-retromer assembly is essential for Wntless transport and requires an evolutionarily conserved endosome-associated membrane-remodelling complex composed of MON2, DOPEY2, and the putative aminophospholipid translocase ATP9A. In vivo suppression of MON2, DOPEY2, or ATP9A orthologues phenocopies SNX3-retromer loss and leads to enhanced lysosomal degradation of Wntless. Phospholipid flippase activity of ATP9A is implicated in this process.","method":"Co-immunoprecipitation of SNX3 with MON2/DOPEY2/ATP9A complex, C. elegans in vivo RNAi epistasis, ATPase-inhibited mutant overexpression, Wntless trafficking assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vivo epistasis in C. elegans, ATPase mutant mechanistic test, multiple orthogonal methods in one study","pmids":["30213940"],"is_preprint":false},{"year":2018,"finding":"Alpha-synuclein inhibits Snx3-retromer-mediated recycling of the iron transporter Fet3/Ftr1 in S. cerevisiae by blocking the association of Snx3 with endocytic vesicles, possibly by interfering with Snx3 binding to phosphatidylinositol-3-monophosphate. This shunts Fet3/Ftr1 into the MVB pathway for vacuolar degradation.","method":"Yeast fluorescence microscopy tracking Snx3-mCherry on endosomes with/without α-syn expression, cargo trafficking assays under low-iron conditions, C. elegans genetic epistasis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — live imaging of SNX3 displacement from vesicles, genetic evidence in two model organisms, single lab","pmids":["29452354"],"is_preprint":false},{"year":2018,"finding":"Overexpression of SNX3 in HEK293T cells reduces internalization of amyloid precursor protein (APP), resulting in increased cell-surface APP, decreased association of APP with BACE1 (assessed by bimolecular fluorescence complementation), and reduced secretion of Aβ peptides and sAPPβ.","method":"SNX3 overexpression, immunoassay for Aβ, BiFC for APP-BACE1 interaction, α-bungarotoxin-binding internalization assay, flow cytometry for surface APP","journal":"Neuro-degenerative diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal readouts (BiFC, surface assay, secretion) but only overexpression approach, single lab","pmids":["29414832"],"is_preprint":false},{"year":2019,"finding":"SNX3 is transported to Borrelia phagosomes via Rab5a-positive vesicles; its PX domain enables vesicle-phagosome contact by binding PI(3)P in the phagosomal coat. The C-terminal region of SNX3 recruits galectin-9, forming a hub that coordinates two distinct vesicle populations to promote phagosomal compaction and phagolysosome maturation.","method":"Live-cell imaging of SNX3 on Rab5a vesicles, PI(3)P binding assay, domain-function analysis (C-terminal region for galectin-9 recruitment), phagosome compaction assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization directly tied to phagosome maturation mechanism, domain-level dissection, single lab","pmids":["31337623"],"is_preprint":false},{"year":2020,"finding":"Snx3 knockout mouse embryos display a fully-penetrant cranial neural tube defect caused by defective WLS recycling (mis-trafficking to lysosomes for degradation) and decreased canonical WNT target gene expression. A human NTD-associated point mutation in SNX3 produces functionally impaired SNX3 that fails to co-localize with WLS and leads to WLS degradation. Rescue with a WNT agonist restores neural tube closure in Snx3 mutant embryos.","method":"Snx3 knockout mouse model, live-cell imaging of WLS recycling, WNT target gene expression (in vivo), WNT agonist rescue, human SNX3 point mutant functional analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO with specific NTD phenotype, live imaging of WLS mis-trafficking, pharmacological rescue, human mutation functional validation — multiple orthogonal methods","pmids":["33214242"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, SNX-3 organizes tubular endosomes for recycling of clathrin-independent endocytic (CIE) cargoes (hTAC) back to the plasma membrane in a retromer trimer (VPS-26/-29/-35)-independent manner. Loss of SNX-3 abolishes recycling tubules, causes hTAC to be captured by ESCRT and degraded in lysosomes, and leads to increased recruitment of EEA-1 to early endosomes. In HeLa cells, SNX3 and EEA1 compete for binding to PI(3)P on early endosomes.","method":"C. elegans snx-3 mutants with tubule morphology imaging, cargo surface/total level quantification, ESCRT pathway epistasis, EEA-1 localization assay, PI(3)P competition assay in HeLa cells","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in two systems with defined tubule morphology and cargo trafficking readouts, competition binding demonstrated, epistasis with retromer and ESCRT","pmids":["34081703"],"is_preprint":false},{"year":2021,"finding":"EGF stimulation upregulates SNX3 abundance (initially at the protein level, then transcriptionally) and increases interaction between SNX3 and EGFR. Long-term SNX3 silencing forces EGFR mRNA/protein overexpression, while SNX3 is required to maintain EGFR protein levels. SNX3 co-localizes with early endosomes and endocytosed EGF.","method":"Proximity labeling (BioID) for SNX3-EGFR interaction upon EGF, siRNA knockdown (transient and long-term), EGFR protein/mRNA quantification, co-localization imaging, syngeneic in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proximity labeling for interaction, two distinct knockdown paradigms, in vivo validation, single lab","pmids":["34718348"],"is_preprint":false},{"year":2022,"finding":"Alpha-synuclein disrupts Snx3-retromer-mediated retrograde trafficking of the conserved proprotein convertase Kex2 and dipeptidyl aminopeptidase Ste13 from late endosomes to the TGN, diverting them to vacuolar degradation. The membrane-binding ability of α-syn (absent in A30P mutant) is required for this inhibition of Snx3-retromer function.","method":"Fluorescence microscopy of Kex2-GFP/GFP-Ste13 trafficking in yeast, western blotting, yeast mating assay (α-factor secretion readout), α-syn variant analysis (A53T, A30P, ΔC)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cargo readouts, structure-function analysis with α-syn variants, mechanistically consistent with PMID 29452354, single lab","pmids":["34570221"],"is_preprint":false},{"year":2025,"finding":"SNX3-retromer directly interacts with HMGB1 and mediates its efflux from the nucleus to the cytoplasm (nuclear-cytoplasmic translocation). HMGB1 functions as a direct cargo protein of the SNX3-retromer complex in cardiomyocytes, and this interaction promotes pathological cardiac hypertrophy and heart failure. SNX3 cardiac-specific knockout rescues detrimental heart function in pressure-overload (TAC) mice.","method":"Immunoprecipitation-based mass spectrometry, localized surface plasmon resonance (direct SNX3-HMGB1 binding), cardiac-specific SNX3 KO mouse (TAC model), adenoviral SNX3 overexpression, HMGB1 overexpression/knockdown epistasis in NRCMs","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by SPR, genetic epistasis with HMGB1, in vivo cardiac KO phenotype, single lab","pmids":["39753981"],"is_preprint":false},{"year":2026,"finding":"SNX-3 is required for basal autophagy under nutrient-adequate conditions in C. elegans and mammalian cells by conferring lysosomal fusion competence. Loss of SNX-3 causes accumulation of autophagosomes and amphisomes and impairs autophagic cargo clearance. Mechanistically, SNX-3 loss reroutes the Q-SNARE components SYX-17 and SNAP-29 to autophagosomes (promoting amphisome formation via VAMP-7/8) while impairing lysosomal delivery of VAMP-8 and RAB-7, generating fusion-incompetent lysosomes. Starvation restores lysosomal fusion capability lost upon snx-3 depletion.","method":"C. elegans snx-3 mutants, mammalian cell knockdown, autophagosome/amphisome accumulation imaging, SQST-1/p62 cargo clearance assay, SNARE component localization analysis, lysosomal VAMP-8/RAB-7 delivery assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two systems, mechanistic SNARE pathway dissection, multiple cargo readouts, single lab with recent publication","pmids":["41537964"],"is_preprint":false},{"year":2025,"finding":"SNX3-retromer forms hybrid endosomal coats with SNX-BAR proteins (Vps5-Vps17). Although simultaneous binding of Snx3 and SNX-BARs to retromer is sterically prohibited in a simple complex, hybrid coats incorporate both SNX classes—likely linked by retromer oligomerisation—at variable subunit ratios and diameters. Hybrid coats show greater membrane scaffolding activity than homogeneous coats. In vivo, Snx3 and SNX-BARs co-localise and mutually impact sorting of their respective cargos.","method":"In vitro reconstitution with purified proteins, electron microscopy of coat assemblies, in vivo co-localization and cargo sorting assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution with purified components is Tier 1, but preprint with single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.29.667382"],"is_preprint":true},{"year":2025,"finding":"The AAV receptor AAVR functions as a retromer cargo that engages the SNX3-retromer complex through its cytosolic tail, driving membrane tubulation in vitro. SNX3-retromer-dependent trafficking of AAVR to the trans-Golgi network is required for productive AAV2 transduction.","method":"In vitro reconstitution of SNX3-retromer with AAVR cytosolic tail, membrane tubulation assay, AAVR-knockout cell trafficking and transduction assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution and tubulation assay, but preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.22.689972"],"is_preprint":true}],"current_model":"SNX3 is a PX-domain-only sorting nexin that binds PI(3)P on early endosomes and acts as a cargo-specific adaptor for the retromer cargo-selective subcomplex (VPS26/VPS29/VPS35), directing distinct transmembrane cargos—including the Wnt sorting receptor Wntless, the iron transporter Ftr1/Fet3 (yeast), transferrin receptor, HMGB1, and AAVR—from endosomes back to the Golgi or plasma membrane; it also competes with EEA1 for PI(3)P binding to regulate tubular recycling endosome formation and lysosomal fusion competence, while its activity can be inhibited by alpha-synuclein through displacement from endosomal membranes."},"narrative":{"mechanistic_narrative":"SNX3 is a PX-domain sorting nexin that anchors to early endosomes by directly binding phosphatidylinositol-3-phosphate (PI(3)P) and acts as a cargo-selective adaptor that couples specific transmembrane cargos to the retromer cargo-selective subcomplex (VPS26/VPS29/VPS35) for retrieval away from degradation [PMID:11433298, PMID:21725319]. Through this PI(3)P-dependent membrane recruitment, SNX3 sorts a defined set of cargos: it interacts directly with the retromer subcomplex to recycle the Wnt sorting receptor Wntless from endosomes back to the Golgi, a function independent of the SNX-BAR nexins SNX1/2/5/6 and conserved from yeast and Drosophila to mammals, and required for efficient Wnt secretion [PMID:21725319, PMID:22041890, PMID:30213940]. The same machinery recycles the iron-uptake receptors Ftr1/Fet3 in yeast and the transferrin receptor in vertebrates, such that loss of SNX3 traps iron in early endosomes and produces anemia [PMID:17420293, PMID:23416069], and engages additional cargos including HMGB1, whose SNX3-retromer-dependent nuclear-to-cytoplasmic efflux drives pathological cardiac hypertrophy [PMID:39753981]. SNX3-retromer assembly for Wntless transport additionally requires a conserved MON2/DOPEY2/ATP9A membrane-remodelling module [PMID:30213940]. SNX3 competes with EEA1 for endosomal PI(3)P to organize tubular recycling endosomes and govern cargo fate, with loss of SNX3 abolishing recycling tubules and diverting cargo into the ESCRT/lysosomal route [PMID:34081703]. Beyond classical retrograde sorting, SNX3 is required for MVB biogenesis [PMID:18767904] and confers lysosomal fusion competence needed for basal autophagy [PMID:41537964]. The SNX3-retromer pathway is inhibited by alpha-synuclein, which displaces SNX3 from endosomal membranes [PMID:29452354]. In vivo, Snx3 knockout causes a fully-penetrant cranial neural tube defect driven by defective WLS recycling and reduced canonical WNT signaling, and a human neural-tube-defect mutation produces functionally impaired SNX3 that fails to co-localize with WLS [PMID:33214242].","teleology":[{"year":2001,"claim":"Established the biochemical basis for SNX3 membrane targeting: how a PX-domain-only nexin localizes and what it does there.","evidence":"PX domain-PtdIns(3)P binding assay with overexpression and antibody microinjection transport assays","pmids":["11433298"],"confidence":"High","gaps":["No cargo or coat partner identified at this stage","Mechanism linking SNX3 to specific transport steps unresolved"]},{"year":2007,"claim":"Defined SNX3 as a cargo-specific retromer adaptor by showing a cargo tail recycling signal binds SNX3 directly to drive endosome-to-surface recycling via the Golgi.","evidence":"Yeast direct binding of Ftr1p signal to Grd19/Snx3p, genetic epistasis with retromer and Ypt6p, deletion-mutant cargo trafficking","pmids":["17420293"],"confidence":"High","gaps":["Generality beyond Ftr1p cargo unknown","Structural basis of cargo-tail recognition not defined"]},{"year":2008,"claim":"Showed cargo fate at the endosome is a competition: ubiquitylation diverts cargo from the SNX3-retromer recycling route to the ESCRT/MVB degradative route.","evidence":"Yeast ESCRT deletions, ubiquitylation-site and rsp5 mutants, Vps27/Snx3/retromer co-localization, cargo assays","pmids":["18768754"],"confidence":"High","gaps":["How ubiquitin status mechanistically excludes SNX3 binding not shown","Conservation of the recycling/degradation switch in mammals not tested here"]},{"year":2008,"claim":"Separated PI(3)P effector functions, assigning SNX3 to MVB biogenesis while sparing receptor degradation.","evidence":"siRNA knockdown with MVB morphology and EGFR degradation assays","pmids":["18767904"],"confidence":"Medium","gaps":["Single lab","Molecular role of SNX3 in MVB formation versus its retromer adaptor role not reconciled"]},{"year":2011,"claim":"Identified Wntless as a physiological SNX3-retromer cargo, defining a SNX-BAR-independent retrieval pathway essential for Wnt secretion.","evidence":"C. elegans, mammalian and Drosophila genetics, direct SNX3-VPS26/29/35 interaction and reciprocal Co-IP with Vps35, Wls/Wg secretion assays","pmids":["21725319","22041890"],"confidence":"High","gaps":["Structural geometry of SNX3 on the retromer coat not defined","How this pathway is morphologically distinct from SNX-BAR retromer unclear"]},{"year":2013,"claim":"Extended SNX3-retromer cargo recognition to the transferrin receptor and linked the pathway to systemic iron homeostasis and anemia.","evidence":"Zebrafish morpholino knockdown with hematological phenotype, tripartite SNX3/VPS35/Tfrc Co-IP, non-Tf iron rescue","pmids":["23416069"],"confidence":"High","gaps":["Whether Tfrc tail binds SNX3 directly not resolved","Relationship to mammalian recycling endosome tubules not detailed"]},{"year":2013,"claim":"Revealed a non-retromer role and a regulatory mechanism: SNX3 competes with EEA1 for phagosomal PI(3)P to restrain phagocytic uptake.","evidence":"Live imaging of SNX3 phagosome recruitment, siRNA phagocytosis assay, EEA1 competition assay in dendritic cells","pmids":["23237080"],"confidence":"Medium","gaps":["Single lab","Downstream PI(3)P effectors displaced by SNX3 not identified"]},{"year":2018,"claim":"Defined the accessory machinery for SNX3-retromer Wntless transport, implicating a MON2/DOPEY2/ATP9A membrane-remodelling module with flippase activity.","evidence":"Reciprocal Co-IP of SNX3 with MON2/DOPEY2/ATP9A, C. elegans RNAi epistasis, ATPase-dead mutant, Wntless trafficking","pmids":["30213940"],"confidence":"High","gaps":["How lipid flipping couples to coat assembly not mechanistically resolved","Whether the module serves cargos beyond Wntless untested"]},{"year":2018,"claim":"Identified alpha-synuclein as a pathological inhibitor of SNX3 function, acting by displacing SNX3 from endosomal membranes.","evidence":"Yeast Snx3-mCherry live imaging with/without alpha-syn, low-iron cargo trafficking assays, C. elegans epistasis","pmids":["29452354"],"confidence":"Medium","gaps":["Single lab","Direct evidence that alpha-syn blocks SNX3-PI(3)P binding not established"]},{"year":2018,"claim":"Linked SNX3 to APP processing, showing SNX3 overexpression reduces APP internalization and amyloidogenic cleavage.","evidence":"SNX3 overexpression in HEK293T, BiFC for APP-BACE1, surface APP flow cytometry, Abeta immunoassay","pmids":["29414832"],"confidence":"Medium","gaps":["Overexpression only, no loss-of-function","Single lab; physiological relevance to disease not tested"]},{"year":2019,"claim":"Dissected SNX3 domain functions in phagosome maturation: PX-domain PI(3)P binding for vesicle contact and a C-terminal galectin-9 recruitment hub.","evidence":"Live imaging of SNX3 on Rab5a vesicles, PI(3)P binding, domain mutation analysis, phagosome compaction assay","pmids":["31337623"],"confidence":"Medium","gaps":["Single lab","Structural basis of galectin-9 recruitment unknown"]},{"year":2020,"claim":"Established SNX3 as a developmentally essential gene and a candidate human neural tube defect gene via WLS recycling.","evidence":"Snx3 knockout mouse with cranial NTD, WLS recycling imaging, WNT agonist rescue, human point-mutant functional analysis","pmids":["33214242"],"confidence":"High","gaps":["Human genetic causality beyond a single mutation not established","Whether other SNX3 cargos contribute to the NTD phenotype unresolved"]},{"year":2021,"claim":"Showed SNX3 organizes recycling tubules for clathrin-independent cargo retromer-trimer-independently, and quantified its EEA1 competition on early-endosome PI(3)P.","evidence":"C. elegans snx-3 mutants with tubule and cargo imaging, ESCRT epistasis, EEA1 localization, HeLa PI(3)P competition","pmids":["34081703"],"confidence":"High","gaps":["How SNX3 builds tubules without the retromer trimer mechanistically unclear","Identity of mammalian CIE cargos using this route not defined"]},{"year":2021,"claim":"Connected SNX3 to EGFR homeostasis and tumor biology, showing EGF-induced SNX3 upregulation and SNX3 requirement to maintain EGFR levels.","evidence":"BioID for SNX3-EGFR interaction, transient and long-term siRNA, EGFR mRNA/protein quantification, syngeneic tumor model","pmids":["34718348"],"confidence":"Medium","gaps":["Single lab","Whether EGFR is a direct retromer cargo not established"]},{"year":2022,"claim":"Generalized alpha-synuclein inhibition of SNX3-retromer to late-endosome-to-TGN retrograde cargos and tied it to alpha-syn membrane binding.","evidence":"Yeast Kex2-GFP/GFP-Ste13 trafficking, mating assay, alpha-syn A53T/A30P/deltaC variant analysis","pmids":["34570221"],"confidence":"Medium","gaps":["Single lab","Direct competition at the SNX3-membrane interface not biochemically shown"]},{"year":2025,"claim":"Identified HMGB1 as a direct SNX3-retromer cargo whose translocation drives pathological cardiac hypertrophy.","evidence":"IP-mass spectrometry, SPR for direct SNX3-HMGB1 binding, cardiac-specific Snx3 KO in TAC mice, NRCM epistasis","pmids":["39753981"],"confidence":"Medium","gaps":["Single lab","How a soluble nuclear protein is handled as a membrane retromer cargo mechanistically unclear"]},{"year":2025,"claim":"Reconstituted SNX3-retromer cargo engagement and tubulation in vitro using the AAVR cytosolic tail, defining AAVR as a cargo required for AAV transduction.","evidence":"In vitro reconstitution of SNX3-retromer with AAVR tail, membrane tubulation, AAVR-KO trafficking/transduction (preprint)","pmids":["bio_10.1101_2025.11.22.689972"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Single lab"]},{"year":2025,"claim":"Reconstituted hybrid SNX3/SNX-BAR retromer coats, revealing cooperative coat architecture despite mutually exclusive direct binding.","evidence":"In vitro reconstitution with purified proteins, EM of coat assemblies, in vivo co-localization and cargo sorting (preprint)","pmids":["bio_10.1101_2025.07.29.667382"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","How retromer oligomerization links the two SNX classes structurally not resolved"]},{"year":2026,"claim":"Assigned SNX3 a role in basal autophagy by conferring lysosomal fusion competence via correct SNARE delivery.","evidence":"C. elegans snx-3 mutants and mammalian knockdown, autophagosome/amphisome imaging, SQST-1/p62 clearance, SNARE and VAMP-8/RAB-7 localization","pmids":["41537964"],"confidence":"Medium","gaps":["Single lab","Whether this requires retromer or is an independent SNX3 function not resolved"]},{"year":null,"claim":"How SNX3 selects among its diverse cargos and switches between retromer-dependent retrograde sorting, tubular recycling, MVB biogenesis, and lysosomal fusion competence remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of cargo-tail recognition across cargos","Mechanistic relationship between SNX3 retromer-dependent and retromer-independent roles unclear","Determinants directing SNX3 to recycling versus degradative endosomal subdomains undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,7,11,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,6,8]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[1,4,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,4,5,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9,11,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,4,15,19]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,4,6,8,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,6,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12]}],"complexes":["SNX3-retromer (VPS26/VPS29/VPS35)"],"partners":["VPS35","VPS26","VPS29","MON2","DOPEY2","ATP9A","HMGB1","EEA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60493","full_name":"Sorting nexin-3","aliases":["Protein SDP3"],"length_aa":162,"mass_kda":18.8,"function":"Phosphoinositide-binding protein required for multivesicular body formation. Specifically binds phosphatidylinositol 3-phosphate (PtdIns(P3)). Can also bind phosphatidylinositol 4-phosphate (PtdIns(P4)), phosphatidylinositol 5-phosphate (PtdIns(P5)) and phosphatidylinositol 3,5-biphosphate (PtdIns(3,5)P2) (By similarity). Plays a role in protein transport between cellular compartments. Together with RAB7A facilitates endosome membrane association of the retromer cargo-selective subcomplex (CSC/VPS). May in part act as component of the SNX3-retromer complex which mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway (PubMed:21725319, PubMed:24344282, PubMed:30213940). Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G (By similarity). Not involved in EGFR degradation. Involved in the regulation of phagocytosis in dendritic cells possibly by regulating EEA1 recruitment to the nascent phagosomes (PubMed:23237080). Involved in iron homeostasis through regulation of endocytic recycling of the transferrin receptor TFRC presumably by delivering the transferrin:transferrin receptor complex to recycling endosomes; the function may involve the CSC retromer subcomplex (By similarity). Involved in regulation of neurite outgrowth in primary neurons (By similarity). Required for trafficking of WLS to the early endosome for recycling which promotes both canonical and non-canonical WNT signaling and is essential for neural tube closure (By similarity) (Microbial infection) In the case of Salmonella enterica infection, plays a role in maturation of the Salmonella-containing vacuole (SCV) and promotes recruitment of LAMP1 to SCVs","subcellular_location":"Early endosome; Cytoplasmic vesicle, phagosome","url":"https://www.uniprot.org/uniprotkb/O60493/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000112335","cell_line_id":"CID000680","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"POLR1C","stoichiometry":0.2},{"gene":"RAB7A","stoichiometry":0.2},{"gene":"VPS29","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000680","total_profiled":1310},"omim":[{"mim_id":"605931","title":"SORTING NEXIN 4; SNX4","url":"https://www.omim.org/entry/605931"},{"mim_id":"605930","title":"SORTING NEXIN 3; SNX3","url":"https://www.omim.org/entry/605930"},{"mim_id":"605929","title":"SORTING NEXIN 2; SNX2","url":"https://www.omim.org/entry/605929"},{"mim_id":"601349","title":"MICROPHTHALMIA, SYNDROMIC 8; MCOPS8","url":"https://www.omim.org/entry/601349"},{"mim_id":"601272","title":"SORTING NEXIN 1; SNX1","url":"https://www.omim.org/entry/601272"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX3"},"hgnc":{"alias_symbol":["Grd19"],"prev_symbol":[]},"alphafold":{"accession":"O60493","domains":[{"cath_id":"3.30.1520.10","chopping":"23-145","consensus_level":"high","plddt":93.365,"start":23,"end":145}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60493","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60493-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60493-F1-predicted_aligned_error_v6.png","plddt_mean":88.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX3","jax_strain_url":"https://www.jax.org/strain/search?query=SNX3"},"sequence":{"accession":"O60493","fasta_url":"https://rest.uniprot.org/uniprotkb/O60493.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60493/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60493"}},"corpus_meta":[{"pmid":"21725319","id":"PMC_21725319","title":"A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21725319","citation_count":277,"is_preprint":false},{"pmid":"11433298","id":"PMC_11433298","title":"SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P.","date":"2001","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11433298","citation_count":252,"is_preprint":false},{"pmid":"17420293","id":"PMC_17420293","title":"Grd19/Snx3p functions as a cargo-specific adapter for retromer-dependent endocytic recycling.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17420293","citation_count":145,"is_preprint":false},{"pmid":"23416069","id":"PMC_23416069","title":"Snx3 regulates recycling of the transferrin receptor and iron assimilation.","date":"2013","source":"Cell 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cells.","date":"2013","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23237080","citation_count":19,"is_preprint":false},{"pmid":"34718348","id":"PMC_34718348","title":"EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34718348","citation_count":17,"is_preprint":false},{"pmid":"34081703","id":"PMC_34081703","title":"SNX-3 mediates retromer-independent tubular endosomal recycling by opposing EEA-1-facilitated trafficking.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34081703","citation_count":17,"is_preprint":false},{"pmid":"17655765","id":"PMC_17655765","title":"Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes.","date":"2007","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17655765","citation_count":13,"is_preprint":false},{"pmid":"33214242","id":"PMC_33214242","title":"Snx3 is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33214242","citation_count":11,"is_preprint":false},{"pmid":"31612043","id":"PMC_31612043","title":"SNX3 suppresses the migration and invasion of colorectal cancer cells by reversing epithelial-to-mesenchymal transition via the β-catenin pathway.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31612043","citation_count":10,"is_preprint":false},{"pmid":"22159558","id":"PMC_22159558","title":"SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells.","date":"2011","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/22159558","citation_count":9,"is_preprint":false},{"pmid":"31337623","id":"PMC_31337623","title":"SNX3 drives maturation of Borrelia phagosomes by forming a hub for PI(3)P, Rab5a, and galectin-9.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31337623","citation_count":9,"is_preprint":false},{"pmid":"39310106","id":"PMC_39310106","title":"Honokiol enhances the sensitivity of cetuximab in KRASG13D mutant colorectal cancer through destroying SNX3-retromer complex.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/39310106","citation_count":8,"is_preprint":false},{"pmid":"29414832","id":"PMC_29414832","title":"Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein.","date":"2018","source":"Neuro-degenerative diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29414832","citation_count":8,"is_preprint":false},{"pmid":"34570221","id":"PMC_34570221","title":"α-synuclein inhibits Snx3-retromer retrograde trafficking of the conserved membrane-bound proprotein convertase Kex2 in the secretory pathway of Saccharomyces cerevisiae.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34570221","citation_count":5,"is_preprint":false},{"pmid":"39006843","id":"PMC_39006843","title":"SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis.","date":"2024","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39006843","citation_count":2,"is_preprint":false},{"pmid":"39753981","id":"PMC_39753981","title":"SNX3 mediates heart failure by interacting with HMGB1 and subsequently facilitating its nuclear-cytoplasmic translocation.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39753981","citation_count":1,"is_preprint":false},{"pmid":"41537964","id":"PMC_41537964","title":"SNX-3 confers lysosomal fusion-competence to sustain basal autophagy.","date":"2026","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41537964","citation_count":1,"is_preprint":false},{"pmid":"42239321","id":"PMC_42239321","title":"A proteomic atlas of organelle remodeling identifies lysosomal SNX3 as a regulator of Notch signaling in epidermal differentiation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239321","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.29.667382","title":"Hybrid endosomal coats containing different classes of sorting 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activation","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.652881","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16705,"output_tokens":5833,"usd":0.068805,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14296,"output_tokens":5728,"usd":0.10734,"stage2_stop_reason":"end_turn"},"total_usd":0.176145,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SNX3 associates with early endosomes through its PX domain by directly binding 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 early to recycling endosomes.\",\n      \"method\": \"PX domain-PtdIns(3)P binding assay, overexpression morphology analysis, antibody microinjection with transport assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct lipid-binding interaction demonstrated, functional consequences shown with two orthogonal perturbation methods (overexpression and antibody microinjection), independently cited and replicated across the field\",\n      \"pmids\": [\"11433298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast Grd19/Snx3p functions as a cargo-specific adaptor for the retromer complex. A recycling signal in the iron transporter subunit Ftr1p binds directly to Grd19/Snx3p, and Grd19/Snx3p physically associates with retromer on tubular endosomes to sort Fet3p-Ftr1p into an endocytic recycling pathway that returns the transporter to the plasma membrane via the Golgi (Ypt6p Rab GTPase module).\",\n      \"method\": \"Direct binding assay (recycling signal in Ftr1p to Grd19/Snx3p), co-localization on tubular endosomes, genetic epistasis with retromer and Ypt6p module, yeast deletion mutants with cargo trafficking readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding of cargo tail to SNX3 demonstrated, genetic epistasis established pathway position, replicated by independent studies\",\n      \"pmids\": [\"17420293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Snx3/Grd19p-retromer recycling pathway and the ESCRT-dependent MVB sorting pathway act in opposition at a common endosome (marked by Vps27, Snx3, and retromer). Iron-induced ubiquitylation of Fet3-Ftr1 by Rsp5 at this endosome diverts cargo from the Snx3-retromer recycling route to the MVB/degradative route; loss of ESCRT components or ubiquitin-acceptor lysines constitutively shunts Fet3-Ftr1 into the Snx3-retromer recycling pathway.\",\n      \"method\": \"Yeast genetics (ESCRT deletion, ubiquitylation site mutants, rsp5 mutants), co-localization of Vps27/Snx3/retromer on endosomes, cargo trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple ESCRT components, ubiquitylation site mutagenesis, co-localization, replicated/consistent with companion paper\",\n      \"pmids\": [\"18768754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX3 is required for multivesicular body (MVB) formation but is dispensable for EGF receptor degradation. PtdIns(3)P controls complementary functions: Hrs mediates lysosomal targeting while SNX3 mediates MVB biogenesis.\",\n      \"method\": \"siRNA knockdown of SNX3 with morphological analysis of MVB formation and EGF receptor degradation assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (MVB biogenesis vs. degradation), single lab but two distinct readouts separating the two functions\",\n      \"pmids\": [\"18767904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNX3 mediates retrograde endosome-to-Golgi recycling of the Wnt sorting receptor Wntless (Wls) through a retromer pathway that is independent of SNX1/SNX2 and SNX5/SNX6. SNX3 interacts directly with the cargo-selective VPS26/VPS29/VPS35 subcomplex of retromer to sort Wls into a morphologically distinct retrieval pathway required for efficient Wnt secretion.\",\n      \"method\": \"C. elegans and mammalian cell genetics (RNAi/knockdown), direct interaction assay of SNX3 with retromer cargo-selective subcomplex, epistasis showing SNX1/2/5/6 independence, Wls recycling and Wnt secretion assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding to retromer subcomplex demonstrated, epistasis in multiple organisms, functional readout (Wnt secretion), replicated by companion Drosophila paper\",\n      \"pmids\": [\"21725319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila SNX3 (DSNX3) is required for retromer-mediated Wls recycling and Wingless secretion. DSNX3 interacts with retromer component Vps35 and co-localizes with Vps35 on early endosomes. SNX1 and SNX6 cannot substitute for SNX3 in Wls recycling, establishing SNX3 specificity in this pathway.\",\n      \"method\": \"Drosophila genetic mutants (all 8 snx members), S2 cell RNAi, Wg secretion assay (medium levels), Wls overexpression rescue, co-immunoprecipitation with Vps35, co-localization imaging\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mutants, reciprocal Co-IP, rescue experiments, confirmed by companion mammalian paper (PMID 21725319)\",\n      \"pmids\": [\"22041890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX3 and retromer component VPS35 interact with the transferrin receptor (Tfrc) to sort it to recycling endosomes. Loss of Snx3 impairs Tfrc recycling, causing iron to accumulate in early endosomes, leading to impaired transferrin-mediated iron uptake and anemia in vertebrates.\",\n      \"method\": \"Zebrafish/vertebrate morpholino knockdown with hematological phenotype, co-immunoprecipitation of SNX3, VPS35, and Tfrc, endosomal accumulation assay, rescue with non-Tf iron chelates\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of tripartite complex, in vivo loss-of-function with specific mechanistic rescue, functional iron assimilation readout\",\n      \"pmids\": [\"23416069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX3 recruits to nascent phagosomes via its PI3P-binding PX domain and negatively regulates phagocytic uptake of bacteria in dendritic cells. SNX3 competes with EEA1 for PI3P-binding at phagosomal membranes, suggesting it modulates recruitment of essential PI3P effectors during phagocytosis.\",\n      \"method\": \"Live cell imaging of SNX3 recruitment to phagosomes, siRNA knockdown with phagocytosis assay (bacterial uptake), competition assay with EEA1 for membrane recruitment\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — localization directly tied to functional consequence (phagocytosis), competition mechanism supported by imaging, single lab\",\n      \"pmids\": [\"23237080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX3-retromer assembly is essential for Wntless transport and requires an evolutionarily conserved endosome-associated membrane-remodelling complex composed of MON2, DOPEY2, and the putative aminophospholipid translocase ATP9A. In vivo suppression of MON2, DOPEY2, or ATP9A orthologues phenocopies SNX3-retromer loss and leads to enhanced lysosomal degradation of Wntless. Phospholipid flippase activity of ATP9A is implicated in this process.\",\n      \"method\": \"Co-immunoprecipitation of SNX3 with MON2/DOPEY2/ATP9A complex, C. elegans in vivo RNAi epistasis, ATPase-inhibited mutant overexpression, Wntless trafficking assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vivo epistasis in C. elegans, ATPase mutant mechanistic test, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30213940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Alpha-synuclein inhibits Snx3-retromer-mediated recycling of the iron transporter Fet3/Ftr1 in S. cerevisiae by blocking the association of Snx3 with endocytic vesicles, possibly by interfering with Snx3 binding to phosphatidylinositol-3-monophosphate. This shunts Fet3/Ftr1 into the MVB pathway for vacuolar degradation.\",\n      \"method\": \"Yeast fluorescence microscopy tracking Snx3-mCherry on endosomes with/without α-syn expression, cargo trafficking assays under low-iron conditions, C. elegans genetic epistasis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — live imaging of SNX3 displacement from vesicles, genetic evidence in two model organisms, single lab\",\n      \"pmids\": [\"29452354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of SNX3 in HEK293T cells reduces internalization of amyloid precursor protein (APP), resulting in increased cell-surface APP, decreased association of APP with BACE1 (assessed by bimolecular fluorescence complementation), and reduced secretion of Aβ peptides and sAPPβ.\",\n      \"method\": \"SNX3 overexpression, immunoassay for Aβ, BiFC for APP-BACE1 interaction, α-bungarotoxin-binding internalization assay, flow cytometry for surface APP\",\n      \"journal\": \"Neuro-degenerative diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal readouts (BiFC, surface assay, secretion) but only overexpression approach, single lab\",\n      \"pmids\": [\"29414832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX3 is transported to Borrelia phagosomes via Rab5a-positive vesicles; its PX domain enables vesicle-phagosome contact by binding PI(3)P in the phagosomal coat. The C-terminal region of SNX3 recruits galectin-9, forming a hub that coordinates two distinct vesicle populations to promote phagosomal compaction and phagolysosome maturation.\",\n      \"method\": \"Live-cell imaging of SNX3 on Rab5a vesicles, PI(3)P binding assay, domain-function analysis (C-terminal region for galectin-9 recruitment), phagosome compaction assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization directly tied to phagosome maturation mechanism, domain-level dissection, single lab\",\n      \"pmids\": [\"31337623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Snx3 knockout mouse embryos display a fully-penetrant cranial neural tube defect caused by defective WLS recycling (mis-trafficking to lysosomes for degradation) and decreased canonical WNT target gene expression. A human NTD-associated point mutation in SNX3 produces functionally impaired SNX3 that fails to co-localize with WLS and leads to WLS degradation. Rescue with a WNT agonist restores neural tube closure in Snx3 mutant embryos.\",\n      \"method\": \"Snx3 knockout mouse model, live-cell imaging of WLS recycling, WNT target gene expression (in vivo), WNT agonist rescue, human SNX3 point mutant functional analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO with specific NTD phenotype, live imaging of WLS mis-trafficking, pharmacological rescue, human mutation functional validation — multiple orthogonal methods\",\n      \"pmids\": [\"33214242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, SNX-3 organizes tubular endosomes for recycling of clathrin-independent endocytic (CIE) cargoes (hTAC) back to the plasma membrane in a retromer trimer (VPS-26/-29/-35)-independent manner. Loss of SNX-3 abolishes recycling tubules, causes hTAC to be captured by ESCRT and degraded in lysosomes, and leads to increased recruitment of EEA-1 to early endosomes. In HeLa cells, SNX3 and EEA1 compete for binding to PI(3)P on early endosomes.\",\n      \"method\": \"C. elegans snx-3 mutants with tubule morphology imaging, cargo surface/total level quantification, ESCRT pathway epistasis, EEA-1 localization assay, PI(3)P competition assay in HeLa cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in two systems with defined tubule morphology and cargo trafficking readouts, competition binding demonstrated, epistasis with retromer and ESCRT\",\n      \"pmids\": [\"34081703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGF stimulation upregulates SNX3 abundance (initially at the protein level, then transcriptionally) and increases interaction between SNX3 and EGFR. Long-term SNX3 silencing forces EGFR mRNA/protein overexpression, while SNX3 is required to maintain EGFR protein levels. SNX3 co-localizes with early endosomes and endocytosed EGF.\",\n      \"method\": \"Proximity labeling (BioID) for SNX3-EGFR interaction upon EGF, siRNA knockdown (transient and long-term), EGFR protein/mRNA quantification, co-localization imaging, syngeneic in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proximity labeling for interaction, two distinct knockdown paradigms, in vivo validation, single lab\",\n      \"pmids\": [\"34718348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Alpha-synuclein disrupts Snx3-retromer-mediated retrograde trafficking of the conserved proprotein convertase Kex2 and dipeptidyl aminopeptidase Ste13 from late endosomes to the TGN, diverting them to vacuolar degradation. The membrane-binding ability of α-syn (absent in A30P mutant) is required for this inhibition of Snx3-retromer function.\",\n      \"method\": \"Fluorescence microscopy of Kex2-GFP/GFP-Ste13 trafficking in yeast, western blotting, yeast mating assay (α-factor secretion readout), α-syn variant analysis (A53T, A30P, ΔC)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cargo readouts, structure-function analysis with α-syn variants, mechanistically consistent with PMID 29452354, single lab\",\n      \"pmids\": [\"34570221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX3-retromer directly interacts with HMGB1 and mediates its efflux from the nucleus to the cytoplasm (nuclear-cytoplasmic translocation). HMGB1 functions as a direct cargo protein of the SNX3-retromer complex in cardiomyocytes, and this interaction promotes pathological cardiac hypertrophy and heart failure. SNX3 cardiac-specific knockout rescues detrimental heart function in pressure-overload (TAC) mice.\",\n      \"method\": \"Immunoprecipitation-based mass spectrometry, localized surface plasmon resonance (direct SNX3-HMGB1 binding), cardiac-specific SNX3 KO mouse (TAC model), adenoviral SNX3 overexpression, HMGB1 overexpression/knockdown epistasis in NRCMs\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by SPR, genetic epistasis with HMGB1, in vivo cardiac KO phenotype, single lab\",\n      \"pmids\": [\"39753981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNX-3 is required for basal autophagy under nutrient-adequate conditions in C. elegans and mammalian cells by conferring lysosomal fusion competence. Loss of SNX-3 causes accumulation of autophagosomes and amphisomes and impairs autophagic cargo clearance. Mechanistically, SNX-3 loss reroutes the Q-SNARE components SYX-17 and SNAP-29 to autophagosomes (promoting amphisome formation via VAMP-7/8) while impairing lysosomal delivery of VAMP-8 and RAB-7, generating fusion-incompetent lysosomes. Starvation restores lysosomal fusion capability lost upon snx-3 depletion.\",\n      \"method\": \"C. elegans snx-3 mutants, mammalian cell knockdown, autophagosome/amphisome accumulation imaging, SQST-1/p62 cargo clearance assay, SNARE component localization analysis, lysosomal VAMP-8/RAB-7 delivery assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two systems, mechanistic SNARE pathway dissection, multiple cargo readouts, single lab with recent publication\",\n      \"pmids\": [\"41537964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX3-retromer forms hybrid endosomal coats with SNX-BAR proteins (Vps5-Vps17). Although simultaneous binding of Snx3 and SNX-BARs to retromer is sterically prohibited in a simple complex, hybrid coats incorporate both SNX classes—likely linked by retromer oligomerisation—at variable subunit ratios and diameters. Hybrid coats show greater membrane scaffolding activity than homogeneous coats. In vivo, Snx3 and SNX-BARs co-localise and mutually impact sorting of their respective cargos.\",\n      \"method\": \"In vitro reconstitution with purified proteins, electron microscopy of coat assemblies, in vivo co-localization and cargo sorting assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution with purified components is Tier 1, but preprint with single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.29.667382\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The AAV receptor AAVR functions as a retromer cargo that engages the SNX3-retromer complex through its cytosolic tail, driving membrane tubulation in vitro. SNX3-retromer-dependent trafficking of AAVR to the trans-Golgi network is required for productive AAV2 transduction.\",\n      \"method\": \"In vitro reconstitution of SNX3-retromer with AAVR cytosolic tail, membrane tubulation assay, AAVR-knockout cell trafficking and transduction assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution and tubulation assay, but preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.22.689972\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SNX3 is a PX-domain-only sorting nexin that binds PI(3)P on early endosomes and acts as a cargo-specific adaptor for the retromer cargo-selective subcomplex (VPS26/VPS29/VPS35), directing distinct transmembrane cargos—including the Wnt sorting receptor Wntless, the iron transporter Ftr1/Fet3 (yeast), transferrin receptor, HMGB1, and AAVR—from endosomes back to the Golgi or plasma membrane; it also competes with EEA1 for PI(3)P binding to regulate tubular recycling endosome formation and lysosomal fusion competence, while its activity can be inhibited by alpha-synuclein through displacement from endosomal membranes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX3 is a PX-domain sorting nexin that anchors to early endosomes by directly binding phosphatidylinositol-3-phosphate (PI(3)P) and acts as a cargo-selective adaptor that couples specific transmembrane cargos to the retromer cargo-selective subcomplex (VPS26/VPS29/VPS35) for retrieval away from degradation [#0, #4]. Through this PI(3)P-dependent membrane recruitment, SNX3 sorts a defined set of cargos: it interacts directly with the retromer subcomplex to recycle the Wnt sorting receptor Wntless from endosomes back to the Golgi, a function independent of the SNX-BAR nexins SNX1/2/5/6 and conserved from yeast and Drosophila to mammals, and required for efficient Wnt secretion [#4, #5, #8]. The same machinery recycles the iron-uptake receptors Ftr1/Fet3 in yeast and the transferrin receptor in vertebrates, such that loss of SNX3 traps iron in early endosomes and produces anemia [#1, #6], and engages additional cargos including HMGB1, whose SNX3-retromer-dependent nuclear-to-cytoplasmic efflux drives pathological cardiac hypertrophy [#16]. SNX3-retromer assembly for Wntless transport additionally requires a conserved MON2/DOPEY2/ATP9A membrane-remodelling module [#8]. SNX3 competes with EEA1 for endosomal PI(3)P to organize tubular recycling endosomes and govern cargo fate, with loss of SNX3 abolishing recycling tubules and diverting cargo into the ESCRT/lysosomal route [#13]. Beyond classical retrograde sorting, SNX3 is required for MVB biogenesis [#3] and confers lysosomal fusion competence needed for basal autophagy [#17]. The SNX3-retromer pathway is inhibited by alpha-synuclein, which displaces SNX3 from endosomal membranes [#9]. In vivo, Snx3 knockout causes a fully-penetrant cranial neural tube defect driven by defective WLS recycling and reduced canonical WNT signaling, and a human neural-tube-defect mutation produces functionally impaired SNX3 that fails to co-localize with WLS [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the biochemical basis for SNX3 membrane targeting: how a PX-domain-only nexin localizes and what it does there.\",\n      \"evidence\": \"PX domain-PtdIns(3)P binding assay with overexpression and antibody microinjection transport assays\",\n      \"pmids\": [\"11433298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cargo or coat partner identified at this stage\", \"Mechanism linking SNX3 to specific transport steps unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined SNX3 as a cargo-specific retromer adaptor by showing a cargo tail recycling signal binds SNX3 directly to drive endosome-to-surface recycling via the Golgi.\",\n      \"evidence\": \"Yeast direct binding of Ftr1p signal to Grd19/Snx3p, genetic epistasis with retromer and Ypt6p, deletion-mutant cargo trafficking\",\n      \"pmids\": [\"17420293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond Ftr1p cargo unknown\", \"Structural basis of cargo-tail recognition not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed cargo fate at the endosome is a competition: ubiquitylation diverts cargo from the SNX3-retromer recycling route to the ESCRT/MVB degradative route.\",\n      \"evidence\": \"Yeast ESCRT deletions, ubiquitylation-site and rsp5 mutants, Vps27/Snx3/retromer co-localization, cargo assays\",\n      \"pmids\": [\"18768754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitin status mechanistically excludes SNX3 binding not shown\", \"Conservation of the recycling/degradation switch in mammals not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Separated PI(3)P effector functions, assigning SNX3 to MVB biogenesis while sparing receptor degradation.\",\n      \"evidence\": \"siRNA knockdown with MVB morphology and EGFR degradation assays\",\n      \"pmids\": [\"18767904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular role of SNX3 in MVB formation versus its retromer adaptor role not reconciled\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Wntless as a physiological SNX3-retromer cargo, defining a SNX-BAR-independent retrieval pathway essential for Wnt secretion.\",\n      \"evidence\": \"C. elegans, mammalian and Drosophila genetics, direct SNX3-VPS26/29/35 interaction and reciprocal Co-IP with Vps35, Wls/Wg secretion assays\",\n      \"pmids\": [\"21725319\", \"22041890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural geometry of SNX3 on the retromer coat not defined\", \"How this pathway is morphologically distinct from SNX-BAR retromer unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended SNX3-retromer cargo recognition to the transferrin receptor and linked the pathway to systemic iron homeostasis and anemia.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with hematological phenotype, tripartite SNX3/VPS35/Tfrc Co-IP, non-Tf iron rescue\",\n      \"pmids\": [\"23416069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tfrc tail binds SNX3 directly not resolved\", \"Relationship to mammalian recycling endosome tubules not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a non-retromer role and a regulatory mechanism: SNX3 competes with EEA1 for phagosomal PI(3)P to restrain phagocytic uptake.\",\n      \"evidence\": \"Live imaging of SNX3 phagosome recruitment, siRNA phagocytosis assay, EEA1 competition assay in dendritic cells\",\n      \"pmids\": [\"23237080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Downstream PI(3)P effectors displaced by SNX3 not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the accessory machinery for SNX3-retromer Wntless transport, implicating a MON2/DOPEY2/ATP9A membrane-remodelling module with flippase activity.\",\n      \"evidence\": \"Reciprocal Co-IP of SNX3 with MON2/DOPEY2/ATP9A, C. elegans RNAi epistasis, ATPase-dead mutant, Wntless trafficking\",\n      \"pmids\": [\"30213940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lipid flipping couples to coat assembly not mechanistically resolved\", \"Whether the module serves cargos beyond Wntless untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified alpha-synuclein as a pathological inhibitor of SNX3 function, acting by displacing SNX3 from endosomal membranes.\",\n      \"evidence\": \"Yeast Snx3-mCherry live imaging with/without alpha-syn, low-iron cargo trafficking assays, C. elegans epistasis\",\n      \"pmids\": [\"29452354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct evidence that alpha-syn blocks SNX3-PI(3)P binding not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked SNX3 to APP processing, showing SNX3 overexpression reduces APP internalization and amyloidogenic cleavage.\",\n      \"evidence\": \"SNX3 overexpression in HEK293T, BiFC for APP-BACE1, surface APP flow cytometry, Abeta immunoassay\",\n      \"pmids\": [\"29414832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression only, no loss-of-function\", \"Single lab; physiological relevance to disease not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected SNX3 domain functions in phagosome maturation: PX-domain PI(3)P binding for vesicle contact and a C-terminal galectin-9 recruitment hub.\",\n      \"evidence\": \"Live imaging of SNX3 on Rab5a vesicles, PI(3)P binding, domain mutation analysis, phagosome compaction assay\",\n      \"pmids\": [\"31337623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of galectin-9 recruitment unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established SNX3 as a developmentally essential gene and a candidate human neural tube defect gene via WLS recycling.\",\n      \"evidence\": \"Snx3 knockout mouse with cranial NTD, WLS recycling imaging, WNT agonist rescue, human point-mutant functional analysis\",\n      \"pmids\": [\"33214242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human genetic causality beyond a single mutation not established\", \"Whether other SNX3 cargos contribute to the NTD phenotype unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SNX3 organizes recycling tubules for clathrin-independent cargo retromer-trimer-independently, and quantified its EEA1 competition on early-endosome PI(3)P.\",\n      \"evidence\": \"C. elegans snx-3 mutants with tubule and cargo imaging, ESCRT epistasis, EEA1 localization, HeLa PI(3)P competition\",\n      \"pmids\": [\"34081703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SNX3 builds tubules without the retromer trimer mechanistically unclear\", \"Identity of mammalian CIE cargos using this route not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SNX3 to EGFR homeostasis and tumor biology, showing EGF-induced SNX3 upregulation and SNX3 requirement to maintain EGFR levels.\",\n      \"evidence\": \"BioID for SNX3-EGFR interaction, transient and long-term siRNA, EGFR mRNA/protein quantification, syngeneic tumor model\",\n      \"pmids\": [\"34718348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether EGFR is a direct retromer cargo not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized alpha-synuclein inhibition of SNX3-retromer to late-endosome-to-TGN retrograde cargos and tied it to alpha-syn membrane binding.\",\n      \"evidence\": \"Yeast Kex2-GFP/GFP-Ste13 trafficking, mating assay, alpha-syn A53T/A30P/deltaC variant analysis\",\n      \"pmids\": [\"34570221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct competition at the SNX3-membrane interface not biochemically shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified HMGB1 as a direct SNX3-retromer cargo whose translocation drives pathological cardiac hypertrophy.\",\n      \"evidence\": \"IP-mass spectrometry, SPR for direct SNX3-HMGB1 binding, cardiac-specific Snx3 KO in TAC mice, NRCM epistasis\",\n      \"pmids\": [\"39753981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How a soluble nuclear protein is handled as a membrane retromer cargo mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconstituted SNX3-retromer cargo engagement and tubulation in vitro using the AAVR cytosolic tail, defining AAVR as a cargo required for AAV transduction.\",\n      \"evidence\": \"In vitro reconstitution of SNX3-retromer with AAVR tail, membrane tubulation, AAVR-KO trafficking/transduction (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.22.689972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconstituted hybrid SNX3/SNX-BAR retromer coats, revealing cooperative coat architecture despite mutually exclusive direct binding.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins, EM of coat assemblies, in vivo co-localization and cargo sorting (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.29.667382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"How retromer oligomerization links the two SNX classes structurally not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Assigned SNX3 a role in basal autophagy by conferring lysosomal fusion competence via correct SNARE delivery.\",\n      \"evidence\": \"C. elegans snx-3 mutants and mammalian knockdown, autophagosome/amphisome imaging, SQST-1/p62 clearance, SNARE and VAMP-8/RAB-7 localization\",\n      \"pmids\": [\"41537964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether this requires retromer or is an independent SNX3 function not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX3 selects among its diverse cargos and switches between retromer-dependent retrograde sorting, tubular recycling, MVB biogenesis, and lysosomal fusion competence remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of cargo-tail recognition across cargos\", \"Mechanistic relationship between SNX3 retromer-dependent and retromer-independent roles unclear\", \"Determinants directing SNX3 to recycling versus degradative endosomal subdomains undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 7, 11, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 6, 8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 4, 5, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9, 11, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 4, 15, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 4, 6, 8, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 6, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"SNX3-retromer (VPS26/VPS29/VPS35)\"],\n    \"partners\": [\"VPS35\", \"VPS26\", \"VPS29\", \"MON2\", \"DOPEY2\", \"ATP9A\", \"HMGB1\", \"EEA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}