{"gene":"SNX33","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2008,"finding":"SNX33 was identified as a new activator of APP alpha-secretase cleavage. Exogenous SNX33 expression increased APP alpha-secretase cleavage ~4-fold, with little effect on beta-secretase cleavage. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner, increasing APP at the plasma membrane where alpha-secretase cleavage predominantly occurs.","method":"Expression cloning screen, co-immunoprecipitation (dynamin binding), endocytosis assays, dominant-negative dynamin comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional validation with dynamin binding, endocytosis rate assay, and dominant-negative comparison; multiple orthogonal methods in single study","pmids":["18353773"],"is_preprint":false},{"year":2008,"finding":"SNX33 overexpression in neuronal and non-neuronal cell lines increased shedding of full-length PrP(c) from the plasma membrane and modulated the rate of PrP(c) endocytosis. Using deletion mutants, production of PrP fragment N1 was not influenced by SNX33. Increased PrP shedding was paralleled by reduction of PrP(Sc) formation in persistently and newly infected cells.","method":"Overexpression in cell lines, deletion mutant analysis, endocytosis rate assay, PrPSc formation assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2/3 — clean overexpression with deletion mutants and functional readout (PrPSc reduction), single lab","pmids":["18419754"],"is_preprint":false},{"year":2009,"finding":"SNX33 interacts with itself (homodimerization) and with SNX9, and binds the VCA domain of Wiskott-Aldrich syndrome protein (WASp). SNX33 overexpression induced perinuclear actin accumulation and cytokinesis failure (micronucleation); knockdown caused multinucleation, G1/M delay, and apoptosis. WASp knockdown alleviated the cytokinesis defect induced by SNX33 overexpression, placing SNX33 upstream of WASp in actin polymerization.","method":"Co-immunoprecipitation (SNX33-SNX9, SNX33-WASp VCA domain), siRNA knockdown, overexpression, time-lapse microscopy, flow cytometry cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2/3 — co-IP binding, genetic epistasis (WASp knockdown rescue), and phenotypic readouts; single lab with multiple methods","pmids":["19487689"],"is_preprint":false},{"year":2010,"finding":"Overexpression of SNX33 significantly elevated macropinosome formation (65.25 ± 6.95 macropinosomes per 100 transfected cells vs. 24.44 ± 1.81 for controls), implicating SNX33 in macropinocytosis regulation. Unlike SNX1, SNX5, SNX9, and SNX18, SNX33 did not associate with early-stage macropinosomes.","method":"Image-based screening, systematic overexpression, quantitative macropinosome counting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression with quantitative phenotypic readout, single lab, no mechanistic follow-up for SNX33 specifically","pmids":["21048941"],"is_preprint":false},{"year":2011,"finding":"SNX33 forms homodimers but not heterodimers with other BAR domain-containing proteins such as SNX9. The BAR domain (not the SH3 domain) is required for SNX33 homodimerization and prevents heterodimerization with SNX9. Molecular modeling of the SNX33 BAR domain identified key non-conserved amino acids at the dimer interface; replacing these residues in SNX9 with corresponding SNX33 residues enabled SNX9 to heterodimerize with SNX33.","method":"Co-immunoprecipitation, domain deletion analysis, domain swap experiments, molecular modeling","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1/2 — domain deletion and swap experiments with co-IP validation and structural modeling; multiple orthogonal methods establishing molecular determinants","pmids":["20964629"],"is_preprint":false},{"year":2011,"finding":"C. elegans LST-4, the SNX9-family ortholog of mammalian SNX33, functions at the same genetic step as DYN-1 (dynamin) during apoptotic cell corpse clearance, upstream of RAB-5. Mammalian SNX33 rescued C. elegans lst-4 mutants, and truncated SNX33 fragments interfered with phagosome maturation in mammalian cells, demonstrating evolutionary conservation of function in apoptotic phagosome maturation.","method":"C. elegans genetic epistasis (lst-4/dyn-1/rab-5 double mutants), cross-species rescue, truncated domain overexpression in mammalian cells, electron microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo combined with cross-species rescue and mammalian cell domain analysis; strong mechanistic placement upstream of RAB-5","pmids":["21494661"],"is_preprint":false},{"year":2012,"finding":"SNX33 (along with SNX9 and SNX18) is required for progression through and completion of mitosis. siRNA depletion of SNX33 induced multinucleation (cytokinesis failure) and accumulation of cytokinetic cells. Depletion disrupted MRLC(S19) localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge. Endocytosis of transferrin was blocked during cytokinesis upon SNX33 depletion, suggesting an endocytosis-dependent role in cytokinesis.","method":"siRNA knockdown, time-lapse microscopy, immunofluorescence (MRLC, Rab11), transferrin endocytosis assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — siRNA with time-lapse imaging plus multiple specific molecular markers; replicated across three SNX9-subfamily members with consistent phenotypes","pmids":["22718350"],"is_preprint":false},{"year":2014,"finding":"SNX33 interacts with ADAM15 isoforms via SH3 domain binding to a proline-rich region in the ADAM15 cytoplasmic tail. Robust cellular co-precipitation with SNX33 was observed only for ADAM15 isoforms containing the most carboxyterminal proline cluster (absent in isoforms i1 and i3), demonstrating that alternative splicing of ADAM15 regulates its interaction with SNX33.","method":"Co-precipitation from cell lysates, ADAM15 isoform panel analysis","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — co-precipitation with isoform specificity established; single lab, no in vitro reconstitution","pmids":["19718658"],"is_preprint":false},{"year":2019,"finding":"Donepezil treatment upregulates SNX33 expression in primary cortical neurons, leading to increased APP surface expression, elevated sAPPα secretion, and reduced amyloid β levels. SNX33 knockdown by morpholino oligos prevented all effects of donepezil on APP processing, demonstrating that donepezil acts through SNX33 to decrease APP endocytosis and promote non-amyloidogenic α-secretase cleavage.","method":"Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA (sAPPα, Aβ), surface biotinylation of APP, Western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2/3 — morpholino knockdown with multiple molecular readouts in primary neurons; single lab","pmids":["31417133"],"is_preprint":false},{"year":2023,"finding":"SNX33 (Snx33) acts as a curvature-sensitive BAR domain protein that inhibits actin polymerization at the advancing edge of migrating cells in regions with inward plasma membrane curvature. Genetic perturbation of Snx33 reduced the cells' capacity to evade obstacles while increasing migration speed and persistence in obstacle-free environments, establishing Snx33 as a mechanosensory regulator of directed cell migration.","method":"Genetic perturbation (knockout/knockdown), live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic perturbation with quantitative live-imaging phenotypes; single lab but multiple functional readouts","pmids":["37704612"],"is_preprint":false}],"current_model":"SNX33 is a BAR-PX-SH3 domain-containing sorting nexin that forms homodimers (but not heterodimers with SNX9) via its BAR domain, binds dynamin and WASp through its SH3 domain, and functions as an endocytic regulator that reduces APP and PrP endocytosis to modulate their proteolytic processing; it also acts as a curvature-sensitive inhibitor of actin polymerization at the plasma membrane to regulate cell migration and obstacle evasion, and is required—along with SNX9 and SNX18—for cytokinesis completion through endocytosis-dependent regulation of MRLC localization and Rab11-recycling endosome recruitment."},"narrative":{"teleology":[{"year":2008,"claim":"Identification of SNX33 as an endocytic regulator that modulates alpha-secretase processing of APP by binding dynamin and slowing APP internalization established its core mechanism: controlling substrate residence time at the plasma membrane.","evidence":"Expression cloning screen, co-IP of SNX33–dynamin, endocytosis rate assays, and dominant-negative dynamin comparison in mammalian cell lines","pmids":["18353773"],"confidence":"High","gaps":["Direct binding stoichiometry and affinity between SNX33 SH3 domain and dynamin not measured","Whether SNX33 affects APP processing in neurons in vivo not addressed"]},{"year":2008,"claim":"Extension of the endocytic-regulation paradigm to prion protein showed SNX33's effect is not APP-specific: overexpression increased PrP shedding and reduced PrPSc formation, broadening SNX33's substrate scope.","evidence":"Overexpression in neuronal and non-neuronal cell lines, deletion mutant analysis, PrPSc formation assay","pmids":["18419754"],"confidence":"Medium","gaps":["Only overexpression tested; loss-of-function data for PrP processing absent","Whether SNX33 directly binds PrP or acts solely via dynamin not resolved"]},{"year":2009,"claim":"Discovery that SNX33 binds WASp and that WASp knockdown rescues SNX33-induced cytokinesis failure placed SNX33 upstream of WASp-dependent actin polymerization, revealing a second effector axis beyond dynamin.","evidence":"Co-IP of SNX33–WASp VCA domain, siRNA epistasis, time-lapse microscopy, flow cytometry","pmids":["19487689"],"confidence":"Medium","gaps":["In vitro reconstitution of SNX33–WASp interaction not performed","Relative contributions of WASp and dynamin to SNX33-dependent phenotypes not dissected"]},{"year":2011,"claim":"Structural analysis of the BAR domain demonstrated that SNX33 homodimerizes but cannot heterodimerize with SNX9, with non-conserved residues at the dimer interface dictating specificity—explaining functional non-redundancy within the SNX9 subfamily.","evidence":"Co-IP, domain deletion and swap mutagenesis, molecular modeling of BAR domain interface","pmids":["20964629"],"confidence":"High","gaps":["Crystal structure of the SNX33 BAR domain not solved","Whether homodimerization is required for each of SNX33's distinct functions not tested"]},{"year":2011,"claim":"Cross-species rescue of C. elegans lst-4 mutants by mammalian SNX33 and genetic epistasis placing lst-4/SNX33 at the same step as dynamin upstream of RAB-5 demonstrated evolutionarily conserved function in phagosome maturation during apoptotic cell clearance.","evidence":"C. elegans double-mutant epistasis, cross-species rescue, truncated domain expression in mammalian cells, EM","pmids":["21494661"],"confidence":"High","gaps":["Whether mammalian SNX33 participates in apoptotic cell clearance in vivo in vertebrates not shown","Mechanism by which SNX33 promotes RAB-5 recruitment not defined"]},{"year":2012,"claim":"Depletion of SNX33 (and SNX9/SNX18) caused cytokinesis failure with disrupted MRLC localization and Rab11-recycling-endosome recruitment to the intracellular bridge, establishing that SNX9-family-dependent endocytosis is required for abscission.","evidence":"siRNA knockdown, time-lapse imaging, immunofluorescence for MRLC and Rab11, transferrin endocytosis assay during cytokinesis","pmids":["22718350"],"confidence":"High","gaps":["Individual contribution of SNX33 versus SNX9/SNX18 to cytokinesis not fully resolved","Whether the endocytic cargo critical for abscission has been identified"]},{"year":2014,"claim":"Identification of ADAM15 as an SH3-domain-dependent interaction partner revealed that alternative splicing of a substrate's cytoplasmic tail gates its interaction with SNX33, adding a selectivity mechanism for SNX33-regulated trafficking.","evidence":"Co-precipitation with ADAM15 isoform panel from cell lysates","pmids":["19718658"],"confidence":"Medium","gaps":["Functional consequence of SNX33–ADAM15 interaction on ADAM15 trafficking or shedding not tested","No in vitro reconstitution of direct binding"]},{"year":2019,"claim":"Demonstration that donepezil promotes non-amyloidogenic APP processing through SNX33 upregulation in primary cortical neurons provided a pharmacological validation of the SNX33–endocytosis–alpha-secretase axis in a disease-relevant system.","evidence":"Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA for sAPPα and Aβ, surface biotinylation","pmids":["31417133"],"confidence":"Medium","gaps":["In vivo validation in animal models not provided","Mechanism by which donepezil upregulates SNX33 expression unknown"]},{"year":2023,"claim":"Identification of SNX33 as a curvature-sensitive inhibitor of actin polymerization at the leading edge reframed the protein as a mechanosensory regulator: SNX33 loss increased migration speed but impaired obstacle evasion, linking membrane curvature sensing to steering decisions.","evidence":"Genetic knockout/knockdown, live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis","pmids":["37704612"],"confidence":"Medium","gaps":["Direct measurement of SNX33 BAR domain curvature preference not reported","Whether SNX33-mediated actin inhibition acts through WASp or a distinct effector not resolved","In vivo migration phenotype not tested"]},{"year":null,"claim":"The mechanism by which SNX33 integrates its dual roles—dynamin-dependent endocytic regulation and curvature-dependent actin inhibition—in the same cell, and whether these represent a unified membrane-remodeling activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for SNX33 BAR or full-length protein","Relative importance of homodimerization for endocytic versus actin-regulatory functions untested","No unbiased interactome or proximity-labeling study reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":[],"partners":["DNM1","DNM2","WASL","ADAM15","SNX9","RAB11A"],"other_free_text":[]},"mechanistic_narrative":"SNX33 is a BAR-PX-SH3 domain-containing sorting nexin that regulates endocytosis, actin dynamics, and membrane trafficking to control substrate availability at the plasma membrane, cell division, and directed cell migration. Through its SH3 domain, SNX33 binds dynamin and WASp, reducing the endocytic rate of transmembrane substrates such as APP and PrP and thereby promoting their alpha-secretase-mediated shedding at the cell surface [PMID:18353773, PMID:18419754]. SNX33 homodimerizes via its BAR domain—but does not heterodimerize with SNX9—and is required, together with SNX9 and SNX18, for cytokinesis completion through endocytosis-dependent recruitment of Rab11-positive recycling endosomes and proper MRLC localization at the intracellular bridge [PMID:20964629, PMID:22718350]. SNX33 also functions as a curvature-sensitive inhibitor of actin polymerization at the leading edge of migrating cells, enabling obstacle evasion during directed migration [PMID:37704612]."},"prefetch_data":{"uniprot":{"accession":"Q8WV41","full_name":"Sorting nexin-33","aliases":["SH3 and PX domain-containing protein 3"],"length_aa":574,"mass_kda":65.3,"function":"Plays a role in the reorganization of the cytoskeleton, endocytosis and cellular vesicle trafficking via its interactions with membranes, WASL, DNM1 and DNM2. Acts both during interphase and at the end of mitotic cell divisions. Required for efficient progress through mitosis and cytokinesis. Required for normal formation of the cleavage furrow at the end of mitosis. Modulates endocytosis of cell-surface proteins, such as APP and PRNP; this then modulates the secretion of APP and PRNP peptides. Promotes membrane tubulation (in vitro). May promote the formation of macropinosomes","subcellular_location":"Cytoplasm, cytosol; Membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q8WV41/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX33","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD54","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SNX33","total_profiled":1310},"omim":[{"mim_id":"619107","title":"SORTING NEXIN 33; SNX33","url":"https://www.omim.org/entry/619107"},{"mim_id":"605952","title":"SORTING NEXIN 9; SNX9","url":"https://www.omim.org/entry/605952"},{"mim_id":"176640","title":"PRION PROTEIN; PRNP","url":"https://www.omim.org/entry/176640"},{"mim_id":"104760","title":"AMYLOID BETA A4 PRECURSOR PROTEIN; APP","url":"https://www.omim.org/entry/104760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX33"},"hgnc":{"alias_symbol":["MGC32065","SH3PXD3C","SNX30"],"prev_symbol":["SH3PX3"]},"alphafold":{"accession":"Q8WV41","domains":[{"cath_id":"2.30.30.40","chopping":"4-59","consensus_level":"high","plddt":88.5418,"start":4,"end":59},{"cath_id":"3.30.1520.10","chopping":"233-364","consensus_level":"medium","plddt":92.1494,"start":233,"end":364},{"cath_id":"1.20.1270.60","chopping":"372-571","consensus_level":"medium","plddt":96.7934,"start":372,"end":571}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV41","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV41-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WV41-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX33","jax_strain_url":"https://www.jax.org/strain/search?query=SNX33"},"sequence":{"accession":"Q8WV41","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WV41.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WV41/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WV41"}},"corpus_meta":[{"pmid":"16374509","id":"PMC_16374509","title":"Identification 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cleavage predominantly occurs, thereby increasing APP alpha-secretase cleavage ~4-fold.\",\n      \"method\": \"Expression cloning screen, co-immunoprecipitation, endocytosis assay, comparison with dominant-negative dynamin-1 K44A mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with dominant-negative dynamin, mechanistic link between dynamin binding, endocytosis rate, and secretase cleavage established with multiple orthogonal methods\",\n      \"pmids\": [\"18353773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX33 overexpression increases shedding of full-length PrP from the plasma membrane and modulates the rate of PrPc endocytosis, reducing PrPSc formation. Deletion mutant analysis showed the PrP N1 fragment production is not influenced by SNX33.\",\n      \"method\": \"Overexpression in neuronal and non-neuronal cell lines, deletion mutant analysis, PrPSc formation assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with domain deletion analysis, single lab\",\n      \"pmids\": [\"18419754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX33 interacts with itself (homodimerizes) and with SNX9, and also interacts with the VCA domain of Wiskott-Aldrich syndrome protein (WASp), mediating actin polymerization indirectly. Knockdown of WASp alleviates the cytokinesis/micronucleation phenotype induced by SNX33 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, time-lapse microscopy, cell lineage analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus genetic epistasis (WASp KD rescues SNX33 overexpression phenotype), single lab\",\n      \"pmids\": [\"19487689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX33 overexpression induces accumulation of actin at the perinuclear space, causes cytokinesis failure (micronucleation), and delays G1/M transition. Transient knockdown induces formation of multiple long processes and increased apoptosis.\",\n      \"method\": \"siRNA knockdown, overexpression, time-lapse microscopy, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with specific cellular phenotype readouts, single lab\",\n      \"pmids\": [\"19487689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The BAR domain of SNX33 is required for homodimerization and prevents heterodimerization with SNX9. Specific amino acids at the BAR domain dimer interface (not conserved between SNX9 and SNX33) determine dimerization specificity; substituting these residues in SNX9 with SNX33 counterparts allowed mutant SNX9 to heterodimerize with SNX33.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, domain swap experiments, molecular modelling\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis with domain swaps, co-IP, and structural modelling identifying specific interface residues\",\n      \"pmids\": [\"20964629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans LST-4 (the SNX9-family member and closest ortholog of mammalian SNX33) functions at the same epistatic step as DYN-1 during apoptotic cell corpse clearance, upstream of RAB-5, and is required for phagosome maturation. Mammalian SNX33 rescues C. elegans lst-4 mutants, and truncated SNX33 fragments interfere with phagosome maturation in a mammalian cell system.\",\n      \"method\": \"C. elegans genetic epistasis, electron microscopy, cross-species rescue (mammalian SNX33 in C. elegans), dominant-negative truncation in mammalian cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in C. elegans plus cross-species rescue and mammalian cell experiments, multiple orthogonal methods\",\n      \"pmids\": [\"21494661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX33 (along with SNX9 and SNX18) is required for progression through and completion of mitosis. siRNA depletion of SNX33 induces multinucleation (cytokinesis failure), accumulation of cytokinetic cells, disrupts MRLC(S19) localization during ingression, and impairs Rab11-positive recycling endosome recruitment to the intracellular bridge. SNX33 depletion also blocks endocytosis of transferrin during cytokinesis.\",\n      \"method\": \"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin endocytosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple specific cellular phenotype readouts replicated across three SNX9-subfamily members, mechanistic link to endocytosis established\",\n      \"pmids\": [\"22718350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of SNX33 significantly increases macropinosome formation (65.25 macropinosomes per 100 transfected cells vs. 24.44 in controls), implicating SNX33 in macropinocytosis regulation.\",\n      \"method\": \"Systematic overexpression, image-based quantitative screening of macropinosome numbers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with quantitative phenotypic readout, single lab, no mechanistic pathway placement beyond the SNX-PX-BAR family\",\n      \"pmids\": [\"21048941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX33 (also known as SNX30) binds selectively to specific ADAM15 isoforms containing the most carboxyterminal proline cluster (absent in isoforms i1 and i3), as identified by phage-display SH3 proteome screening and confirmed by co-precipitation from cell lysates.\",\n      \"method\": \"Phage-display SH3 proteome screen, co-precipitation from cell lysates\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-precipitation with isoform specificity mapping, replicated from initial phage-display identification\",\n      \"pmids\": [\"19718658\", \"16374509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Donepezil increases SNX33 expression in primary cortical neurons, which in turn decreases APP endocytosis and increases APP at the cell surface, promoting alpha-secretase cleavage (sAPPα) and reducing Aβ. SNX33 knockdown by morpholino oligos blocks the effects of donepezil on APP processing.\",\n      \"method\": \"SNX33 knockdown (morpholino), Western blotting, cell surface APP measurement, sAPPα/Aβ ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (morpholino) with specific molecular phenotype, consistent with mechanism established by Schöbel et al., single lab\",\n      \"pmids\": [\"31417133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The BAR domain protein Snx33 senses inward plasma membrane curvature at the advancing edge of migrating immune-like cells and inhibits actin polymerization in those regions. Genetic perturbation of Snx33 reduces obstacle evasion capacity and increases the speed and persistence of migration in obstacle-free environments.\",\n      \"method\": \"Genetic perturbation (knockout/knockdown), live-cell imaging, actin dynamics measurement, curvature analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific functional phenotype (obstacle evasion, migration directionality), mechanistic model of curvature sensing linked to actin regulation\",\n      \"pmids\": [\"37704612\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX33 is a BAR-PX-SH3 domain sorting nexin that homodimerizes via its BAR domain, binds dynamin through its SH3 domain to inhibit endocytosis (retaining APP and PrP at the plasma membrane to modulate their processing by secretases), interacts with WASp to regulate actin polymerization and cytokinesis, senses inward plasma membrane curvature to inhibit actin-driven protrusion, and is required for macropinosome formation, phagosome maturation, and mitotic progression including cytokinesis through both endocytosis-dependent and -independent mechanisms.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX33 was identified as a new activator of APP alpha-secretase cleavage. Exogenous SNX33 expression increased APP alpha-secretase cleavage ~4-fold, with little effect on beta-secretase cleavage. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner, increasing APP at the plasma membrane where alpha-secretase cleavage predominantly occurs.\",\n      \"method\": \"Expression cloning screen, co-immunoprecipitation (dynamin binding), endocytosis assays, dominant-negative dynamin comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional validation with dynamin binding, endocytosis rate assay, and dominant-negative comparison; multiple orthogonal methods in single study\",\n      \"pmids\": [\"18353773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX33 overexpression in neuronal and non-neuronal cell lines increased shedding of full-length PrP(c) from the plasma membrane and modulated the rate of PrP(c) endocytosis. Using deletion mutants, production of PrP fragment N1 was not influenced by SNX33. Increased PrP shedding was paralleled by reduction of PrP(Sc) formation in persistently and newly infected cells.\",\n      \"method\": \"Overexpression in cell lines, deletion mutant analysis, endocytosis rate assay, PrPSc formation assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — clean overexpression with deletion mutants and functional readout (PrPSc reduction), single lab\",\n      \"pmids\": [\"18419754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX33 interacts with itself (homodimerization) and with SNX9, and binds the VCA domain of Wiskott-Aldrich syndrome protein (WASp). SNX33 overexpression induced perinuclear actin accumulation and cytokinesis failure (micronucleation); knockdown caused multinucleation, G1/M delay, and apoptosis. WASp knockdown alleviated the cytokinesis defect induced by SNX33 overexpression, placing SNX33 upstream of WASp in actin polymerization.\",\n      \"method\": \"Co-immunoprecipitation (SNX33-SNX9, SNX33-WASp VCA domain), siRNA knockdown, overexpression, time-lapse microscopy, flow cytometry cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP binding, genetic epistasis (WASp knockdown rescue), and phenotypic readouts; single lab with multiple methods\",\n      \"pmids\": [\"19487689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of SNX33 significantly elevated macropinosome formation (65.25 ± 6.95 macropinosomes per 100 transfected cells vs. 24.44 ± 1.81 for controls), implicating SNX33 in macropinocytosis regulation. Unlike SNX1, SNX5, SNX9, and SNX18, SNX33 did not associate with early-stage macropinosomes.\",\n      \"method\": \"Image-based screening, systematic overexpression, quantitative macropinosome counting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with quantitative phenotypic readout, single lab, no mechanistic follow-up for SNX33 specifically\",\n      \"pmids\": [\"21048941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNX33 forms homodimers but not heterodimers with other BAR domain-containing proteins such as SNX9. The BAR domain (not the SH3 domain) is required for SNX33 homodimerization and prevents heterodimerization with SNX9. Molecular modeling of the SNX33 BAR domain identified key non-conserved amino acids at the dimer interface; replacing these residues in SNX9 with corresponding SNX33 residues enabled SNX9 to heterodimerize with SNX33.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, domain swap experiments, molecular modeling\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — domain deletion and swap experiments with co-IP validation and structural modeling; multiple orthogonal methods establishing molecular determinants\",\n      \"pmids\": [\"20964629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans LST-4, the SNX9-family ortholog of mammalian SNX33, functions at the same genetic step as DYN-1 (dynamin) during apoptotic cell corpse clearance, upstream of RAB-5. Mammalian SNX33 rescued C. elegans lst-4 mutants, and truncated SNX33 fragments interfered with phagosome maturation in mammalian cells, demonstrating evolutionary conservation of function in apoptotic phagosome maturation.\",\n      \"method\": \"C. elegans genetic epistasis (lst-4/dyn-1/rab-5 double mutants), cross-species rescue, truncated domain overexpression in mammalian cells, electron microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo combined with cross-species rescue and mammalian cell domain analysis; strong mechanistic placement upstream of RAB-5\",\n      \"pmids\": [\"21494661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX33 (along with SNX9 and SNX18) is required for progression through and completion of mitosis. siRNA depletion of SNX33 induced multinucleation (cytokinesis failure) and accumulation of cytokinetic cells. Depletion disrupted MRLC(S19) localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge. Endocytosis of transferrin was blocked during cytokinesis upon SNX33 depletion, suggesting an endocytosis-dependent role in cytokinesis.\",\n      \"method\": \"siRNA knockdown, time-lapse microscopy, immunofluorescence (MRLC, Rab11), transferrin endocytosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with time-lapse imaging plus multiple specific molecular markers; replicated across three SNX9-subfamily members with consistent phenotypes\",\n      \"pmids\": [\"22718350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX33 interacts with ADAM15 isoforms via SH3 domain binding to a proline-rich region in the ADAM15 cytoplasmic tail. Robust cellular co-precipitation with SNX33 was observed only for ADAM15 isoforms containing the most carboxyterminal proline cluster (absent in isoforms i1 and i3), demonstrating that alternative splicing of ADAM15 regulates its interaction with SNX33.\",\n      \"method\": \"Co-precipitation from cell lysates, ADAM15 isoform panel analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-precipitation with isoform specificity established; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"19718658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Donepezil treatment upregulates SNX33 expression in primary cortical neurons, leading to increased APP surface expression, elevated sAPPα secretion, and reduced amyloid β levels. SNX33 knockdown by morpholino oligos prevented all effects of donepezil on APP processing, demonstrating that donepezil acts through SNX33 to decrease APP endocytosis and promote non-amyloidogenic α-secretase cleavage.\",\n      \"method\": \"Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA (sAPPα, Aβ), surface biotinylation of APP, Western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — morpholino knockdown with multiple molecular readouts in primary neurons; single lab\",\n      \"pmids\": [\"31417133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNX33 (Snx33) acts as a curvature-sensitive BAR domain protein that inhibits actin polymerization at the advancing edge of migrating cells in regions with inward plasma membrane curvature. Genetic perturbation of Snx33 reduced the cells' capacity to evade obstacles while increasing migration speed and persistence in obstacle-free environments, establishing Snx33 as a mechanosensory regulator of directed cell migration.\",\n      \"method\": \"Genetic perturbation (knockout/knockdown), live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic perturbation with quantitative live-imaging phenotypes; single lab but multiple functional readouts\",\n      \"pmids\": [\"37704612\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX33 is a BAR-PX-SH3 domain-containing sorting nexin that forms homodimers (but not heterodimers with SNX9) via its BAR domain, binds dynamin and WASp through its SH3 domain, and functions as an endocytic regulator that reduces APP and PrP endocytosis to modulate their proteolytic processing; it also acts as a curvature-sensitive inhibitor of actin polymerization at the plasma membrane to regulate cell migration and obstacle evasion, and is required—along with SNX9 and SNX18—for cytokinesis completion through endocytosis-dependent regulation of MRLC localization and Rab11-recycling endosome recruitment.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNX33 is a BAR-PX-SH3 domain sorting nexin that regulates endocytosis, actin dynamics, and membrane trafficking to coordinate cell surface protein processing, cytokinesis, and cell migration. It binds the GTPase dynamin via its SH3 domain to inhibit clathrin-mediated endocytosis, thereby retaining substrates such as APP and PrP at the plasma membrane where they undergo increased alpha-secretase-mediated shedding [PMID:18353773, PMID:18419754, PMID:31417133]. SNX33 homodimerizes through its BAR domain—with dimerization specificity determined by non-conserved interface residues that prevent heterodimerization with SNX9—and interacts with WASp to regulate actin polymerization during cytokinesis and macropinocytosis, while also sensing inward plasma membrane curvature to locally inhibit actin-driven protrusion during cell migration [PMID:20964629, PMID:19487689, PMID:37704612]. Loss of SNX33 causes cytokinesis failure with disrupted MRLC and Rab11-positive recycling endosome localization at the intracellular bridge, and impairs phagosome maturation in a pathway epistatic with dynamin upstream of Rab5 [PMID:22718350, PMID:21494661].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that SNX33 functions as an endocytic regulator: SNX33 was shown to bind dynamin and slow APP endocytosis, thereby increasing cell-surface APP availability for alpha-secretase cleavage—providing the first mechanistic link between an SNX-BAR protein and regulated ectodomain shedding.\",\n      \"evidence\": \"Expression cloning screen, co-immunoprecipitation, endocytosis assay, comparison with dominant-negative dynamin K44A in cell lines\",\n      \"pmids\": [\"18353773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of SH3–dynamin interaction not resolved\", \"Whether SNX33 regulates endocytosis of substrates beyond APP was untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extending the endocytic regulatory function to prion protein: SNX33 overexpression modulated PrPc endocytosis and increased full-length PrP shedding, reducing PrPSc formation, demonstrating that SNX33's dynamin-dependent endocytic regulation generalizes beyond APP.\",\n      \"evidence\": \"Overexpression in neuronal and non-neuronal cell lines, deletion mutant analysis, PrPSc formation assay\",\n      \"pmids\": [\"18419754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous SNX33 loss-of-function effect on PrP not tested\", \"Mechanism of PrP shedding increase not distinguished from general endocytic slowing\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking SNX33 to actin regulation and cytokinesis via WASp: SNX33 was shown to homodimerize, interact with the WASp VCA domain, and induce actin accumulation and cytokinesis failure upon overexpression—phenotypes rescued by WASp knockdown—establishing a second effector axis independent of dynamin.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown of WASp, time-lapse microscopy, cell cycle analysis\",\n      \"pmids\": [\"19487689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of SNX33-WASp interaction not resolved\", \"Whether the cytokinesis phenotype requires the PX or BAR domain specifically was not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying isoform-specific physical interaction with ADAM15: SNX33 SH3 domain binds specific ADAM15 splice variants containing C-terminal proline-rich motifs, expanding the repertoire of SNX33 SH3 domain partners beyond dynamin.\",\n      \"evidence\": \"Phage-display SH3 proteome screen and co-precipitation from cell lysates\",\n      \"pmids\": [\"19718658\", \"16374509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SNX33–ADAM15 interaction not determined\", \"Whether SNX33 regulates ADAM15 trafficking or activity is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Implicating SNX33 in macropinocytosis: Overexpression of SNX33 significantly increased macropinosome formation, connecting its membrane-remodeling properties to fluid-phase uptake.\",\n      \"evidence\": \"Systematic overexpression with image-based quantitative screening of macropinosome numbers\",\n      \"pmids\": [\"21048941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss-of-function effect on macropinocytosis not tested\", \"Mechanism linking SNX33 to macropinosome closure or scission not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining BAR domain homodimerization specificity: Specific non-conserved residues at the BAR domain dimer interface were shown to prevent SNX33–SNX9 heterodimerization; swapping these residues enabled heterodimerization, resolving how paralog specificity is encoded.\",\n      \"evidence\": \"Co-immunoprecipitation, domain deletion, domain swap mutagenesis, molecular modeling\",\n      \"pmids\": [\"20964629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the SNX33 BAR domain not determined\", \"Whether homodimerization versus heterodimerization has distinct functional outputs in vivo unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing a conserved role in phagocytosis: Cross-species rescue showed mammalian SNX33 substitutes for C. elegans LST-4 in phagosome maturation, placing SNX33 at the same epistatic step as dynamin upstream of Rab5 during apoptotic corpse clearance.\",\n      \"evidence\": \"C. elegans genetic epistasis, electron microscopy, cross-species rescue, dominant-negative truncation in mammalian cells\",\n      \"pmids\": [\"21494661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian SNX33 is required for phagosome maturation in mammalian macrophages not directly tested\", \"Mechanism of action at the phagosome—membrane scission versus coat recruitment—unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating a required role in mitotic cytokinesis: SNX33 depletion caused cytokinesis failure with disrupted MRLC localization and impaired Rab11-positive recycling endosome delivery to the intracellular bridge, linking endocytic trafficking to abscission.\",\n      \"evidence\": \"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin endocytosis assay\",\n      \"pmids\": [\"22718350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of SNX33 versus SNX9 and SNX18 during cytokinesis not separated\", \"Whether SNX33 is directly recruited to the midbody not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validating SNX33 as a pharmacologically inducible modifier of APP processing: Donepezil was shown to upregulate SNX33, and morpholino-mediated SNX33 knockdown blocked donepezil's ability to increase surface APP and sAPPα, confirming SNX33 as a necessary effector in neurons.\",\n      \"evidence\": \"Morpholino knockdown in primary cortical neurons, Western blot, sAPPα/Aβ ELISA\",\n      \"pmids\": [\"31417133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether donepezil acts transcriptionally or post-transcriptionally on SNX33 not resolved\", \"In vivo relevance in animal models of Alzheimer's disease not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing a curvature-sensing function: SNX33 BAR domain senses inward plasma membrane curvature at the cell leading edge and locally inhibits actin polymerization, with loss of SNX33 reducing obstacle evasion and increasing migration speed and persistence.\",\n      \"evidence\": \"Genetic knockout/knockdown, live-cell imaging, actin dynamics measurement, curvature analysis in immune-like cells\",\n      \"pmids\": [\"37704612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediates between curvature sensing and actin inhibition not identified\", \"Whether this curvature-sensing role operates in non-immune cell types unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of SNX33 BAR domain curvature sensing, the mechanism by which SNX33 coordinates its three effector axes (dynamin-mediated endocytic inhibition, WASp-mediated actin regulation, and curvature-dependent actin suppression), and whether SNX33 has non-redundant functions versus SNX9/SNX18 in specific tissues remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of SNX33\", \"Tissue-specific or conditional knockout phenotype in mammals not reported\", \"Mechanistic integration of the dynamin, WASp, and curvature-sensing pathways not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DNM1\", \"DNM2\", \"WASP\", \"SNX9\", \"ADAM15\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SNX33 is a BAR-PX-SH3 domain-containing sorting nexin that regulates endocytosis, actin dynamics, and membrane trafficking to control substrate availability at the plasma membrane, cell division, and directed cell migration. Through its SH3 domain, SNX33 binds dynamin and WASp, reducing the endocytic rate of transmembrane substrates such as APP and PrP and thereby promoting their alpha-secretase-mediated shedding at the cell surface [PMID:18353773, PMID:18419754]. SNX33 homodimerizes via its BAR domain—but does not heterodimerize with SNX9—and is required, together with SNX9 and SNX18, for cytokinesis completion through endocytosis-dependent recruitment of Rab11-positive recycling endosomes and proper MRLC localization at the intracellular bridge [PMID:20964629, PMID:22718350]. SNX33 also functions as a curvature-sensitive inhibitor of actin polymerization at the leading edge of migrating cells, enabling obstacle evasion during directed migration [PMID:37704612].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of SNX33 as an endocytic regulator that modulates alpha-secretase processing of APP by binding dynamin and slowing APP internalization established its core mechanism: controlling substrate residence time at the plasma membrane.\",\n      \"evidence\": \"Expression cloning screen, co-IP of SNX33–dynamin, endocytosis rate assays, and dominant-negative dynamin comparison in mammalian cell lines\",\n      \"pmids\": [\"18353773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding stoichiometry and affinity between SNX33 SH3 domain and dynamin not measured\",\n        \"Whether SNX33 affects APP processing in neurons in vivo not addressed\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extension of the endocytic-regulation paradigm to prion protein showed SNX33's effect is not APP-specific: overexpression increased PrP shedding and reduced PrPSc formation, broadening SNX33's substrate scope.\",\n      \"evidence\": \"Overexpression in neuronal and non-neuronal cell lines, deletion mutant analysis, PrPSc formation assay\",\n      \"pmids\": [\"18419754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only overexpression tested; loss-of-function data for PrP processing absent\",\n        \"Whether SNX33 directly binds PrP or acts solely via dynamin not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that SNX33 binds WASp and that WASp knockdown rescues SNX33-induced cytokinesis failure placed SNX33 upstream of WASp-dependent actin polymerization, revealing a second effector axis beyond dynamin.\",\n      \"evidence\": \"Co-IP of SNX33–WASp VCA domain, siRNA epistasis, time-lapse microscopy, flow cytometry\",\n      \"pmids\": [\"19487689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro reconstitution of SNX33–WASp interaction not performed\",\n        \"Relative contributions of WASp and dynamin to SNX33-dependent phenotypes not dissected\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structural analysis of the BAR domain demonstrated that SNX33 homodimerizes but cannot heterodimerize with SNX9, with non-conserved residues at the dimer interface dictating specificity—explaining functional non-redundancy within the SNX9 subfamily.\",\n      \"evidence\": \"Co-IP, domain deletion and swap mutagenesis, molecular modeling of BAR domain interface\",\n      \"pmids\": [\"20964629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure of the SNX33 BAR domain not solved\",\n        \"Whether homodimerization is required for each of SNX33's distinct functions not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cross-species rescue of C. elegans lst-4 mutants by mammalian SNX33 and genetic epistasis placing lst-4/SNX33 at the same step as dynamin upstream of RAB-5 demonstrated evolutionarily conserved function in phagosome maturation during apoptotic cell clearance.\",\n      \"evidence\": \"C. elegans double-mutant epistasis, cross-species rescue, truncated domain expression in mammalian cells, EM\",\n      \"pmids\": [\"21494661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mammalian SNX33 participates in apoptotic cell clearance in vivo in vertebrates not shown\",\n        \"Mechanism by which SNX33 promotes RAB-5 recruitment not defined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Depletion of SNX33 (and SNX9/SNX18) caused cytokinesis failure with disrupted MRLC localization and Rab11-recycling-endosome recruitment to the intracellular bridge, establishing that SNX9-family-dependent endocytosis is required for abscission.\",\n      \"evidence\": \"siRNA knockdown, time-lapse imaging, immunofluorescence for MRLC and Rab11, transferrin endocytosis assay during cytokinesis\",\n      \"pmids\": [\"22718350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contribution of SNX33 versus SNX9/SNX18 to cytokinesis not fully resolved\",\n        \"Whether the endocytic cargo critical for abscission has been identified\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of ADAM15 as an SH3-domain-dependent interaction partner revealed that alternative splicing of a substrate's cytoplasmic tail gates its interaction with SNX33, adding a selectivity mechanism for SNX33-regulated trafficking.\",\n      \"evidence\": \"Co-precipitation with ADAM15 isoform panel from cell lysates\",\n      \"pmids\": [\"19718658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of SNX33–ADAM15 interaction on ADAM15 trafficking or shedding not tested\",\n        \"No in vitro reconstitution of direct binding\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that donepezil promotes non-amyloidogenic APP processing through SNX33 upregulation in primary cortical neurons provided a pharmacological validation of the SNX33–endocytosis–alpha-secretase axis in a disease-relevant system.\",\n      \"evidence\": \"Primary cortical neuron culture, morpholino knockdown of SNX33, ELISA for sAPPα and Aβ, surface biotinylation\",\n      \"pmids\": [\"31417133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo validation in animal models not provided\",\n        \"Mechanism by which donepezil upregulates SNX33 expression unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of SNX33 as a curvature-sensitive inhibitor of actin polymerization at the leading edge reframed the protein as a mechanosensory regulator: SNX33 loss increased migration speed but impaired obstacle evasion, linking membrane curvature sensing to steering decisions.\",\n      \"evidence\": \"Genetic knockout/knockdown, live-cell imaging, obstacle evasion assays, plasma membrane curvature analysis\",\n      \"pmids\": [\"37704612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct measurement of SNX33 BAR domain curvature preference not reported\",\n        \"Whether SNX33-mediated actin inhibition acts through WASp or a distinct effector not resolved\",\n        \"In vivo migration phenotype not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which SNX33 integrates its dual roles—dynamin-dependent endocytic regulation and curvature-dependent actin inhibition—in the same cell, and whether these represent a unified membrane-remodeling activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data for SNX33 BAR or full-length protein\",\n        \"Relative importance of homodimerization for endocytic versus actin-regulatory functions untested\",\n        \"No unbiased interactome or proximity-labeling study reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DNM1\",\n      \"DNM2\",\n      \"WASL\",\n      \"ADAM15\",\n      \"SNX9\",\n      \"RAB11A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}