{"gene":"SNX18","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2013,"finding":"SNX18 directly interacts with LC3 and ATG16L1, promotes recruitment of ATG16L1-positive recycling endosomes to a perinuclear area, and delivers ATG16L1- and LC3-positive membranes to autophagosome precursors. Its pro-autophagic activity depends on membrane binding and tubulation capacity. Phosphorylation of S233 negatively regulates SNX18 membrane tubulation and autophagy function.","method":"siRNA screen, co-immunoprecipitation, live-cell imaging, phosphorylation-site mutagenesis, membrane tubulation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA screen, co-IP, live imaging, mutagenesis) in a focused study, replicated in Drosophila fat body","pmids":["23878278"],"is_preprint":false},{"year":2013,"finding":"SNX18 functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 interacts with ATG16L1 and LC3, facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes to provide membrane for phagophore expansion.","method":"siRNA knockdown, overexpression, genetic epistasis with ATG14/PI3K complex, fluorescence microscopy","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway position via epistasis combined with co-IP and imaging, independently consistent with PMID:23878278","pmids":["24113029"],"is_preprint":false},{"year":2018,"finding":"SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2. ATG9A accumulates in juxtanuclear recycling endosomes in SNX18-depleted cells. SNX18-Dynamin-2 binding is required for ATG9A trafficking from recycling endosomes and for formation of ATG16L1- and WIPI2-positive autophagosome precursor membranes.","method":"SNX18 knockout/knockdown, co-immunoprecipitation, fluorescence microscopy, membrane tubulation assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO cells with defined phenotypic readout, multiple orthogonal imaging methods","pmids":["29437695"],"is_preprint":false},{"year":2010,"finding":"SNX18 interacts with dynamin and stimulates its basal GTPase activity. SNX18 also interacts with N-WASP and synaptojanin. SNX18 and SNX9 form a heterodimer, colocalize in tubular membrane structures, and are functionally redundant in clathrin-mediated endocytosis at the plasma membrane. Depletion of SNX18 inhibits transferrin uptake.","method":"Co-immunoprecipitation, GTPase activity assay, shRNA knockdown, transferrin uptake assay, TIRF microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro GTPase assay, reciprocal Co-IP, functional rescue, live-cell TIRF imaging","pmids":["20427313"],"is_preprint":false},{"year":2011,"finding":"SNX18 directly interacts with FIP5 (a Rab11 GTPase binding protein); the FIP5-SNX18 complex is required for early apical lumen formation in epithelial cells. FIP5 promotes SNX18 membrane tubulation capacity, implicating the complex in endocytic carrier formation/scission during polarized transport of apical proteins.","method":"Co-immunoprecipitation, siRNA knockdown, 3D lumen formation assay, membrane tubulation assay, lipid-binding assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KD phenotype in 3D lumen assay, membrane tubulation assay with multiple constructs","pmids":["21969467"],"is_preprint":false},{"year":2010,"finding":"SNX18 overexpression significantly increases macropinosome formation and SNX18 associates with early-stage macropinosomes within 5 minutes of formation. The effect of SNX18 on macropinocytosis is synergistic with elevated PI(3,4,5)P3 levels.","method":"Systematic overexpression, image-based quantitation, co-expression with PTEN/PTEN(G129E), live-cell imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression-based quantitative imaging, two orthogonal conditions (co-expression with PTEN variants), single lab","pmids":["21048941"],"is_preprint":false},{"year":2012,"finding":"SNX18 is required for progression through and completion of mitosis, specifically the ingression and abscission stages of cytokinesis. Depletion of SNX18 induces multinucleation (cytokinesis failure), disrupts MRLC(S19) localization during ingression, and impairs recruitment of Rab11-positive recycling endosomes to the intracellular bridge. SNX18 depletion also blocks endocytosis of transferrin during cytokinesis.","method":"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple defined phenotypic readouts (cytokinesis, MRLC localization, endocytosis), single lab","pmids":["22718350"],"is_preprint":false},{"year":2017,"finding":"During Salmonella invasion, SNX18 is recruited to bacteria-induced membrane ruffles and nascent Salmonella-containing vacuoles in a manner requiring the inositol-phosphatase activity of the bacterial effector SopB and an intact PX domain phosphoinositide-binding site in SNX18. SNX18 acts as a scaffold to recruit Dynamin-2 and N-WASP via its SH3 domain to promote Salmonella-containing vacuole formation and bacterial internalization.","method":"Overexpression and knockdown, phosphoinositide-binding mutant (R303Q), ΔSH3 mutant, bacteria uptake quantification, fluorescence microscopy","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutants with functional readout, multiple constructs, single lab","pmids":["28664153"],"is_preprint":false},{"year":2019,"finding":"SNX18 and N-WASP cooperate to promote LPA receptor (LPAR1) recycling and prevent its degradation, thereby maintaining RhoA-mediated contractility and force generation in pancreatic cancer cells. This SNX18-dependent receptor recycling loop drives chemotaxis, collagen remodeling, and metastasis.","method":"Knockdown, receptor trafficking assay (recycling vs. degradation), RhoA activation assay, traction force microscopy, in vivo metastasis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple functional readouts (recycling, RhoA activation, in vivo), single lab","pmids":["31668663"],"is_preprint":false},{"year":2016,"finding":"Mib1 (an E3 ubiquitin ligase) promotes the interaction between Dynamin-2 and SNX18 in an ubiquitin-ligase-activity-dependent manner, thereby modulating Dynamin-2 recruitment to facilitate Dll1 (Notch ligand) endocytosis for efficient Notch signaling activation.","method":"Co-immunoprecipitation, ubiquitin ligase activity mutants, Dll1 endocytosis assay, Notch signaling reporter","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, activity-dependent mutants, functional endocytosis assay, single lab","pmids":["26923255"],"is_preprint":false},{"year":2010,"finding":"SNX18 binds to the E3 ubiquitin ligase Itch via the SH3 domain of SNX18 and the proline-rich domain (PRD) of Itch, similarly to the related SNX9.","method":"Co-immunoprecipitation with truncated proteins","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP result, SNX18 is a secondary finding in a paper focused on SNX9, no functional follow-up for SNX18","pmids":["20491914"],"is_preprint":false},{"year":2018,"finding":"SNX18 (together with SNX9, redundantly) promotes ADAM9 internalization via clathrin-dependent endocytosis. Double knockdown of SNX9 and SNX18 significantly decreased ADAM9 internalization, demonstrating functional redundancy.","method":"siRNA knockdown (single and double), surface biotinylation, internalization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-KD rescue design, quantitative internalization assay, single lab","pmids":["29622675"],"is_preprint":false},{"year":2015,"finding":"HIV-1 Nef associates with SNX18, and this interaction is localized to AP-1-positive endosomal vesicles, as demonstrated by bimolecular fluorescence complementation during viral infection.","method":"Viral bimolecular fluorescence complementation (BiFC), co-localization imaging","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single BiFC method, no functional follow-up for SNX18, single lab","pmids":["25915798"],"is_preprint":false},{"year":2024,"finding":"SNX18 (together with SNX9) is necessary for agonist-stimulated, β-arrestin-independent endocytosis of the chemokine receptor CXCR4. SNX9/SNX18 depletion blocks CXCR4 endocytosis, while β-arrestin depletion does not.","method":"siRNA knockdown, receptor internalization assay, co-immunoprecipitation","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined receptor trafficking phenotype, comparison to β-arrestin pathway, single lab","pmids":["39511325"],"is_preprint":false},{"year":2011,"finding":"SNX18 localizes dynamically to growth cones in developing spinal motor neurons and accumulates at areas of contact with permissive substrates, suggesting a role in membrane trafficking during axonal elongation.","method":"EGFP-SNX18 live-cell imaging, immunofluorescence in embryonic spinal cord","journal":"The journal of histochemistry and cytochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by live imaging, no direct functional loss-of-function or pathway placement","pmids":["21339182"],"is_preprint":false},{"year":2025,"finding":"MAP1LC3B recognizes SNX18 on the surface of endosome-escaped extracellular vesicles (EVs) to facilitate their sorting into the autolysosomal pathway for degradation.","method":"Mechanistic studies of EV degradation, SNX18 surface display, LC3-SNX18 interaction assays","journal":"Cell chemical biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, abstract provides limited methodological detail, novel finding not yet replicated","pmids":["41932333"],"is_preprint":false}],"current_model":"SNX18 is a PX-BAR sorting nexin that remodels membranes — primarily recycling endosomes — to support multiple trafficking processes: it directly binds LC3 and ATG16L1 and recruits Dynamin-2 to tubulate recycling endosomes and deliver ATG9A-, ATG16L1-, and LC3-positive membranes to forming autophagosomes (acting downstream of the ATG14/class III PI3K complex); it functions redundantly with SNX9 in clathrin-mediated endocytosis and GPCR internalization by stimulating dynamin GTPase activity and interacting with N-WASP and synaptojanin; it forms a complex with FIP5/Rab11 to support apical lumen formation; its membrane tubulation and autophagy activities are negatively regulated by phosphorylation of S233; and its interactions with Dynamin-2 (modulated by the Mib1 ubiquitin ligase) couple it to Notch ligand endocytosis and Salmonella invasion."},"narrative":{"mechanistic_narrative":"SNX18 is a PX-BAR sorting nexin that remodels endosomal membranes to drive membrane tubulation and carrier formation across multiple trafficking pathways [PMID:20427313, PMID:21969467]. It directly binds dynamin and stimulates its basal GTPase activity, and also engages N-WASP and synaptojanin; SNX18 and SNX9 form a heterodimer and act redundantly in clathrin-mediated endocytosis, with SNX18 depletion impairing transferrin uptake [PMID:20427313]. This redundant SNX9/SNX18 module supports clathrin-dependent internalization of diverse cargoes, including ADAM9 and the GPCRs CXCR4 (via a β-arrestin-independent route) and LPAR1 recycling [PMID:29622675, PMID:39511325, PMID:31668663]. In autophagy, SNX18 acts downstream of the ATG14/class III PtdIns3K complex, directly binding LC3 and ATG16L1 and recruiting ATG16L1- and LC3-positive recycling endosomes to a perinuclear region to provide membrane for phagophore expansion; this pro-autophagic activity requires its membrane-binding and tubulation capacity and is negatively regulated by phosphorylation of S233 [PMID:23878278, PMID:24113029]. SNX18 recruits Dynamin-2 to tubulate recycling endosomes and traffic ATG9A toward autophagosome precursor membranes [PMID:29437695]. Beyond autophagy, SNX18 forms a complex with FIP5/Rab11 required for apical lumen formation [PMID:21969467], is required for cytokinesis [PMID:22718350], and its scaffolding of Dynamin-2 and N-WASP is exploited during Salmonella invasion (downstream of the effector SopB) and coupled to Notch ligand (Dll1) endocytosis via the Mib1 ubiquitin ligase [PMID:28664153, PMID:26923255].","teleology":[{"year":2010,"claim":"Established SNX18 as a dynamin-activating BAR-domain protein functioning in clathrin-mediated endocytosis, defining its core biochemical activity and its relationship to SNX9.","evidence":"Co-IP, in vitro GTPase activity assay, shRNA knockdown, transferrin uptake, TIRF microscopy","pmids":["20427313"],"confidence":"High","gaps":["Structural basis of dynamin GTPase stimulation not resolved","Division of labor versus full redundancy with SNX9 not delineated"]},{"year":2010,"claim":"Linked SNX18 to macropinosome formation, broadening its membrane-remodeling role beyond classical endocytosis.","evidence":"Systematic overexpression, image-based quantitation, co-expression with PTEN variants, live imaging","pmids":["21048941"],"confidence":"Medium","gaps":["Based on overexpression rather than loss of function","PI(3,4,5)P3 dependence shown indirectly via PTEN co-expression"]},{"year":2011,"claim":"Showed SNX18 partners with FIP5/Rab11 to drive apical lumen formation, connecting its tubulation activity to polarized epithelial transport.","evidence":"Co-IP, siRNA knockdown, 3D lumen formation assay, membrane tubulation and lipid-binding assays","pmids":["21969467"],"confidence":"High","gaps":["Specific apical cargoes trafficked not enumerated","Mechanism of FIP5-stimulated tubulation unresolved"]},{"year":2012,"claim":"Identified a requirement for SNX18 in cytokinesis, implicating recycling-endosome delivery to the intracellular bridge in cell division.","evidence":"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay","pmids":["22718350"],"confidence":"Medium","gaps":["Single-lab siRNA without genetic rescue","Direct molecular link between SNX18 and MRLC localization unclear"]},{"year":2013,"claim":"Defined SNX18 as a pro-autophagic factor that directly binds LC3 and ATG16L1 and supplies recycling-endosome-derived membrane to autophagosomes, with phospho-regulation at S233.","evidence":"siRNA screen, co-IP, live imaging, phosphosite mutagenesis, tubulation assays; epistasis with ATG14/class III PI3K","pmids":["23878278","24113029"],"confidence":"High","gaps":["Kinase responsible for S233 phosphorylation not identified","How LC3/ATG16L1 binding is spatially coordinated with tubulation not resolved"]},{"year":2018,"claim":"Showed SNX18 recruits Dynamin-2 to mobilize ATG9A from recycling endosomes, mechanistically connecting its dynamin partnership to autophagosome precursor formation.","evidence":"SNX18 KO/KD, reciprocal co-IP, fluorescence microscopy, membrane tubulation assays","pmids":["29437695"],"confidence":"High","gaps":["How ATG9A is selected as cargo not defined","Relationship between ATG9A and ATG16L1/LC3 membrane sources not fully integrated"]},{"year":2016,"claim":"Demonstrated that the Mib1 ubiquitin ligase tunes SNX18–Dynamin-2 interaction to drive Dll1 endocytosis, linking SNX18 to Notch signaling.","evidence":"Co-IP, ubiquitin-ligase activity mutants, Dll1 endocytosis assay, Notch reporter","pmids":["26923255"],"confidence":"Medium","gaps":["Direct ubiquitination target not pinpointed","Single-lab finding without independent confirmation"]},{"year":2017,"claim":"Established SNX18 as a host scaffold hijacked during Salmonella invasion, recruiting Dynamin-2 and N-WASP via its SH3 domain downstream of the bacterial effector SopB.","evidence":"Overexpression/knockdown, PX-domain (R303Q) and ΔSH3 mutants, bacterial uptake quantification, microscopy","pmids":["28664153"],"confidence":"Medium","gaps":["Phosphoinositide species recognized by PX domain in this context not specified","Single-lab study"]},{"year":2018,"claim":"Extended SNX9/SNX18 redundancy to ADAM9 internalization, reinforcing the heterodimer's general role in clathrin-dependent cargo uptake.","evidence":"Single and double siRNA knockdown, surface biotinylation, internalization assay","pmids":["29622675"],"confidence":"Medium","gaps":["Direct binding of SNX18 to ADAM9 machinery not shown","Single-lab study"]},{"year":2019,"claim":"Connected SNX18-driven LPAR1 recycling to RhoA-mediated contractility and pancreatic cancer metastasis, demonstrating a disease-relevant trafficking loop.","evidence":"Knockdown, receptor recycling vs degradation assays, RhoA activation, traction force microscopy, in vivo metastasis","pmids":["31668663"],"confidence":"Medium","gaps":["Whether SNX18 directly sorts LPAR1 or acts indirectly not resolved","Single-lab study"]},{"year":2024,"claim":"Defined SNX18 (with SNX9) as required for β-arrestin-independent CXCR4 endocytosis, distinguishing its trafficking route from canonical GPCR internalization.","evidence":"siRNA knockdown, receptor internalization assay, co-IP, comparison to β-arrestin depletion","pmids":["39511325"],"confidence":"Medium","gaps":["Adaptor coupling SNX18 to CXCR4 not identified","Single-lab study"]},{"year":null,"claim":"It remains unresolved how SNX18 cargo selectivity and pathway choice (endocytosis vs autophagy vs lumen formation vs cytokinesis) are coordinated, and what upstream signals beyond S233 phosphorylation govern its membrane-remodeling deployment.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model integrating PX, BAR, and SH3 functions across pathways","Kinase/phosphatase network controlling S233 not mapped","Determinants of SNX9 vs SNX18 functional specialization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,4,11,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,13]}],"complexes":["SNX9-SNX18 heterodimer","FIP5-SNX18 complex"],"partners":["DNM2","SNX9","LC3","ATG16L1","N-WASP","FIP5","SYNAPTOJANIN","MIB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96RF0","full_name":"Sorting nexin-18","aliases":["SH3 and PX domain-containing protein 3B"],"length_aa":628,"mass_kda":68.9,"function":"Involved in endocytosis and intracellular vesicle trafficking, both during interphase and at the end of mitosis (PubMed:18411244, PubMed:20427313, PubMed:21048941, PubMed:22718350). Required for efficient progress through mitosis and cytokinesis (PubMed:22718350). Required for normal formation of the cleavage furrow at the end of mitosis (PubMed:22718350). Plays a role in endocytosis via clathrin-coated pits, but also clathrin-independent, actin-dependent fluid-phase endocytosis (PubMed:20427313). Plays a role in macropinocytosis (PubMed:21048941). Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate and promotes membrane tubulation (PubMed:18411244). Stimulates the GTPase activity of DNM2 (PubMed:20427313). Promotes DNM2 location at the plasma membrane (PubMed:20427313). Together with DNM2, involved in autophagosome assembly by regulating trafficking from recycling endosomes of phospholipid scramblase ATG9A (PubMed:29437695)","subcellular_location":"Endomembrane system; Endosome membrane; Recycling endosome membrane; Cell membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q96RF0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX18","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNX18","total_profiled":1310},"omim":[{"mim_id":"621000","title":"SORTING NEXIN 18; SNX18","url":"https://www.omim.org/entry/621000"},{"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":"602713","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 9; ADAM9","url":"https://www.omim.org/entry/602713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":64.2}],"url":"https://www.proteinatlas.org/search/SNX18"},"hgnc":{"alias_symbol":["SH3PX2","SH3PXD3B"],"prev_symbol":["SNAG1"]},"alphafold":{"accession":"Q96RF0","domains":[{"cath_id":"2.30.30.40","chopping":"5-60","consensus_level":"high","plddt":90.838,"start":5,"end":60},{"cath_id":"3.30.1520.10","chopping":"269-413","consensus_level":"high","plddt":90.7314,"start":269,"end":413},{"cath_id":"1.20.1270.60","chopping":"420-540","consensus_level":"medium","plddt":90.5159,"start":420,"end":540},{"cath_id":"-","chopping":"560-573_583-628","consensus_level":"medium","plddt":29.4595,"start":560,"end":628}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RF0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RF0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RF0-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX18","jax_strain_url":"https://www.jax.org/strain/search?query=SNX18"},"sequence":{"accession":"Q96RF0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RF0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RF0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RF0"}},"corpus_meta":[{"pmid":"23878278","id":"PMC_23878278","title":"Membrane 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ATG16L1-positive recycling endosomes to a perinuclear area, and delivers ATG16L1- and LC3-positive membranes to autophagosome precursors. Its pro-autophagic activity depends on membrane binding and tubulation capacity. Phosphorylation of S233 negatively regulates SNX18 membrane tubulation and autophagy function.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, live-cell imaging, phosphorylation-site mutagenesis, membrane tubulation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA screen, co-IP, live imaging, mutagenesis) in a focused study, replicated in Drosophila fat body\",\n      \"pmids\": [\"23878278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX18 functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 interacts with ATG16L1 and LC3, facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes to provide membrane for phagophore expansion.\",\n      \"method\": \"siRNA knockdown, overexpression, genetic epistasis with ATG14/PI3K complex, fluorescence microscopy\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway position via epistasis combined with co-IP and imaging, independently consistent with PMID:23878278\",\n      \"pmids\": [\"24113029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2. ATG9A accumulates in juxtanuclear recycling endosomes in SNX18-depleted cells. SNX18-Dynamin-2 binding is required for ATG9A trafficking from recycling endosomes and for formation of ATG16L1- and WIPI2-positive autophagosome precursor membranes.\",\n      \"method\": \"SNX18 knockout/knockdown, co-immunoprecipitation, fluorescence microscopy, membrane tubulation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO cells with defined phenotypic readout, multiple orthogonal imaging methods\",\n      \"pmids\": [\"29437695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SNX18 interacts with dynamin and stimulates its basal GTPase activity. SNX18 also interacts with N-WASP and synaptojanin. SNX18 and SNX9 form a heterodimer, colocalize in tubular membrane structures, and are functionally redundant in clathrin-mediated endocytosis at the plasma membrane. Depletion of SNX18 inhibits transferrin uptake.\",\n      \"method\": \"Co-immunoprecipitation, GTPase activity assay, shRNA knockdown, transferrin uptake assay, TIRF microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro GTPase assay, reciprocal Co-IP, functional rescue, live-cell TIRF imaging\",\n      \"pmids\": [\"20427313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNX18 directly interacts with FIP5 (a Rab11 GTPase binding protein); the FIP5-SNX18 complex is required for early apical lumen formation in epithelial cells. FIP5 promotes SNX18 membrane tubulation capacity, implicating the complex in endocytic carrier formation/scission during polarized transport of apical proteins.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, 3D lumen formation assay, membrane tubulation assay, lipid-binding assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KD phenotype in 3D lumen assay, membrane tubulation assay with multiple constructs\",\n      \"pmids\": [\"21969467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SNX18 overexpression significantly increases macropinosome formation and SNX18 associates with early-stage macropinosomes within 5 minutes of formation. The effect of SNX18 on macropinocytosis is synergistic with elevated PI(3,4,5)P3 levels.\",\n      \"method\": \"Systematic overexpression, image-based quantitation, co-expression with PTEN/PTEN(G129E), live-cell imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression-based quantitative imaging, two orthogonal conditions (co-expression with PTEN variants), single lab\",\n      \"pmids\": [\"21048941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX18 is required for progression through and completion of mitosis, specifically the ingression and abscission stages of cytokinesis. Depletion of SNX18 induces multinucleation (cytokinesis failure), disrupts MRLC(S19) localization during ingression, and impairs recruitment of Rab11-positive recycling endosomes to the intracellular bridge. SNX18 depletion also blocks endocytosis of transferrin during cytokinesis.\",\n      \"method\": \"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple defined phenotypic readouts (cytokinesis, MRLC localization, endocytosis), single lab\",\n      \"pmids\": [\"22718350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During Salmonella invasion, SNX18 is recruited to bacteria-induced membrane ruffles and nascent Salmonella-containing vacuoles in a manner requiring the inositol-phosphatase activity of the bacterial effector SopB and an intact PX domain phosphoinositide-binding site in SNX18. SNX18 acts as a scaffold to recruit Dynamin-2 and N-WASP via its SH3 domain to promote Salmonella-containing vacuole formation and bacterial internalization.\",\n      \"method\": \"Overexpression and knockdown, phosphoinositide-binding mutant (R303Q), ΔSH3 mutant, bacteria uptake quantification, fluorescence microscopy\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutants with functional readout, multiple constructs, single lab\",\n      \"pmids\": [\"28664153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX18 and N-WASP cooperate to promote LPA receptor (LPAR1) recycling and prevent its degradation, thereby maintaining RhoA-mediated contractility and force generation in pancreatic cancer cells. This SNX18-dependent receptor recycling loop drives chemotaxis, collagen remodeling, and metastasis.\",\n      \"method\": \"Knockdown, receptor trafficking assay (recycling vs. degradation), RhoA activation assay, traction force microscopy, in vivo metastasis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple functional readouts (recycling, RhoA activation, in vivo), single lab\",\n      \"pmids\": [\"31668663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mib1 (an E3 ubiquitin ligase) promotes the interaction between Dynamin-2 and SNX18 in an ubiquitin-ligase-activity-dependent manner, thereby modulating Dynamin-2 recruitment to facilitate Dll1 (Notch ligand) endocytosis for efficient Notch signaling activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin ligase activity mutants, Dll1 endocytosis assay, Notch signaling reporter\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, activity-dependent mutants, functional endocytosis assay, single lab\",\n      \"pmids\": [\"26923255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SNX18 binds to the E3 ubiquitin ligase Itch via the SH3 domain of SNX18 and the proline-rich domain (PRD) of Itch, similarly to the related SNX9.\",\n      \"method\": \"Co-immunoprecipitation with truncated proteins\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP result, SNX18 is a secondary finding in a paper focused on SNX9, no functional follow-up for SNX18\",\n      \"pmids\": [\"20491914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX18 (together with SNX9, redundantly) promotes ADAM9 internalization via clathrin-dependent endocytosis. Double knockdown of SNX9 and SNX18 significantly decreased ADAM9 internalization, demonstrating functional redundancy.\",\n      \"method\": \"siRNA knockdown (single and double), surface biotinylation, internalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-KD rescue design, quantitative internalization assay, single lab\",\n      \"pmids\": [\"29622675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIV-1 Nef associates with SNX18, and this interaction is localized to AP-1-positive endosomal vesicles, as demonstrated by bimolecular fluorescence complementation during viral infection.\",\n      \"method\": \"Viral bimolecular fluorescence complementation (BiFC), co-localization imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single BiFC method, no functional follow-up for SNX18, single lab\",\n      \"pmids\": [\"25915798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX18 (together with SNX9) is necessary for agonist-stimulated, β-arrestin-independent endocytosis of the chemokine receptor CXCR4. SNX9/SNX18 depletion blocks CXCR4 endocytosis, while β-arrestin depletion does not.\",\n      \"method\": \"siRNA knockdown, receptor internalization assay, co-immunoprecipitation\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined receptor trafficking phenotype, comparison to β-arrestin pathway, single lab\",\n      \"pmids\": [\"39511325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNX18 localizes dynamically to growth cones in developing spinal motor neurons and accumulates at areas of contact with permissive substrates, suggesting a role in membrane trafficking during axonal elongation.\",\n      \"method\": \"EGFP-SNX18 live-cell imaging, immunofluorescence in embryonic spinal cord\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by live imaging, no direct functional loss-of-function or pathway placement\",\n      \"pmids\": [\"21339182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAP1LC3B recognizes SNX18 on the surface of endosome-escaped extracellular vesicles (EVs) to facilitate their sorting into the autolysosomal pathway for degradation.\",\n      \"method\": \"Mechanistic studies of EV degradation, SNX18 surface display, LC3-SNX18 interaction assays\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, abstract provides limited methodological detail, novel finding not yet replicated\",\n      \"pmids\": [\"41932333\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX18 is a PX-BAR sorting nexin that remodels membranes — primarily recycling endosomes — to support multiple trafficking processes: it directly binds LC3 and ATG16L1 and recruits Dynamin-2 to tubulate recycling endosomes and deliver ATG9A-, ATG16L1-, and LC3-positive membranes to forming autophagosomes (acting downstream of the ATG14/class III PI3K complex); it functions redundantly with SNX9 in clathrin-mediated endocytosis and GPCR internalization by stimulating dynamin GTPase activity and interacting with N-WASP and synaptojanin; it forms a complex with FIP5/Rab11 to support apical lumen formation; its membrane tubulation and autophagy activities are negatively regulated by phosphorylation of S233; and its interactions with Dynamin-2 (modulated by the Mib1 ubiquitin ligase) couple it to Notch ligand endocytosis and Salmonella invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX18 is a PX-BAR sorting nexin that remodels endosomal membranes to drive membrane tubulation and carrier formation across multiple trafficking pathways [#3, #4]. It directly binds dynamin and stimulates its basal GTPase activity, and also engages N-WASP and synaptojanin; SNX18 and SNX9 form a heterodimer and act redundantly in clathrin-mediated endocytosis, with SNX18 depletion impairing transferrin uptake [#3]. This redundant SNX9/SNX18 module supports clathrin-dependent internalization of diverse cargoes, including ADAM9 and the GPCRs CXCR4 (via a \\u03b2-arrestin-independent route) and LPAR1 recycling [#11, #13, #8]. In autophagy, SNX18 acts downstream of the ATG14/class III PtdIns3K complex, directly binding LC3 and ATG16L1 and recruiting ATG16L1- and LC3-positive recycling endosomes to a perinuclear region to provide membrane for phagophore expansion; this pro-autophagic activity requires its membrane-binding and tubulation capacity and is negatively regulated by phosphorylation of S233 [#0, #1]. SNX18 recruits Dynamin-2 to tubulate recycling endosomes and traffic ATG9A toward autophagosome precursor membranes [#2]. Beyond autophagy, SNX18 forms a complex with FIP5/Rab11 required for apical lumen formation [#4], is required for cytokinesis [#6], and its scaffolding of Dynamin-2 and N-WASP is exploited during Salmonella invasion (downstream of the effector SopB) and coupled to Notch ligand (Dll1) endocytosis via the Mib1 ubiquitin ligase [#7, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established SNX18 as a dynamin-activating BAR-domain protein functioning in clathrin-mediated endocytosis, defining its core biochemical activity and its relationship to SNX9.\",\n      \"evidence\": \"Co-IP, in vitro GTPase activity assay, shRNA knockdown, transferrin uptake, TIRF microscopy\",\n      \"pmids\": [\"20427313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dynamin GTPase stimulation not resolved\", \"Division of labor versus full redundancy with SNX9 not delineated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked SNX18 to macropinosome formation, broadening its membrane-remodeling role beyond classical endocytosis.\",\n      \"evidence\": \"Systematic overexpression, image-based quantitation, co-expression with PTEN variants, live imaging\",\n      \"pmids\": [\"21048941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression rather than loss of function\", \"PI(3,4,5)P3 dependence shown indirectly via PTEN co-expression\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed SNX18 partners with FIP5/Rab11 to drive apical lumen formation, connecting its tubulation activity to polarized epithelial transport.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, 3D lumen formation assay, membrane tubulation and lipid-binding assays\",\n      \"pmids\": [\"21969467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific apical cargoes trafficked not enumerated\", \"Mechanism of FIP5-stimulated tubulation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a requirement for SNX18 in cytokinesis, implicating recycling-endosome delivery to the intracellular bridge in cell division.\",\n      \"evidence\": \"siRNA knockdown, time-lapse microscopy, immunofluorescence, transferrin uptake assay\",\n      \"pmids\": [\"22718350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab siRNA without genetic rescue\", \"Direct molecular link between SNX18 and MRLC localization unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined SNX18 as a pro-autophagic factor that directly binds LC3 and ATG16L1 and supplies recycling-endosome-derived membrane to autophagosomes, with phospho-regulation at S233.\",\n      \"evidence\": \"siRNA screen, co-IP, live imaging, phosphosite mutagenesis, tubulation assays; epistasis with ATG14/class III PI3K\",\n      \"pmids\": [\"23878278\", \"24113029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S233 phosphorylation not identified\", \"How LC3/ATG16L1 binding is spatially coordinated with tubulation not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SNX18 recruits Dynamin-2 to mobilize ATG9A from recycling endosomes, mechanistically connecting its dynamin partnership to autophagosome precursor formation.\",\n      \"evidence\": \"SNX18 KO/KD, reciprocal co-IP, fluorescence microscopy, membrane tubulation assays\",\n      \"pmids\": [\"29437695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATG9A is selected as cargo not defined\", \"Relationship between ATG9A and ATG16L1/LC3 membrane sources not fully integrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that the Mib1 ubiquitin ligase tunes SNX18\\u2013Dynamin-2 interaction to drive Dll1 endocytosis, linking SNX18 to Notch signaling.\",\n      \"evidence\": \"Co-IP, ubiquitin-ligase activity mutants, Dll1 endocytosis assay, Notch reporter\",\n      \"pmids\": [\"26923255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination target not pinpointed\", \"Single-lab finding without independent confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established SNX18 as a host scaffold hijacked during Salmonella invasion, recruiting Dynamin-2 and N-WASP via its SH3 domain downstream of the bacterial effector SopB.\",\n      \"evidence\": \"Overexpression/knockdown, PX-domain (R303Q) and \\u0394SH3 mutants, bacterial uptake quantification, microscopy\",\n      \"pmids\": [\"28664153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoinositide species recognized by PX domain in this context not specified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended SNX9/SNX18 redundancy to ADAM9 internalization, reinforcing the heterodimer's general role in clathrin-dependent cargo uptake.\",\n      \"evidence\": \"Single and double siRNA knockdown, surface biotinylation, internalization assay\",\n      \"pmids\": [\"29622675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SNX18 to ADAM9 machinery not shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SNX18-driven LPAR1 recycling to RhoA-mediated contractility and pancreatic cancer metastasis, demonstrating a disease-relevant trafficking loop.\",\n      \"evidence\": \"Knockdown, receptor recycling vs degradation assays, RhoA activation, traction force microscopy, in vivo metastasis\",\n      \"pmids\": [\"31668663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNX18 directly sorts LPAR1 or acts indirectly not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined SNX18 (with SNX9) as required for \\u03b2-arrestin-independent CXCR4 endocytosis, distinguishing its trafficking route from canonical GPCR internalization.\",\n      \"evidence\": \"siRNA knockdown, receptor internalization assay, co-IP, comparison to \\u03b2-arrestin depletion\",\n      \"pmids\": [\"39511325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Adaptor coupling SNX18 to CXCR4 not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SNX18 cargo selectivity and pathway choice (endocytosis vs autophagy vs lumen formation vs cytokinesis) are coordinated, and what upstream signals beyond S233 phosphorylation govern its membrane-remodeling deployment.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model integrating PX, BAR, and SH3 functions across pathways\", \"Kinase/phosphatase network controlling S233 not mapped\", \"Determinants of SNX9 vs SNX18 functional specialization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 4, 11, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 13]}\n    ],\n    \"complexes\": [\n      \"SNX9-SNX18 heterodimer\",\n      \"FIP5-SNX18 complex\"\n    ],\n    \"partners\": [\n      \"DNM2\",\n      \"SNX9\",\n      \"LC3\",\n      \"ATG16L1\",\n      \"N-WASP\",\n      \"FIP5\",\n      \"synaptojanin\",\n      \"MIB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}