{"gene":"SNX6","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2001,"finding":"SNX6 was identified as a novel sorting nexin that interacts with members of the TGF-β family of receptor serine-threonine kinases (ActRIIB, TβRII, inactivated TβRI), as well as receptor tyrosine kinases, and forms strong heteromeric complexes with SNX1, SNX2, and SNX4, suggesting formation of oligomeric SNX complexes in vivo.","method":"Yeast two-hybrid screen and co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and Y2H; original discovery paper with multiple receptor interactions tested","pmids":["11279102"],"is_preprint":false},{"year":2001,"finding":"SNX6, along with SNX1, SNX2, SNX4, and SNX5, localizes to early endosomes (overlapping with EEA1) in HeLa cells, consistent with a role in endosomal sorting.","method":"Confocal microscopy with GFP-fusion proteins and endosome marker colocalization","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment, single study","pmids":["11485546"],"is_preprint":false},{"year":2006,"finding":"RNAi knockdown screen identified SNX5 and SNX6 as required for retromer-mediated endosome-to-TGN retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); SNX6 co-immunoprecipitates with SNX1, forming a stable endosomally associated complex. Suppression of SNX5 and/or SNX6 caused significant post-translational loss of SNX1 protein levels.","method":"RNAi loss-of-function screen, immunoprecipitation, colocalization with SNX1 on early endosomes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional screen with Co-IP and phenotypic readout; highly cited foundational paper","pmids":["17148574"],"is_preprint":false},{"year":2009,"finding":"SNX6 interacts directly with the p150(Glued) subunit of the dynein/dynactin motor complex, and this interaction is required for recruitment of the motor complex to the membrane-associated retromer, formation and detachment of tubulovesicular sorting structures from endosomes, and CI-MPR retrieval from endosomes to the TGN. Disruption of the SNX6–p150(Glued) interaction blocks retrograde transport.","method":"Co-immunoprecipitation, dominant-negative disruption experiments, CI-MPR trafficking assay","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional rescue/disruption with specific phenotypic readout; replicated in parallel by Wassmer et al. 2009","pmids":["19935774"],"is_preprint":false},{"year":2009,"finding":"Four distinct mammalian retromer complexes exist whose membrane-bound subcomplexes contain specific combinations of SNX1, SNX2, SNX5, and SNX6; SNX5/SNX6 associate with p150(Glued) of dynactin to regulate the spatial organization of the endosomal network and dynein-mediated transport, validated by genetic studies in C. elegans.","method":"Biochemical fractionation, Co-IP, C. elegans genetic epistasis, live cell imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic validation in C. elegans; highly cited study","pmids":["19619496"],"is_preprint":false},{"year":2011,"finding":"The N-terminal region of BRMS1 (residues 51–98), which mediates interaction with SNX6, forms an antiparallel coiled-coil that homo-oligomerizes into a hexameric (trimer of dimers) conformation, as determined by X-ray crystallography and hydrodynamic experiments.","method":"X-ray crystallography, analytical ultracentrifugation/hydrodynamic analysis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure, but characterizes BRMS1 domain rather than SNX6 itself; SNX6 interaction region is contextually relevant but SNX6 structure not directly solved","pmids":["21777593"],"is_preprint":false},{"year":2015,"finding":"The Chlamydia trachomatis inclusion membrane protein IncE binds directly to SNX5/6 (retromer components), relocalizing them to the inclusion membrane and augmenting inclusion membrane tubulation; depletion of retromer components (including SNX6) enhances bacterial progeny production, demonstrating that the SNX5/6-containing retromer restricts Chlamydia infection.","method":"AP-MS, co-immunoprecipitation, fluorescence microscopy, RNAi knockdown with bacterial progeny assay","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — AP-MS plus Co-IP plus functional knockdown with quantitative phenotypic readout","pmids":["26118995"],"is_preprint":false},{"year":2016,"finding":"miR-98-5p negatively regulates SNX6 expression by targeting its 3′-UTR; downregulation of miR-98-5p upregulates SNX6 and decreases SNX6-dependent levels of Aβ40, Aβ42, BACE1, sAPPβ, and βCTF in neuronal cells, indicating SNX6 participates in amyloid precursor protein processing.","method":"3′-UTR luciferase reporter assay, miRNA overexpression/inhibition, Western blot for APP processing products","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — reporter + knockdown/overexpression; single study with cellular APP processing readout","pmids":["27541017"],"is_preprint":false},{"year":2017,"finding":"CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory and loss of dendritic spines from distal dendrites of hippocampal CA1 pyramidal neurons. SNX6 interacts with the postsynaptic scaffold Homer1b/c and regulates its distribution in the dendritic shaft independently of retromer function. Loss of SNX6 reduces surface AMPAR levels and impairs AMPAR-mediated synaptic transmission.","method":"Conditional knockout mice, electrophysiology, co-immunoprecipitation, confocal imaging, behavioral tests (Morris water maze)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple orthogonal readouts (behavioral, electrophysiological, biochemical, imaging)","pmids":["28134614"],"is_preprint":false},{"year":2018,"finding":"SNX1 and SNX6 form a 1:1 heterodimer in solution (from both worm and human proteins), requiring co-expression of both subunits and glycerol in buffer for stability; this biochemical reconstitution provides the basis for structural and in vitro transport studies of the ESCPE-1 complex.","method":"Recombinant co-expression and purification, size-exclusion chromatography, solution biochemistry","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro reconstitution of heterodimer; single study, no structural validation yet","pmids":["29908913"],"is_preprint":false},{"year":2019,"finding":"Rab32 directly interacts with SNX6, and both Rab32 and SNX6 affect the localization of CI-MPR (recycled by retromer to the TGN), linking Rab32 to SNX6/retromer-dependent Golgi trafficking.","method":"Co-immunoprecipitation, fluorescence microscopy, CI-MPR localization assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus localization assay; single study","pmids":["30640902"],"is_preprint":false},{"year":2024,"finding":"ESCPE-1 (SNX2/SNX6 heterodimer) deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted system using purified mammalian proteins, but does not recruit Retromer on its own; VARP is required to reconstitute the proposed endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes.","method":"In vitro membrane tubulation reconstitution with purified proteins, AlphaFold2 Multimer modeling, biochemical binding assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.07.11.603126"],"is_preprint":true},{"year":2025,"finding":"SNX6 selectively mediates sorting of newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to assembly with GluA1; loss of SNX6 diverts GluA2 to lysosomal degradation, reducing constitutive and activity-dependent surface AMPAR expression, impairing AMPAR-mediated synaptic transmission, NMDAR-dependent LTP, and causing learning and memory deficits.","method":"Conditional knockout mice, hippocampal neuron cultures, pulse-chase trafficking assays, electrophysiology, Western blot, confocal imaging","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple orthogonal methods (trafficking, electrophysiology, behavior); novel secretory pathway mechanism","pmids":["41429886"],"is_preprint":false}],"current_model":"SNX6 is a PX-BAR sorting nexin that functions as a component of the ESCPE-1 (SNX1/SNX6 or SNX2/SNX6) membrane-deforming subcomplex of the retromer, mediating endosome-to-TGN retrograde transport of CI-MPR by recruiting the dynein/dynactin motor via direct interaction with p150(Glued); in neurons, SNX6 additionally acts independently of retromer to regulate Homer1b/c distribution in dendrites and to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway, thereby controlling surface AMPAR levels, synaptic transmission, LTP, and spatial memory."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of SNX6 as a sorting nexin that forms heteromeric complexes with SNX1/SNX2 and localizes to early endosomes established the molecular context for its subsequent role in endosomal sorting.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and GFP-confocal colocalization with EEA1 in HeLa cells","pmids":["11279102","11485546"],"confidence":"Medium","gaps":["No cargo or trafficking phenotype identified at this stage","Receptor interactions (TGF-β family) not functionally validated in a trafficking assay","Stoichiometry and domain contributions to SNX heteromeric complexes undefined"]},{"year":2006,"claim":"An RNAi screen demonstrated that SNX6 (together with SNX5) is required for retromer-mediated endosome-to-TGN retrieval of CI-MPR, establishing SNX6 as a functional retromer subunit and showing that SNX6 depletion destabilizes SNX1 protein levels.","evidence":"RNAi loss-of-function screen with CI-MPR redistribution readout; co-immunoprecipitation of SNX6–SNX1","pmids":["17148574"],"confidence":"High","gaps":["Motor coupling mechanism for retromer-associated tubule transport unknown","Relative contributions of SNX5 versus SNX6 not resolved"]},{"year":2009,"claim":"Two independent studies revealed that SNX6 directly binds p150(Glued) of dynein/dynactin, linking the ESCPE-1/retromer membrane tubule to microtubule-based transport and explaining how endosomal tubulovesicular carriers detach and traffic toward the TGN.","evidence":"Reciprocal co-immunoprecipitation, dominant-negative disruption, live cell imaging, C. elegans genetic epistasis","pmids":["19935774","19619496"],"confidence":"High","gaps":["Structural basis of the SNX6–p150(Glued) interface unresolved","Whether SNX5 and SNX6 have distinct or redundant dynactin-binding roles unclear"]},{"year":2015,"claim":"The discovery that Chlamydia trachomatis IncE hijacks SNX5/SNX6 to the bacterial inclusion membrane demonstrated a host-defense role for the SNX6-containing retromer, as its depletion enhanced bacterial replication.","evidence":"AP-MS, co-immunoprecipitation, RNAi knockdown with bacterial progeny quantification","pmids":["26118995"],"confidence":"High","gaps":["Whether pathogen subversion reflects a broader innate immune role for SNX6/retromer is untested","Structural basis of IncE–SNX6 interaction not determined in this study"]},{"year":2017,"claim":"CNS-specific Snx6 knockout revealed a retromer-independent neuronal function: SNX6 interacts with Homer1b/c to regulate its dendritic distribution and is required for normal dendritic spine density, surface AMPAR levels, synaptic transmission, and spatial memory.","evidence":"Conditional knockout mice with electrophysiology, Morris water maze, co-immunoprecipitation, confocal imaging","pmids":["28134614"],"confidence":"High","gaps":["Mechanism by which SNX6 regulates Homer1b/c trafficking independently of retromer not defined","Whether AMPAR reduction is a direct or indirect consequence of Homer1b/c mislocalization unclear"]},{"year":2025,"claim":"SNX6 was shown to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to GluA1 assembly, resolving the molecular basis for AMPAR reduction: without SNX6, GluA2 is diverted to lysosomes, impairing constitutive and activity-dependent surface AMPAR expression, LTP, and memory.","evidence":"Conditional knockout mice, pulse-chase trafficking assays in hippocampal neurons, electrophysiology, behavioral tests","pmids":["41429886"],"confidence":"High","gaps":["Cargo recognition mechanism by which SNX6 selects GluA2 for post-Golgi sorting is undefined","Whether SNX6 cooperates with other sorting factors at the TGN for GluA2 export is unknown","Relevance to neurodegenerative or neurodevelopmental disease in humans not established"]},{"year":null,"claim":"A high-resolution structure of the full SNX1/SNX6 or SNX2/SNX6 heterodimer on membranes, the structural basis of the SNX6–p150(Glued) and SNX6–GluA2 interactions, and the mechanism by which VARP bridges ESCPE-1 to SNX27–Retromer remain to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the full SNX6-containing ESCPE-1 complex","Cargo recognition motifs on GluA2 for SNX6-mediated TGN export unidentified","In vivo reconstitution of the SNX27–ESCPE-1–Retromer supercomplex awaits peer-reviewed validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,11]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,10,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,4,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,12]}],"complexes":["ESCPE-1 (SNX1/SNX6 or SNX2/SNX6 heterodimer)","Retromer-associated complex"],"partners":["SNX1","SNX2","SNX5","DCTN1","HOMER1","GRIA2","RAB32","VPS35"],"other_free_text":[]},"mechanistic_narrative":"SNX6 is a PX-BAR domain sorting nexin that functions as a core subunit of the ESCPE-1 membrane-deforming complex (heterodimerizing with SNX1 or SNX2) within the retromer pathway, mediating endosome-to-TGN retrograde retrieval of cation-independent mannose-6-phosphate receptor (CI-MPR) [PMID:17148574, PMID:29908913]. SNX6 recruits the dynein/dynactin motor complex to retromer-associated endosomal tubules through direct interaction with p150(Glued), coupling cargo sorting to microtubule-based transport required for tubulovesicular carrier formation and detachment [PMID:19935774, PMID:19619496]. In hippocampal neurons, SNX6 operates independently of canonical retromer to regulate postsynaptic Homer1b/c distribution in dendrites and to sort newly synthesized GluA2 AMPA receptor subunits into the post-Golgi secretory pathway; loss of neuronal SNX6 diverts GluA2 to lysosomal degradation, reduces surface AMPAR levels, impairs LTP, and causes spatial learning and memory deficits [PMID:28134614, PMID:41429886]."},"prefetch_data":{"uniprot":{"accession":"Q9UNH7","full_name":"Sorting nexin-6","aliases":["TRAF4-associated factor 2"],"length_aa":406,"mass_kda":46.6,"function":"Involved in several stages of intracellular trafficking. Interacts with membranes phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 4,5-bisphosphate (Probable). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex (PubMed:19935774). The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Does not have in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptor IGF2R (PubMed:17148574). May function as link between transport vesicles and dynactin (Probable). Negatively regulates retrograde transport of BACE1 from the cell surface to the trans-Golgi network (PubMed:20354142). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation (PubMed:24610942). In association with GIT1 involved in EGFR degradation. Promotes lysosomal degradation of CDKN1B (By similarity). May contribute to transcription regulation (Probable)","subcellular_location":"Early endosome; Early endosome membrane; Cytoplasmic vesicle; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UNH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX6","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNX1","stoichiometry":10.0},{"gene":"SNX2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/SNX6","total_profiled":1310},"omim":[{"mim_id":"621073","title":"SORTING NEXIN 32; SNX32","url":"https://www.omim.org/entry/621073"},{"mim_id":"606098","title":"SORTING NEXIN 6; SNX6","url":"https://www.omim.org/entry/606098"},{"mim_id":"605937","title":"SORTING NEXIN 5; SNX5","url":"https://www.omim.org/entry/605937"},{"mim_id":"605929","title":"SORTING NEXIN 2; SNX2","url":"https://www.omim.org/entry/605929"},{"mim_id":"601272","title":"SORTING NEXIN 1; SNX1","url":"https://www.omim.org/entry/601272"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endosomes","reliability":"Supported"},{"location":"Lysosomes","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UNH7","domains":[{"cath_id":"3.30.1520.10","chopping":"24-171","consensus_level":"medium","plddt":91.2707,"start":24,"end":171},{"cath_id":"1.20.1270.60","chopping":"220-406","consensus_level":"medium","plddt":94.8791,"start":220,"end":406}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNH7-F1-predicted_aligned_error_v6.png","plddt_mean":88.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX6","jax_strain_url":"https://www.jax.org/strain/search?query=SNX6"},"sequence":{"accession":"Q9UNH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UNH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UNH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNH7"}},"corpus_meta":[{"pmid":"17148574","id":"PMC_17148574","title":"A 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standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":18259,"output_tokens":3080,"usd":0.050488},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6709,"output_tokens":2271,"usd":0.13548}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"SNX6 forms a stable complex with SNX1 on early endosomes and is required for retromer-mediated endosome-to-TGN retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); RNAi suppression of SNX6 caused loss of SNX1 protein via post-translational regulation and phenocopied suppression of core retromer components.\",\n      \"method\": \"RNAi loss-of-function screen, immunoprecipitation, co-localization on early endosomes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional RNAi phenotype, >200 citations, independently built upon by subsequent work\",\n      \"pmids\": [\"17148574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX6 directly interacts with the p150(Glued) subunit of the dynein/dynactin motor complex, and this interaction is required for recruitment of the motor to the membrane-associated retromer, formation and detachment of tubulovesicular sorting structures from endosomes, and CI-MPR retrieval to the TGN.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative disruption of SNX6–p150(Glued) interaction, live-cell imaging of tubular intermediate formation\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional disruption assay with defined phenotypic readout, >100 citations\",\n      \"pmids\": [\"19935774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX6 interacts with the postsynaptic scaffold protein Homer1b/c and regulates its distribution along dendritic shafts of hippocampal CA1 pyramidal neurons independently of the retromer; loss of SNX6 in CNS-specific knockout mice reduced Homer1b/c in distal dendrites, decreased surface AMPAR levels, impaired AMPAR-mediated synaptic transmission, and caused loss of distal dendritic spines and spatial memory deficits.\",\n      \"method\": \"CNS-specific conditional knockout mouse, co-immunoprecipitation (SNX6–Homer1b/c), spine morphology analysis, electrophysiology (AMPAR-mediated synaptic transmission), spatial memory assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal readouts (Co-IP, electrophysiology, behavior, morphology) in a single rigorous study\",\n      \"pmids\": [\"28134614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab32 directly interacts with SNX6, and both Rab32 and SNX6 affect the localization of CI-MPR, linking Rab32 to SNX6/retromer-dependent Golgi trafficking.\",\n      \"method\": \"Co-immunoprecipitation (Rab32–SNX6 pulldown), CI-MPR localization assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus CI-MPR localization, single lab, moderate follow-up\",\n      \"pmids\": [\"30640902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX1 and SNX6 form a 1:1 heterodimer (ESCPE-1 subcomplex); solution studies of purified recombinant human and C. elegans SNX1/SNX6 complex confirmed heterodimer stoichiometry and provided a basis for biochemical reconstitution of SNX1/SNX6-mediated transport.\",\n      \"method\": \"Co-expression and co-purification, solution biophysical characterization (size-exclusion chromatography)\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstitution of purified complex with stoichiometry determination, single study\",\n      \"pmids\": [\"29908913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SNX6 mediates retromer-dependent processing of APP; downregulation of SNX6 (via miR-98-5p overexpression) increased levels of Aβ40, Aβ42, BACE1, sAPPβ, and βCTF, while restoring SNX6 expression reversed these effects, placing SNX6 in the pathway controlling amyloidogenic APP processing.\",\n      \"method\": \"miRNA overexpression/knockdown in SK-N-SH, SH-SY5Y, and HEK293 cells; ELISA for Aβ; Western blot for BACE1/APP fragments\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional KD/OE with defined molecular readouts, single lab\",\n      \"pmids\": [\"27541017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The ESCPE-1 complex (SNX2/SNX6) deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted in vitro system using purified mammalian proteins, but does not by itself recruit the Retromer heterotrimer; formation of an endosomal supercomplex containing SNX27, ESCPE-1, and Retromer requires VARP.\",\n      \"method\": \"In vitro membrane tubulation reconstitution with purified proteins, liposome-based assays, AlphaFold2 Multimer modeling, biochemical binding assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified components, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.11.603126\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX6 selectively mediates sorting of newly synthesized GluA2 (AMPAR subunit) into the post-Golgi secretory pathway before its assembly with GluA1; loss of SNX6 diverts GluA2 to lysosomal degradation, reducing constitutive and activity-dependent surface AMPAR expression, impairing AMPAR-mediated synaptic transmission and NMDAR-dependent LTP, and causing learning and memory deficits.\",\n      \"method\": \"Hippocampal neuron culture, conditional knockout mice, surface biotinylation, pulse-chase trafficking assays, electrophysiology (AMPAR synaptic transmission, LTP), behavioral assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (trafficking assays, electrophysiology, in vivo KO, behavior) in a single rigorous peer-reviewed study\",\n      \"pmids\": [\"41429886\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX6 is a PX-BAR sorting nexin that functions as a subunit of the ESCPE-1 (SNX1/SNX6 or SNX2/SNX6) heterodimer on endosomal membranes, where it drives retromer-mediated endosome-to-TGN retrograde transport of CI-MPR by recruiting the dynein/dynactin motor complex via direct interaction with p150(Glued); in neurons, SNX6 additionally acts independently of retromer to regulate Homer1b/c distribution in dendritic shafts and to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway, thereby controlling surface AMPAR levels, synaptic transmission, LTP, and memory.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SNX6 was identified as a novel sorting nexin that interacts with members of the TGF-β family of receptor serine-threonine kinases (ActRIIB, TβRII, inactivated TβRI), as well as receptor tyrosine kinases, and forms strong heteromeric complexes with SNX1, SNX2, and SNX4, suggesting formation of oligomeric SNX complexes in vivo.\",\n      \"method\": \"Yeast two-hybrid screen and co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and Y2H; original discovery paper with multiple receptor interactions tested\",\n      \"pmids\": [\"11279102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SNX6, along with SNX1, SNX2, SNX4, and SNX5, localizes to early endosomes (overlapping with EEA1) in HeLa cells, consistent with a role in endosomal sorting.\",\n      \"method\": \"Confocal microscopy with GFP-fusion proteins and endosome marker colocalization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment, single study\",\n      \"pmids\": [\"11485546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNAi knockdown screen identified SNX5 and SNX6 as required for retromer-mediated endosome-to-TGN retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); SNX6 co-immunoprecipitates with SNX1, forming a stable endosomally associated complex. Suppression of SNX5 and/or SNX6 caused significant post-translational loss of SNX1 protein levels.\",\n      \"method\": \"RNAi loss-of-function screen, immunoprecipitation, colocalization with SNX1 on early endosomes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional screen with Co-IP and phenotypic readout; highly cited foundational paper\",\n      \"pmids\": [\"17148574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SNX6 interacts directly with the p150(Glued) subunit of the dynein/dynactin motor complex, and this interaction is required for recruitment of the motor complex to the membrane-associated retromer, formation and detachment of tubulovesicular sorting structures from endosomes, and CI-MPR retrieval from endosomes to the TGN. Disruption of the SNX6–p150(Glued) interaction blocks retrograde transport.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative disruption experiments, CI-MPR trafficking assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional rescue/disruption with specific phenotypic readout; replicated in parallel by Wassmer et al. 2009\",\n      \"pmids\": [\"19935774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Four distinct mammalian retromer complexes exist whose membrane-bound subcomplexes contain specific combinations of SNX1, SNX2, SNX5, and SNX6; SNX5/SNX6 associate with p150(Glued) of dynactin to regulate the spatial organization of the endosomal network and dynein-mediated transport, validated by genetic studies in C. elegans.\",\n      \"method\": \"Biochemical fractionation, Co-IP, C. elegans genetic epistasis, live cell imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic validation in C. elegans; highly cited study\",\n      \"pmids\": [\"19619496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The N-terminal region of BRMS1 (residues 51–98), which mediates interaction with SNX6, forms an antiparallel coiled-coil that homo-oligomerizes into a hexameric (trimer of dimers) conformation, as determined by X-ray crystallography and hydrodynamic experiments.\",\n      \"method\": \"X-ray crystallography, analytical ultracentrifugation/hydrodynamic analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, but characterizes BRMS1 domain rather than SNX6 itself; SNX6 interaction region is contextually relevant but SNX6 structure not directly solved\",\n      \"pmids\": [\"21777593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Chlamydia trachomatis inclusion membrane protein IncE binds directly to SNX5/6 (retromer components), relocalizing them to the inclusion membrane and augmenting inclusion membrane tubulation; depletion of retromer components (including SNX6) enhances bacterial progeny production, demonstrating that the SNX5/6-containing retromer restricts Chlamydia infection.\",\n      \"method\": \"AP-MS, co-immunoprecipitation, fluorescence microscopy, RNAi knockdown with bacterial progeny assay\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS plus Co-IP plus functional knockdown with quantitative phenotypic readout\",\n      \"pmids\": [\"26118995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-98-5p negatively regulates SNX6 expression by targeting its 3′-UTR; downregulation of miR-98-5p upregulates SNX6 and decreases SNX6-dependent levels of Aβ40, Aβ42, BACE1, sAPPβ, and βCTF in neuronal cells, indicating SNX6 participates in amyloid precursor protein processing.\",\n      \"method\": \"3′-UTR luciferase reporter assay, miRNA overexpression/inhibition, Western blot for APP processing products\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter + knockdown/overexpression; single study with cellular APP processing readout\",\n      \"pmids\": [\"27541017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory and loss of dendritic spines from distal dendrites of hippocampal CA1 pyramidal neurons. SNX6 interacts with the postsynaptic scaffold Homer1b/c and regulates its distribution in the dendritic shaft independently of retromer function. Loss of SNX6 reduces surface AMPAR levels and impairs AMPAR-mediated synaptic transmission.\",\n      \"method\": \"Conditional knockout mice, electrophysiology, co-immunoprecipitation, confocal imaging, behavioral tests (Morris water maze)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal readouts (behavioral, electrophysiological, biochemical, imaging)\",\n      \"pmids\": [\"28134614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX1 and SNX6 form a 1:1 heterodimer in solution (from both worm and human proteins), requiring co-expression of both subunits and glycerol in buffer for stability; this biochemical reconstitution provides the basis for structural and in vitro transport studies of the ESCPE-1 complex.\",\n      \"method\": \"Recombinant co-expression and purification, size-exclusion chromatography, solution biochemistry\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro reconstitution of heterodimer; single study, no structural validation yet\",\n      \"pmids\": [\"29908913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab32 directly interacts with SNX6, and both Rab32 and SNX6 affect the localization of CI-MPR (recycled by retromer to the TGN), linking Rab32 to SNX6/retromer-dependent Golgi trafficking.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, CI-MPR localization assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus localization assay; single study\",\n      \"pmids\": [\"30640902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESCPE-1 (SNX2/SNX6 heterodimer) deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted system using purified mammalian proteins, but does not recruit Retromer on its own; VARP is required to reconstitute the proposed endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes.\",\n      \"method\": \"In vitro membrane tubulation reconstitution with purified proteins, AlphaFold2 Multimer modeling, biochemical binding assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.11.603126\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX6 selectively mediates sorting of newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to assembly with GluA1; loss of SNX6 diverts GluA2 to lysosomal degradation, reducing constitutive and activity-dependent surface AMPAR expression, impairing AMPAR-mediated synaptic transmission, NMDAR-dependent LTP, and causing learning and memory deficits.\",\n      \"method\": \"Conditional knockout mice, hippocampal neuron cultures, pulse-chase trafficking assays, electrophysiology, Western blot, confocal imaging\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal methods (trafficking, electrophysiology, behavior); novel secretory pathway mechanism\",\n      \"pmids\": [\"41429886\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX6 is a PX-BAR sorting nexin that functions as a component of the ESCPE-1 (SNX1/SNX6 or SNX2/SNX6) membrane-deforming subcomplex of the retromer, mediating endosome-to-TGN retrograde transport of CI-MPR by recruiting the dynein/dynactin motor via direct interaction with p150(Glued); in neurons, SNX6 additionally acts independently of retromer to regulate Homer1b/c distribution in dendrites and to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway, thereby controlling surface AMPAR levels, synaptic transmission, LTP, and spatial memory.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNX6 is a PX-BAR sorting nexin that functions as an obligate heterodimeric partner of SNX1 (or SNX2) within the ESCPE-1 complex on endosomal membranes, where it drives retrograde retrieval of cargo such as CI-MPR to the TGN by recruiting the dynein/dynactin motor via direct interaction with p150(Glued) [PMID:17148574, PMID:19935774, PMID:29908913]. Beyond its canonical retromer-associated role, SNX6 operates in neurons to regulate postsynaptic scaffold protein Homer1b/c distribution along dendritic shafts independently of retromer, and to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway; loss of SNX6 diverts GluA2 to lysosomal degradation, reducing surface AMPAR levels, impairing synaptic transmission and LTP, and causing spatial memory deficits [PMID:28134614, PMID:41429886]. SNX6 downregulation also enhances amyloidogenic processing of APP by increasing BACE1 and Aβ levels, linking its endosomal sorting function to Alzheimer-relevant pathways [PMID:27541017].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that SNX6 is an essential endosomal sorting component answered how retromer-dependent CI-MPR retrieval is organized at the membrane level, revealing that SNX6 forms a stable complex with SNX1 on early endosomes and that loss of SNX6 phenocopies retromer core depletion.\",\n      \"evidence\": \"RNAi knockdown, co-immunoprecipitation, and endosomal co-localization in mammalian cells\",\n      \"pmids\": [\"17148574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the SNX1–SNX6 dimer physically generates membrane tubules was unknown\",\n        \"The motor machinery linking retromer to vesicle transport was unidentified\",\n        \"Whether SNX6 has cargo-specific functions beyond CI-MPR was untested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying SNX6 as the adaptor that recruits dynein/dynactin to retromer-coated endosomes resolved how mechanical force is coupled to cargo-containing tubule formation and scission during endosome-to-TGN transport.\",\n      \"evidence\": \"Co-immunoprecipitation of SNX6 with p150(Glued), dominant-negative disruption, and live-cell imaging of tubular intermediates\",\n      \"pmids\": [\"19935774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis of the SNX6–p150(Glued) interface was not determined\",\n        \"Whether other PX-BAR nexins can substitute for SNX6 in motor recruitment was unclear\",\n        \"Regulation of the SNX6–dynactin interaction by upstream signals was uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that SNX6 depletion increases Aβ production and BACE1 levels connected SNX6's endosomal sorting role to amyloidogenic APP processing, broadening its cargo repertoire to disease-relevant substrates.\",\n      \"evidence\": \"miR-98-5p-mediated SNX6 knockdown and rescue in neuronal cell lines with ELISA and Western blot readouts\",\n      \"pmids\": [\"27541017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SNX6 directly sorts BACE1 or APP, or acts indirectly via CI-MPR pathway perturbation, was not distinguished\",\n        \"In vivo validation in animal models was lacking\",\n        \"The miRNA-based knockdown introduces potential off-target confounds\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealing a retromer-independent neuronal function for SNX6 in distributing Homer1b/c along dendrites and maintaining distal spine density fundamentally expanded the gene's functional scope beyond endosome-to-TGN retrieval.\",\n      \"evidence\": \"CNS-specific conditional knockout mouse with co-immunoprecipitation, electrophysiology, spine morphology, and behavioral testing\",\n      \"pmids\": [\"28134614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The vesicular carrier or transport intermediate used by SNX6 to move Homer1b/c in dendrites was not identified\",\n        \"How SNX6 distinguishes retromer-dependent from retromer-independent cargo was unknown\",\n        \"Whether SNX6's Homer1b/c function involves dynein/dynactin recruitment was untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Biochemical reconstitution of the SNX1/SNX6 heterodimer at 1:1 stoichiometry provided the quantitative biophysical framework needed for mechanistic dissection of ESCPE-1-mediated membrane remodeling.\",\n      \"evidence\": \"Co-expression and co-purification of recombinant human and C. elegans SNX1/SNX6 with size-exclusion chromatography\",\n      \"pmids\": [\"29908913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the heterodimer was obtained\",\n        \"Membrane tubulation activity of the purified complex was not tested in this study\",\n        \"Cargo engagement by the reconstituted dimer was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of Rab32 as a direct SNX6 interactor implicated a new Rab GTPase in regulating SNX6/retromer-dependent CI-MPR trafficking, suggesting upstream regulatory inputs on the sorting machinery.\",\n      \"evidence\": \"Co-immunoprecipitation and CI-MPR localization assays\",\n      \"pmids\": [\"30640902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal validation or in vitro binding with purified proteins\",\n        \"Whether Rab32 acts catalytically (GTP-dependent) or as a scaffold was not resolved\",\n        \"Functional consequence of disrupting Rab32–SNX6 interaction on retromer tubule dynamics was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Full in vitro reconstitution showed that ESCPE-1 (SNX2/SNX6) deforms cargo-containing membranes but does not autonomously recruit the Retromer trimer, establishing that VARP is an essential bridging factor for the endosomal supercomplex.\",\n      \"evidence\": \"Liposome tubulation reconstitution with purified mammalian proteins, AlphaFold2 Multimer modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.11.603126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not yet peer-reviewed\",\n        \"Whether the VARP-dependent supercomplex forms on native endosomes in cells was not shown\",\n        \"The contribution of lipid composition heterogeneity to ESCPE-1 activity in vivo remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovering that SNX6 sorts newly synthesized GluA2 at the post-Golgi level — before heteromerization with GluA1 — established a secretory pathway checkpoint controlling surface AMPAR composition, synaptic plasticity, and memory.\",\n      \"evidence\": \"Conditional knockout mice, surface biotinylation, pulse-chase trafficking, electrophysiology (AMPAR currents, LTP), and behavioral assays in hippocampal neurons\",\n      \"pmids\": [\"41429886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The sorting signal on GluA2 recognized by SNX6 was not identified\",\n        \"Whether SNX6 acts as a direct cargo adaptor or through an intermediate in the post-Golgi pathway is unresolved\",\n        \"How SNX6's Golgi function relates to its endosomal retromer role in the same neuron is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of SNX6 cargo selectivity across its multiple trafficking roles, whether its endosomal and post-Golgi functions are coordinated or independently regulated, and the identity of sorting signals on neuronal cargoes such as GluA2 and Homer1b/c.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of SNX6 in complex with any cargo or motor adaptor\",\n        \"Mechanism distinguishing retromer-dependent from retromer-independent functions in neurons is unknown\",\n        \"Whether SNX6 dysfunction contributes to neurodegenerative disease pathogenesis in vivo remains untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [\n      \"ESCPE-1 (SNX1/SNX6 or SNX2/SNX6)\",\n      \"Retromer-associated sorting complex\"\n    ],\n    \"partners\": [\n      \"SNX1\",\n      \"SNX2\",\n      \"DCTN1\",\n      \"HOMER1\",\n      \"RAB32\",\n      \"GRIA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SNX6 is a PX-BAR domain sorting nexin that functions as a core subunit of the ESCPE-1 membrane-deforming complex (heterodimerizing with SNX1 or SNX2) within the retromer pathway, mediating endosome-to-TGN retrograde retrieval of cation-independent mannose-6-phosphate receptor (CI-MPR) [PMID:17148574, PMID:29908913]. SNX6 recruits the dynein/dynactin motor complex to retromer-associated endosomal tubules through direct interaction with p150(Glued), coupling cargo sorting to microtubule-based transport required for tubulovesicular carrier formation and detachment [PMID:19935774, PMID:19619496]. In hippocampal neurons, SNX6 operates independently of canonical retromer to regulate postsynaptic Homer1b/c distribution in dendrites and to sort newly synthesized GluA2 AMPA receptor subunits into the post-Golgi secretory pathway; loss of neuronal SNX6 diverts GluA2 to lysosomal degradation, reduces surface AMPAR levels, impairs LTP, and causes spatial learning and memory deficits [PMID:28134614, PMID:41429886].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of SNX6 as a sorting nexin that forms heteromeric complexes with SNX1/SNX2 and localizes to early endosomes established the molecular context for its subsequent role in endosomal sorting.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and GFP-confocal colocalization with EEA1 in HeLa cells\",\n      \"pmids\": [\"11279102\", \"11485546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No cargo or trafficking phenotype identified at this stage\",\n        \"Receptor interactions (TGF-β family) not functionally validated in a trafficking assay\",\n        \"Stoichiometry and domain contributions to SNX heteromeric complexes undefined\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"An RNAi screen demonstrated that SNX6 (together with SNX5) is required for retromer-mediated endosome-to-TGN retrieval of CI-MPR, establishing SNX6 as a functional retromer subunit and showing that SNX6 depletion destabilizes SNX1 protein levels.\",\n      \"evidence\": \"RNAi loss-of-function screen with CI-MPR redistribution readout; co-immunoprecipitation of SNX6–SNX1\",\n      \"pmids\": [\"17148574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Motor coupling mechanism for retromer-associated tubule transport unknown\",\n        \"Relative contributions of SNX5 versus SNX6 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two independent studies revealed that SNX6 directly binds p150(Glued) of dynein/dynactin, linking the ESCPE-1/retromer membrane tubule to microtubule-based transport and explaining how endosomal tubulovesicular carriers detach and traffic toward the TGN.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, dominant-negative disruption, live cell imaging, C. elegans genetic epistasis\",\n      \"pmids\": [\"19935774\", \"19619496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the SNX6–p150(Glued) interface unresolved\",\n        \"Whether SNX5 and SNX6 have distinct or redundant dynactin-binding roles unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The discovery that Chlamydia trachomatis IncE hijacks SNX5/SNX6 to the bacterial inclusion membrane demonstrated a host-defense role for the SNX6-containing retromer, as its depletion enhanced bacterial replication.\",\n      \"evidence\": \"AP-MS, co-immunoprecipitation, RNAi knockdown with bacterial progeny quantification\",\n      \"pmids\": [\"26118995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether pathogen subversion reflects a broader innate immune role for SNX6/retromer is untested\",\n        \"Structural basis of IncE–SNX6 interaction not determined in this study\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CNS-specific Snx6 knockout revealed a retromer-independent neuronal function: SNX6 interacts with Homer1b/c to regulate its dendritic distribution and is required for normal dendritic spine density, surface AMPAR levels, synaptic transmission, and spatial memory.\",\n      \"evidence\": \"Conditional knockout mice with electrophysiology, Morris water maze, co-immunoprecipitation, confocal imaging\",\n      \"pmids\": [\"28134614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SNX6 regulates Homer1b/c trafficking independently of retromer not defined\",\n        \"Whether AMPAR reduction is a direct or indirect consequence of Homer1b/c mislocalization unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SNX6 was shown to sort newly synthesized GluA2 AMPAR subunits into the post-Golgi secretory pathway prior to GluA1 assembly, resolving the molecular basis for AMPAR reduction: without SNX6, GluA2 is diverted to lysosomes, impairing constitutive and activity-dependent surface AMPAR expression, LTP, and memory.\",\n      \"evidence\": \"Conditional knockout mice, pulse-chase trafficking assays in hippocampal neurons, electrophysiology, behavioral tests\",\n      \"pmids\": [\"41429886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cargo recognition mechanism by which SNX6 selects GluA2 for post-Golgi sorting is undefined\",\n        \"Whether SNX6 cooperates with other sorting factors at the TGN for GluA2 export is unknown\",\n        \"Relevance to neurodegenerative or neurodevelopmental disease in humans not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the full SNX1/SNX6 or SNX2/SNX6 heterodimer on membranes, the structural basis of the SNX6–p150(Glued) and SNX6–GluA2 interactions, and the mechanism by which VARP bridges ESCPE-1 to SNX27–Retromer remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the full SNX6-containing ESCPE-1 complex\",\n        \"Cargo recognition motifs on GluA2 for SNX6-mediated TGN export unidentified\",\n        \"In vivo reconstitution of the SNX27–ESCPE-1–Retromer supercomplex awaits peer-reviewed validation\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 10, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [\n      \"ESCPE-1 (SNX1/SNX6 or SNX2/SNX6 heterodimer)\",\n      \"Retromer-associated complex\"\n    ],\n    \"partners\": [\n      \"SNX1\",\n      \"SNX2\",\n      \"SNX5\",\n      \"DCTN1\",\n      \"HOMER1\",\n      \"GRIA2\",\n      \"RAB32\",\n      \"VPS35\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}