{"gene":"SNX15","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2000,"finding":"The PX (phox homology) domain of SNX15 is required for its membrane association and for association with the platelet-derived growth factor receptor (PDGFR). SNX15 did not associate with EGF or insulin receptors.","method":"Overexpression, membrane fractionation, co-immunoprecipitation, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain deletion and co-IP in single lab, two complementary methods establishing PX-domain requirement and selective receptor binding","pmids":["11085978"],"is_preprint":false},{"year":2000,"finding":"Overexpression of SNX15 leads to decreased processing of insulin and hepatocyte growth factor receptors to their mature subunits, and causes mislocalization of furin (the endoprotease responsible for cleavage of these receptors), indicating SNX15 disrupts normal trafficking of proteins through the trans-Golgi network or recycling endosomes.","method":"Overexpression in COS-7 cells, immunofluorescence, receptor processing assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with biochemical and imaging readouts in single lab, two orthogonal methods","pmids":["11085978"],"is_preprint":false},{"year":2000,"finding":"Overexpression of myc-SNX15 in COS-7 cells alters morphology of endosomal compartments (generating enlarged ring and amorphous membrane structures containing proteins from lysosomes, late endosomes, early endosomes, and TGN), severely inhibits endocytosis of transferrin, and slows endocytosis and recycling of tac-TGN38 and tac-furin, establishing SNX15 as a regulator of the endocytic trafficking pathway.","method":"Transient transfection, immunofluorescence, endocytosis assays (transferrin, tac-TGN38, tac-furin), recycling assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with multiple orthogonal functional readouts (morphology, endocytosis, recycling) in single lab","pmids":["11208079"],"is_preprint":false},{"year":2013,"finding":"SNX15 associates with early endosomes via its PX domain in a phosphatidylinositol 3-phosphate (PtdIns3P)-dependent manner, and also directly binds clathrin through a non-canonical clathrin-binding box, associating with clathrin-coated pits and vesicles. RNAi-mediated suppression of SNX15 causes a delay in EGF receptor degradation due to a defect in movement of newly internalized EGF-receptor-labeled vesicles into early endosomes.","method":"RNAi loss-of-function screen, live-cell imaging, co-immunoprecipitation/pulldown, PtdIns3P-binding assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with specific phenotypic readout plus direct binding assays establishing clathrin interaction and PtdIns3P-dependent membrane association, single lab with multiple orthogonal methods","pmids":["23986476"],"is_preprint":false},{"year":2013,"finding":"The MIT domain of SNX15a (splice variant) binds phosphoinositides in a Ca2+-dependent manner; the loop between the first and second α-helices of the MIT domain binds a Ca2+ ion and facilitates membrane association.","method":"In vitro phosphoinositide-binding assay, biochemical Ca2+-binding experiments","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding assays establishing a biochemical activity, single lab, single study","pmids":["23423459"],"is_preprint":false},{"year":2015,"finding":"SNX15-decorated EGF-receptor-containing endocytic vesicles are distinct from APPL1-containing endosomes (no heterotypic fusion observed by live imaging), but undergo direct fusion with Rab5-positive early endosomes, and co-label with the ESCRT-0 subunit Hrs at peripheral EEA1-negative endosomal intermediates.","method":"Live-cell fluorescence imaging, co-localization analysis at subpixel resolution, RNA silencing","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — live-cell imaging with quantitative co-localization and RNAi, single lab","pmids":["25588841"],"is_preprint":false},{"year":2015,"finding":"SNX15 overexpression increases APP at the cell surface by accelerating APP recycling, whereas SNX15 downregulation reduces cell-surface APP. Neither manipulation affects BACE1 or γ-secretase activity or levels, demonstrating SNX15 specifically regulates APP recycling to reduce Aβ generation.","method":"Overexpression, siRNA knockdown, cell-surface biotinylation, recycling assay, Aβ ELISA, AAV-mediated expression in transgenic AD mice","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementary gain- and loss-of-function with biochemical trafficking readouts and in vivo validation, single lab","pmids":["26115702"],"is_preprint":false},{"year":2023,"finding":"IST1 interacts with the MIT domain-containing SNX15 on endosomes. SNX15 and IST1 co-occupy a clathrin-containing subdomain on the endosomal perimeter, and CHMP1B and SNX15 alternately recruit IST1 to this subdomain or to the base of endosomal tubules, linking SNX15 to ESCRT-III-mediated recycling carrier scission.","method":"Co-immunoprecipitation, live-cell microscopy, kinetic and spatial co-localization analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and live-cell imaging with temporal/spatial resolution, single lab, peer-reviewed and preprint versions consistent","pmids":["37926552","37577466"],"is_preprint":false},{"year":2022,"finding":"A RARA-SNX15 fusion protein (RARA-SNX15L) formed by chromosomal rearrangement in APL retains the SNX15 PX domain and directly associates with endogenous SNX15 and with itself, as shown by co-immunoprecipitation.","method":"Co-immunoprecipitation of RARA-SNX15L fusion protein","journal":"International journal of hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in a single case report, no functional follow-up on the interaction","pmids":["35854096"],"is_preprint":false}],"current_model":"SNX15 is an endosomal sorting nexin whose PX domain mediates PtdIns3P-dependent association with early endosomes and selective binding to PDGFR, whose MIT domain confers Ca2+-dependent phosphoinositide binding, and which directly binds clathrin to associate with clathrin-coated pits and vesicles; it acts at a clathrin-containing subdomain of the early/sorting endosome—distinct from APPL1 endosomes—to facilitate fusion of newly internalized receptor-containing vesicles with Rab5-positive early endosomes, regulates recycling of cargo (including APP) to the cell surface, and interacts with the ESCRT-III–associated protein IST1 to contribute to endosomal recycling carrier scission."},"narrative":{"mechanistic_narrative":"SNX15 is an endosomal sorting nexin that regulates the early endocytic trafficking pathway, controlling the movement, fusion, and recycling of internalized receptor-containing vesicles [PMID:11208079, PMID:23986476]. Its PX domain mediates association with early endosomes in a PtdIns3P-dependent manner and confers selective binding to PDGFR but not EGF or insulin receptors [PMID:11085978, PMID:23986476], while a Ca2+-binding loop in the MIT domain of the SNX15a splice variant supports Ca2+-dependent phosphoinositide and membrane association [PMID:23423459]. SNX15 additionally binds clathrin directly through a non-canonical clathrin-binding box, localizing it to clathrin-coated pits and vesicles, and its loss delays EGF-receptor degradation by impairing entry of newly internalized receptor vesicles into early endosomes [PMID:23986476]. These SNX15-decorated vesicles are distinct from APPL1 endosomes and instead fuse directly with Rab5-positive early endosomes while co-labeling with the ESCRT-0 subunit Hrs [PMID:25588841]. At a clathrin-containing endosomal subdomain, SNX15 interacts with the ESCRT-III-associated protein IST1 and, in alternation with CHMP1B, partitions IST1 between this subdomain and the base of endosomal tubules, linking SNX15 to ESCRT-III-mediated recycling carrier scission [PMID:37926552, PMID:37577466]. Functionally, SNX15 accelerates recycling of cargo such as APP back to the cell surface, thereby reducing amyloidogenic processing without altering BACE1 or γ-secretase activity [PMID:26115702].","teleology":[{"year":2000,"claim":"Established SNX15 as a PX-domain protein with selective receptor association, defining its molecular determinant for membrane targeting and cargo specificity.","evidence":"Membrane fractionation, co-IP, and domain deletion in overexpression systems showing PX-dependent membrane and PDGFR binding but not EGFR/insulin receptor","pmids":["11085978"],"confidence":"Medium","gaps":["Selectivity for PDGFR over other receptors not mechanistically explained","Endogenous-level binding not demonstrated"]},{"year":2000,"claim":"Showed that SNX15 perturbs receptor maturation and furin localization, implicating it in TGN/recycling-endosome trafficking.","evidence":"Overexpression in COS-7 with receptor processing assays and furin immunofluorescence","pmids":["11085978"],"confidence":"Medium","gaps":["Effects derive from overexpression and may not reflect physiological role","Direct involvement in furin trafficking versus indirect disruption unresolved"]},{"year":2000,"claim":"Demonstrated that SNX15 broadly regulates endocytosis and recycling, marking it as a node in the endocytic pathway.","evidence":"Transient transfection with transferrin, tac-TGN38, and tac-furin endocytosis/recycling assays and endosomal morphology analysis","pmids":["11208079"],"confidence":"Medium","gaps":["Enlarged-compartment phenotype is an overexpression artifact-prone readout","Loss-of-function consequences not tested here"]},{"year":2013,"claim":"Resolved SNX15's membrane-targeting and step-specific role, showing PtdIns3P-dependent early-endosome association, direct clathrin binding, and a requirement for vesicle entry into early endosomes.","evidence":"RNAi loss-of-function, live-cell imaging, PtdIns3P-binding and clathrin pulldown assays","pmids":["23986476"],"confidence":"High","gaps":["Functional significance of the non-canonical clathrin box not dissected","Whether PDGFR and EGFR follow the same SNX15-dependent step unclear"]},{"year":2013,"claim":"Defined a Ca2+-dependent phosphoinositide-binding activity in the MIT domain, adding a second membrane-association module to SNX15.","evidence":"In vitro phosphoinositide-binding and Ca2+-binding assays on the SNX15a MIT domain","pmids":["23423459"],"confidence":"Medium","gaps":["Physiological role of Ca2+-dependent binding in cells not demonstrated","Relationship between MIT- and PX-domain membrane binding untested"]},{"year":2015,"claim":"Placed SNX15-decorated vesicles in a defined trafficking route, distinct from APPL1 endosomes but fusing with Rab5 endosomes and marked by Hrs.","evidence":"Live-cell fluorescence imaging with subpixel co-localization and RNA silencing","pmids":["25588841"],"confidence":"Medium","gaps":["Molecular machinery driving fusion with Rab5 endosomes not identified","Functional consequence of Hrs co-labeling unresolved"]},{"year":2015,"claim":"Linked SNX15 to APP recycling and amyloid biology, establishing a cargo-specific recycling function with disease relevance.","evidence":"Gain- and loss-of-function with cell-surface biotinylation, recycling assays, Aβ ELISA, and AAV expression in transgenic AD mice","pmids":["26115702"],"confidence":"Medium","gaps":["Mechanism by which SNX15 selects APP as cargo unknown","No direct SNX15–APP interaction demonstrated"]},{"year":2023,"claim":"Connected SNX15 to ESCRT-III scission machinery via IST1, defining how a clathrin-containing endosomal subdomain coordinates recycling carrier formation.","evidence":"Co-immunoprecipitation and live-cell microscopy with temporal/spatial co-localization analysis","pmids":["37926552","37577466"],"confidence":"Medium","gaps":["Direct contribution of SNX15 to scission events not biochemically reconstituted","Determinants of SNX15 versus CHMP1B alternation at the subdomain unclear"]},{"year":null,"claim":"How SNX15's two membrane-binding modules, clathrin binding, and IST1/ESCRT-III interaction are integrated to select specific cargoes and execute recycling carrier scission remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted system linking SNX15 binding activities to scission","Cargo selection logic (PDGFR, APP) not mechanistically defined","Structural basis of MIT–IST1 interaction not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":["CLTC","IST1","PDGFR","HGS","CHMP1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRS6","full_name":"Sorting nexin-15","aliases":[],"length_aa":342,"mass_kda":38.3,"function":"May be involved in several stages of intracellular trafficking. Overexpression of SNX15 disrupts the normal trafficking of proteins from the plasma membrane to recycling endosomes or the TGN","subcellular_location":"Cytoplasm; Membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9NRS6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX15","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNX15","total_profiled":1310},"omim":[{"mim_id":"619200","title":"SORTING NEXIN FAMILY, MEMBER 21; SNX21","url":"https://www.omim.org/entry/619200"},{"mim_id":"607111","title":"SPARTIN; SPART","url":"https://www.omim.org/entry/607111"},{"mim_id":"605964","title":"SORTING NEXIN 15; SNX15","url":"https://www.omim.org/entry/605964"},{"mim_id":"173490","title":"PLATELET-DERIVED GROWTH FACTOR RECEPTOR, ALPHA; PDGFRA","url":"https://www.omim.org/entry/173490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX15"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NRS6","domains":[{"cath_id":"3.30.1520.10","chopping":"8-132","consensus_level":"high","plddt":89.6446,"start":8,"end":132},{"cath_id":"1.20.58.80","chopping":"266-342","consensus_level":"medium","plddt":91.1808,"start":266,"end":342}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRS6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRS6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRS6-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX15","jax_strain_url":"https://www.jax.org/strain/search?query=SNX15"},"sequence":{"accession":"Q9NRS6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRS6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRS6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRS6"}},"corpus_meta":[{"pmid":"11085978","id":"PMC_11085978","title":"Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11085978","citation_count":78,"is_preprint":false},{"pmid":"11208079","id":"PMC_11208079","title":"Overexpression of a novel sorting nexin, SNX15, affects endosome morphology and protein trafficking.","date":"2000","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/11208079","citation_count":43,"is_preprint":false},{"pmid":"20145299","id":"PMC_20145299","title":"Transcriptomic signature of cell lines isolated from canine mammary adenocarcinoma metastases to lungs.","date":"2010","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20145299","citation_count":42,"is_preprint":false},{"pmid":"16018968","id":"PMC_16018968","title":"Structural characterization of the MIT domain from human Vps4b.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16018968","citation_count":30,"is_preprint":false},{"pmid":"23986476","id":"PMC_23986476","title":"SNX15 links clathrin endocytosis to the PtdIns3P early endosome independently of the APPL1 endosome.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23986476","citation_count":24,"is_preprint":false},{"pmid":"25588841","id":"PMC_25588841","title":"ESCRT-0 marks an APPL1-independent transit route for EGFR between the cell surface and the EEA1-positive early endosome.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25588841","citation_count":22,"is_preprint":false},{"pmid":"34831096","id":"PMC_34831096","title":"Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831096","citation_count":21,"is_preprint":false},{"pmid":"33539531","id":"PMC_33539531","title":"A Genome-Wide Association Study Identifies Novel Susceptibility loci in Chronic Chagas Cardiomyopathy.","date":"2021","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/33539531","citation_count":16,"is_preprint":false},{"pmid":"26115702","id":"PMC_26115702","title":"SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26115702","citation_count":15,"is_preprint":false},{"pmid":"37926552","id":"PMC_37926552","title":"IST1 regulates select recycling pathways.","date":"2023","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/37926552","citation_count":10,"is_preprint":false},{"pmid":"23423459","id":"PMC_23423459","title":"MIT domain of Vps4 is a Ca2+-dependent phosphoinositide-binding domain.","date":"2013","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23423459","citation_count":10,"is_preprint":false},{"pmid":"15372247","id":"PMC_15372247","title":"A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia.","date":"2004","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15372247","citation_count":9,"is_preprint":false},{"pmid":"35854096","id":"PMC_35854096","title":"A novel RARA-SNX15 fusion in PML-RARA-positive acute promyelocytic leukemia with t(11;17;15)(q13;q21.2;q24.1).","date":"2022","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/35854096","citation_count":2,"is_preprint":false},{"pmid":"37577466","id":"PMC_37577466","title":"IST1 regulates select endosomal recycling pathways.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37577466","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8809,"output_tokens":2233,"usd":0.029961,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9278,"output_tokens":2803,"usd":0.058232,"stage2_stop_reason":"end_turn"},"total_usd":0.088193,"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\": 2000,\n      \"finding\": \"The PX (phox homology) domain of SNX15 is required for its membrane association and for association with the platelet-derived growth factor receptor (PDGFR). SNX15 did not associate with EGF or insulin receptors.\",\n      \"method\": \"Overexpression, membrane fractionation, co-immunoprecipitation, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain deletion and co-IP in single lab, two complementary methods establishing PX-domain requirement and selective receptor binding\",\n      \"pmids\": [\"11085978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of SNX15 leads to decreased processing of insulin and hepatocyte growth factor receptors to their mature subunits, and causes mislocalization of furin (the endoprotease responsible for cleavage of these receptors), indicating SNX15 disrupts normal trafficking of proteins through the trans-Golgi network or recycling endosomes.\",\n      \"method\": \"Overexpression in COS-7 cells, immunofluorescence, receptor processing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with biochemical and imaging readouts in single lab, two orthogonal methods\",\n      \"pmids\": [\"11085978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of myc-SNX15 in COS-7 cells alters morphology of endosomal compartments (generating enlarged ring and amorphous membrane structures containing proteins from lysosomes, late endosomes, early endosomes, and TGN), severely inhibits endocytosis of transferrin, and slows endocytosis and recycling of tac-TGN38 and tac-furin, establishing SNX15 as a regulator of the endocytic trafficking pathway.\",\n      \"method\": \"Transient transfection, immunofluorescence, endocytosis assays (transferrin, tac-TGN38, tac-furin), recycling assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with multiple orthogonal functional readouts (morphology, endocytosis, recycling) in single lab\",\n      \"pmids\": [\"11208079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX15 associates with early endosomes via its PX domain in a phosphatidylinositol 3-phosphate (PtdIns3P)-dependent manner, and also directly binds clathrin through a non-canonical clathrin-binding box, associating with clathrin-coated pits and vesicles. RNAi-mediated suppression of SNX15 causes a delay in EGF receptor degradation due to a defect in movement of newly internalized EGF-receptor-labeled vesicles into early endosomes.\",\n      \"method\": \"RNAi loss-of-function screen, live-cell imaging, co-immunoprecipitation/pulldown, PtdIns3P-binding assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with specific phenotypic readout plus direct binding assays establishing clathrin interaction and PtdIns3P-dependent membrane association, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23986476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The MIT domain of SNX15a (splice variant) binds phosphoinositides in a Ca2+-dependent manner; the loop between the first and second α-helices of the MIT domain binds a Ca2+ ion and facilitates membrane association.\",\n      \"method\": \"In vitro phosphoinositide-binding assay, biochemical Ca2+-binding experiments\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding assays establishing a biochemical activity, single lab, single study\",\n      \"pmids\": [\"23423459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX15-decorated EGF-receptor-containing endocytic vesicles are distinct from APPL1-containing endosomes (no heterotypic fusion observed by live imaging), but undergo direct fusion with Rab5-positive early endosomes, and co-label with the ESCRT-0 subunit Hrs at peripheral EEA1-negative endosomal intermediates.\",\n      \"method\": \"Live-cell fluorescence imaging, co-localization analysis at subpixel resolution, RNA silencing\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — live-cell imaging with quantitative co-localization and RNAi, single lab\",\n      \"pmids\": [\"25588841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX15 overexpression increases APP at the cell surface by accelerating APP recycling, whereas SNX15 downregulation reduces cell-surface APP. Neither manipulation affects BACE1 or γ-secretase activity or levels, demonstrating SNX15 specifically regulates APP recycling to reduce Aβ generation.\",\n      \"method\": \"Overexpression, siRNA knockdown, cell-surface biotinylation, recycling assay, Aβ ELISA, AAV-mediated expression in transgenic AD mice\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementary gain- and loss-of-function with biochemical trafficking readouts and in vivo validation, single lab\",\n      \"pmids\": [\"26115702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IST1 interacts with the MIT domain-containing SNX15 on endosomes. SNX15 and IST1 co-occupy a clathrin-containing subdomain on the endosomal perimeter, and CHMP1B and SNX15 alternately recruit IST1 to this subdomain or to the base of endosomal tubules, linking SNX15 to ESCRT-III-mediated recycling carrier scission.\",\n      \"method\": \"Co-immunoprecipitation, live-cell microscopy, kinetic and spatial co-localization analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and live-cell imaging with temporal/spatial resolution, single lab, peer-reviewed and preprint versions consistent\",\n      \"pmids\": [\"37926552\", \"37577466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A RARA-SNX15 fusion protein (RARA-SNX15L) formed by chromosomal rearrangement in APL retains the SNX15 PX domain and directly associates with endogenous SNX15 and with itself, as shown by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation of RARA-SNX15L fusion protein\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in a single case report, no functional follow-up on the interaction\",\n      \"pmids\": [\"35854096\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX15 is an endosomal sorting nexin whose PX domain mediates PtdIns3P-dependent association with early endosomes and selective binding to PDGFR, whose MIT domain confers Ca2+-dependent phosphoinositide binding, and which directly binds clathrin to associate with clathrin-coated pits and vesicles; it acts at a clathrin-containing subdomain of the early/sorting endosome—distinct from APPL1 endosomes—to facilitate fusion of newly internalized receptor-containing vesicles with Rab5-positive early endosomes, regulates recycling of cargo (including APP) to the cell surface, and interacts with the ESCRT-III–associated protein IST1 to contribute to endosomal recycling carrier scission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX15 is an endosomal sorting nexin that regulates the early endocytic trafficking pathway, controlling the movement, fusion, and recycling of internalized receptor-containing vesicles [#2, #3]. Its PX domain mediates association with early endosomes in a PtdIns3P-dependent manner and confers selective binding to PDGFR but not EGF or insulin receptors [#0, #3], while a Ca2+-binding loop in the MIT domain of the SNX15a splice variant supports Ca2+-dependent phosphoinositide and membrane association [#4]. SNX15 additionally binds clathrin directly through a non-canonical clathrin-binding box, localizing it to clathrin-coated pits and vesicles, and its loss delays EGF-receptor degradation by impairing entry of newly internalized receptor vesicles into early endosomes [#3]. These SNX15-decorated vesicles are distinct from APPL1 endosomes and instead fuse directly with Rab5-positive early endosomes while co-labeling with the ESCRT-0 subunit Hrs [#5]. At a clathrin-containing endosomal subdomain, SNX15 interacts with the ESCRT-III-associated protein IST1 and, in alternation with CHMP1B, partitions IST1 between this subdomain and the base of endosomal tubules, linking SNX15 to ESCRT-III-mediated recycling carrier scission [#7]. Functionally, SNX15 accelerates recycling of cargo such as APP back to the cell surface, thereby reducing amyloidogenic processing without altering BACE1 or γ-secretase activity [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established SNX15 as a PX-domain protein with selective receptor association, defining its molecular determinant for membrane targeting and cargo specificity.\",\n      \"evidence\": \"Membrane fractionation, co-IP, and domain deletion in overexpression systems showing PX-dependent membrane and PDGFR binding but not EGFR/insulin receptor\",\n      \"pmids\": [\"11085978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for PDGFR over other receptors not mechanistically explained\", \"Endogenous-level binding not demonstrated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that SNX15 perturbs receptor maturation and furin localization, implicating it in TGN/recycling-endosome trafficking.\",\n      \"evidence\": \"Overexpression in COS-7 with receptor processing assays and furin immunofluorescence\",\n      \"pmids\": [\"11085978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effects derive from overexpression and may not reflect physiological role\", \"Direct involvement in furin trafficking versus indirect disruption unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that SNX15 broadly regulates endocytosis and recycling, marking it as a node in the endocytic pathway.\",\n      \"evidence\": \"Transient transfection with transferrin, tac-TGN38, and tac-furin endocytosis/recycling assays and endosomal morphology analysis\",\n      \"pmids\": [\"11208079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enlarged-compartment phenotype is an overexpression artifact-prone readout\", \"Loss-of-function consequences not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved SNX15's membrane-targeting and step-specific role, showing PtdIns3P-dependent early-endosome association, direct clathrin binding, and a requirement for vesicle entry into early endosomes.\",\n      \"evidence\": \"RNAi loss-of-function, live-cell imaging, PtdIns3P-binding and clathrin pulldown assays\",\n      \"pmids\": [\"23986476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of the non-canonical clathrin box not dissected\", \"Whether PDGFR and EGFR follow the same SNX15-dependent step unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a Ca2+-dependent phosphoinositide-binding activity in the MIT domain, adding a second membrane-association module to SNX15.\",\n      \"evidence\": \"In vitro phosphoinositide-binding and Ca2+-binding assays on the SNX15a MIT domain\",\n      \"pmids\": [\"23423459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of Ca2+-dependent binding in cells not demonstrated\", \"Relationship between MIT- and PX-domain membrane binding untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SNX15-decorated vesicles in a defined trafficking route, distinct from APPL1 endosomes but fusing with Rab5 endosomes and marked by Hrs.\",\n      \"evidence\": \"Live-cell fluorescence imaging with subpixel co-localization and RNA silencing\",\n      \"pmids\": [\"25588841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery driving fusion with Rab5 endosomes not identified\", \"Functional consequence of Hrs co-labeling unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked SNX15 to APP recycling and amyloid biology, establishing a cargo-specific recycling function with disease relevance.\",\n      \"evidence\": \"Gain- and loss-of-function with cell-surface biotinylation, recycling assays, Aβ ELISA, and AAV expression in transgenic AD mice\",\n      \"pmids\": [\"26115702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SNX15 selects APP as cargo unknown\", \"No direct SNX15–APP interaction demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SNX15 to ESCRT-III scission machinery via IST1, defining how a clathrin-containing endosomal subdomain coordinates recycling carrier formation.\",\n      \"evidence\": \"Co-immunoprecipitation and live-cell microscopy with temporal/spatial co-localization analysis\",\n      \"pmids\": [\"37926552\", \"37577466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution of SNX15 to scission events not biochemically reconstituted\", \"Determinants of SNX15 versus CHMP1B alternation at the subdomain unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX15's two membrane-binding modules, clathrin binding, and IST1/ESCRT-III interaction are integrated to select specific cargoes and execute recycling carrier scission remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted system linking SNX15 binding activities to scission\", \"Cargo selection logic (PDGFR, APP) not mechanistically defined\", \"Structural basis of MIT–IST1 interaction not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLTC\", \"IST1\", \"PDGFR\", \"HGS\", \"CHMP1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}