{"gene":"SNX8","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1995,"finding":"Yeast Mvp1p (SNX8 ortholog) genetically interacts with the dynamin-like GTPase Vps1p and is required for vacuolar protein sorting; overproduction of Mvp1p suppresses dominant-negative vps1 alleles in a manner dependent on wild-type Vps1p, and Mvp1p colocalizes with Vps1p in vps1Δ and vps27Δ cells, indicating they act in concert to promote membrane traffic to the vacuole.","method":"Multicopy suppressor genetic screen, epistasis analysis, fluorescence colocalization in yeast","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus colocalization, single lab, two orthogonal methods","pmids":["7862158"],"is_preprint":false},{"year":2020,"finding":"Full-length Mvp1 (yeast SNX8 ortholog) forms an autoinhibited tetramer (dimer-of-dimers) in which the membrane-interacting BAR surfaces are sequestered and PX lipid-binding sites are occluded; the N-terminal low-complexity region is essential for tetramerization, and deletion of this region produces a dimer with enhanced membrane association and remodeling activity, revealing an autoinhibitory mechanism for membrane binding.","method":"Cryo-EM structure of full-length Mvp1, deletion mutagenesis, membrane-binding/remodeling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with mutagenesis and functional membrane-binding assays in one rigorous study","pmids":["32198400"],"is_preprint":false},{"year":2021,"finding":"Mvp1/SNX8 deforms the endosomal membrane, sorts cargos containing a specific sorting motif into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and tubule release, defining a retromer-independent endosomal recycling pathway conserved from yeast to humans; human SNX8 likewise mediates formation of endosomal recycling tubules.","method":"Live-cell fluorescence microscopy, cargo-sorting assays, genetic and biochemical reconstitution in yeast, human SNX8 functional complementation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, cargo sorting, tubule formation, Vps1 recruitment assays) replicated in two organisms","pmids":["34524084"],"is_preprint":false},{"year":2026,"finding":"Recycling of the endosomal protein Vps68 in yeast depends on both retromer and Mvp1/SNX8; a tyrosine-based recycling signal in the cytosolic tail of Vps68 is required for Mvp1-dependent recycling, and co-immunoprecipitation detected a physical association between Mvp1 and the retromer subunit Vps26, indicating Mvp1 can cooperate with retromer.","method":"Genetic deletion analysis, vacuolar degradation assays, identification of tyrosine recycling signal by mutagenesis, co-immunoprecipitation","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus co-IP, single lab, two orthogonal methods","pmids":["41883240"],"is_preprint":false},{"year":2017,"finding":"SNX8 interacts with JAK1 and IKKβ, promotes their association, and acts as a scaffold in the IFNγ-triggered noncanonical signaling pathway; IFNγ induces JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promotes IKKβ recruitment to the JAK1 complex and is required for IKKβ oligomerization and autophosphorylation at Ser177, selectively inducing downstream effector genes important for defense against Listeria monocytogenes.","method":"Co-immunoprecipitation, phosphorylation-site mutagenesis, Snx8-/- mouse infection model, downstream gene induction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phosphosite mutagenesis, and in vivo KO model with defined molecular phenotype in one study","pmids":["29180417"],"is_preprint":false},{"year":2018,"finding":"SNX8 recruits the class III phosphatidylinositol 3-kinase VPS34 to the innate immune adaptor MITA/STING, and this recruitment is required for trafficking of MITA from the ER to perinuclear microsomes after DNA virus infection, which is critical for MITA activation and induction of antiviral genes; Snx8-/- mice show impaired antiviral cytokine responses and higher HSV-1 lethality.","method":"Co-immunoprecipitation, Snx8-/- mouse infection model, subcellular trafficking assays, downstream gene induction assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying VPS34-SNX8-MITA complex, trafficking assay, and in vivo KO validation with multiple readouts","pmids":["30321235"],"is_preprint":false},{"year":2019,"finding":"Upon RNA virus infection SNX8 translocates from the cytosol to mitochondria, increases its association with the mitochondrial antiviral signaling adaptor VISA/MAVS, and promotes VISA aggregation, which is required for recruitment of downstream signaling components and induction of antiviral genes; Snx8-/- mice show impaired RNA virus-triggered cytokine responses and higher lethality.","method":"Subcellular fractionation/translocation assay, co-immunoprecipitation, VISA aggregation assay, Snx8-/- mouse infection model","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — translocation assay, Co-IP, aggregation assay, and in vivo KO model with multiple readouts in one study","pmids":["31511639"],"is_preprint":false},{"year":2019,"finding":"SNX8 localizes predominantly to early and late endosomes; SNX8 overexpression enhances total APP levels, cell-surface APP distribution, and non-amyloidogenic soluble APPα cleavage, while SNX8 depletion elevates Aβ levels; overexpression of SNX8 reduces Aβ accumulation and rescues cognitive impairment in APP/PS1 AD mice, implicating SNX8 in non-amyloidogenic APP trafficking through the endosomal pathway.","method":"Subcellular localization by fluorescence microscopy, SNX8 overexpression and siRNA knockdown in cells, APP cleavage and Aβ ELISA, APP/PS1 mouse behavioral rescue","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell fractionation/localization, gain- and loss-of-function with defined molecular readouts, and in vivo mouse model, single lab","pmids":["31551717"],"is_preprint":false},{"year":2024,"finding":"SNX8 promotes lysosome tubulation required for lysosome reformation; loss of SNX8 causes enlarged lysosomes and defective lysosomal storage characteristic of Lysosomal Storage Disorders (LSDs), while SNX8 overexpression or AAV-mediated SNX8 delivery to the brain rescues LSD phenotypes in human cells and mice; small molecules that enhance SNX8-lysosome binding similarly reverse LSD phenotypes.","method":"SNX8 KO in human cells (lysosome morphology and storage assays), SNX8 overexpression rescue, AAV delivery in LSD mouse model, small-molecule screen with SNX8-lysosome binding assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, gain-of-function rescue in cells and in vivo, pharmacological enhancement with binding assay) in one rigorous study","pmids":["38519472"],"is_preprint":false},{"year":2013,"finding":"SNX8 is expressed in neurons (soma) but not astrocytes or microglia; overexpression of GFP-SNX8 under moderately high cholesterol conditions caused redistribution of cholesterol within neurons, creating a phenotype similar to lysosomal cholesterol accumulation, suggesting SNX8 modulates intraneuronal cholesterol trafficking.","method":"Immunofluorescence localization in primary CNS cells, GFP-SNX8 lentiviral overexpression, filipin cholesterol staining","journal":"Journal of molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression method with morphological readout, no direct mechanistic pathway defined","pmids":["24362679"],"is_preprint":false}],"current_model":"SNX8 (Mvp1 in yeast) is a PX-BAR sorting nexin that, in its autoinhibited tetrameric state, requires unmasking of its PX and BAR domains to bind membranes; once active it deforms endosomal membranes into recycling tubules, recruits the dynamin-like GTPase Vps1 for tubule scission, and thereby drives a retromer-independent endosomal recycling pathway; in mammals, SNX8 additionally functions as a signaling scaffold that recruits VPS34 to the innate immune adaptor STING to enable its ER-to-perinuclear trafficking after DNA virus infection, promotes VISA/MAVS aggregation during RNA virus infection, and acts as a JAK1/IKKβ scaffold in the IFNγ non-canonical pathway, while also facilitating non-amyloidogenic APP trafficking and lysosome reformation by promoting lysosomal tubulation."},"narrative":{"mechanistic_narrative":"SNX8 (yeast Mvp1) is a PX-BAR sorting nexin that drives a retromer-independent endosomal membrane-remodeling and recycling pathway conserved from yeast to humans [PMID:34524084]. In its resting state the full-length protein adopts an autoinhibited tetramer (dimer-of-dimers) in which the membrane-engaging BAR surfaces and PX lipid-binding sites are occluded; the N-terminal low-complexity region mediates tetramerization, and its removal yields an active dimer with enhanced membrane association and remodeling [PMID:32198400]. Once active, SNX8/Mvp1 deforms the endosomal membrane, captures cargo bearing defined sorting motifs into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze scission and tubule release [PMID:7862158, PMID:34524084]; it can also cooperate with retromer via association with the Vps26 subunit to recycle tyrosine-motif cargo such as Vps68 [PMID:41883240]. The same tubulating activity supports lysosome reformation, where loss of SNX8 produces enlarged lysosomes and storage defects modeling Lysosomal Storage Disorders that are rescued by SNX8 restoration or small molecules enhancing SNX8-lysosome binding [PMID:38519472], and it promotes non-amyloidogenic APP trafficking through the endosomal pathway, reducing Aβ accumulation [PMID:31551717]. In mammals SNX8 additionally serves as a signaling scaffold in antiviral and inflammatory responses: it recruits the PI3-kinase VPS34 to the adaptor MITA/STING to enable ER-to-perinuclear trafficking and activation after DNA virus infection [PMID:30321235], translocates to mitochondria to promote VISA/MAVS aggregation during RNA virus infection [PMID:31511639], and bridges JAK1 and IKKβ as a phosphorylation-dependent scaffold in the noncanonical IFNγ pathway [PMID:29180417].","teleology":[{"year":1995,"claim":"Established the first functional link for the SNX8 ortholog, showing Mvp1 acts together with a dynamin-like GTPase to drive traffic to the vacuole, framing it as a membrane-trafficking factor.","evidence":"Multicopy suppressor genetic screen, epistasis, and colocalization with Vps1p in yeast","pmids":["7862158"],"confidence":"Medium","gaps":["Did not define direct membrane-binding or scission mechanism","No structural basis for Mvp1-Vps1 cooperation"]},{"year":2017,"claim":"Revealed a non-trafficking scaffold role, showing SNX8 bridges JAK1 and IKKβ and must itself be tyrosine-phosphorylated to organize the noncanonical IFNγ signaling complex against intracellular bacteria.","evidence":"Reciprocal Co-IP, phosphosite mutagenesis (Tyr95/Tyr126), and Snx8-/- Listeria infection model","pmids":["29180417"],"confidence":"High","gaps":["Structural basis of JAK1/IKKβ scaffolding unknown","Relationship to its endosomal PX-BAR function unresolved"]},{"year":2018,"claim":"Showed SNX8 functions as an antiviral adaptor by recruiting VPS34 to STING to license its ER-to-perinuclear trafficking, connecting SNX8's trafficking biology to innate immune adaptor activation.","evidence":"Co-IP of VPS34-SNX8-MITA complex, trafficking assays, and Snx8-/- HSV-1 infection model","pmids":["30321235"],"confidence":"High","gaps":["Whether PX/BAR membrane-deforming activity is required for STING trafficking not dissected","Direct binding interfaces not mapped"]},{"year":2019,"claim":"Extended SNX8's antiviral scaffolding to RNA virus sensing, showing it relocates to mitochondria and promotes aggregation of the adaptor VISA/MAVS to enable downstream signaling.","evidence":"Translocation/fractionation assay, Co-IP, VISA aggregation assay, and Snx8-/- RNA virus infection model","pmids":["31511639"],"confidence":"High","gaps":["Trigger for cytosol-to-mitochondria translocation unknown","Mechanism by which SNX8 nucleates VISA aggregation undefined"]},{"year":2019,"claim":"Linked SNX8 to disease-relevant endosomal cargo handling by showing it promotes non-amyloidogenic APP processing and limits Aβ accumulation.","evidence":"Endosomal localization, overexpression/knockdown with APP cleavage and Aβ ELISA, and APP/PS1 mouse behavioral rescue","pmids":["31551717"],"confidence":"Medium","gaps":["Direct SNX8-APP interaction not demonstrated","Sorting motif on APP recognized by SNX8 not identified"]},{"year":2020,"claim":"Defined the regulatory switch for SNX8 membrane engagement, showing full-length Mvp1 is an autoinhibited tetramer whose PX and BAR surfaces must be unmasked for activity.","evidence":"Cryo-EM of full-length Mvp1 with deletion mutagenesis and membrane-binding/remodeling assays","pmids":["32198400"],"confidence":"High","gaps":["Physiological signal that relieves autoinhibition unknown","Whether mammalian SNX8 uses identical autoinhibition not directly shown"]},{"year":2021,"claim":"Resolved the core endosomal mechanism, showing SNX8/Mvp1 deforms membranes, sorts motif-bearing cargo into tubules, and recruits Vps1 for scission in a retromer-independent recycling pathway conserved to human SNX8.","evidence":"Live-cell imaging, cargo-sorting and tubule assays, reconstitution in yeast, and human SNX8 complementation","pmids":["34524084"],"confidence":"High","gaps":["Full cargo repertoire incompletely defined","Coordination between Vps1 recruitment and autoinhibition release unresolved"]},{"year":2024,"claim":"Connected SNX8 tubulation to organelle homeostasis and human disease, showing it drives lysosome reformation and that restoring its activity reverses lysosomal storage phenotypes.","evidence":"SNX8 KO lysosome morphology/storage assays, overexpression and AAV rescue in LSD mouse model, and small-molecule SNX8-lysosome binding screen","pmids":["38519472"],"confidence":"High","gaps":["Cargo and scission machinery for lysosomal tubulation not specified","Mechanism of small-molecule enhancement of SNX8 binding undefined"]},{"year":2026,"claim":"Showed SNX8 is not strictly retromer-independent, demonstrating cooperation with retromer (Vps26) for recycling of tyrosine-motif cargo Vps68.","evidence":"Genetic deletion, vacuolar degradation assays, sorting-signal mutagenesis, and Mvp1-Vps26 co-IP in yeast","pmids":["41883240"],"confidence":"Medium","gaps":["Single co-IP without reciprocal/structural validation of the Mvp1-Vps26 interface","Generality of retromer cooperation beyond Vps68 unknown"]},{"year":null,"claim":"How a single PX-BAR protein partitions between autoinhibited membrane remodeling and its distinct cytosolic/mitochondrial signaling-scaffold roles, and what signals dictate each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking autoinhibition release to immune-scaffold activation","Structural basis of mammalian signaling complexes (STING/VPS34, VISA, JAK1/IKKβ) not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5]}],"complexes":["retromer (via Vps26 association)"],"partners":["VPS1","VPS26","VPS34","STING/MITA","VISA/MAVS","JAK1","IKKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5X2","full_name":"Sorting nexin-8","aliases":[],"length_aa":465,"mass_kda":52.6,"function":"May be involved in several stages of intracellular trafficking. May play a role in intracellular protein transport from early endosomes to the trans-Golgi network","subcellular_location":"Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y5X2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX8","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000106266","cell_line_id":"CID000261","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"POLR3GL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000261","total_profiled":1310},"omim":[{"mim_id":"614905","title":"SORTING NEXIN 8; SNX8","url":"https://www.omim.org/entry/614905"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX8"},"hgnc":{"alias_symbol":["Mvp1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5X2","domains":[{"cath_id":"3.30.1520.10","chopping":"66-197","consensus_level":"medium","plddt":90.9121,"start":66,"end":197},{"cath_id":"1.20.1270.60","chopping":"300-445","consensus_level":"high","plddt":93.3199,"start":300,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X2-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX8","jax_strain_url":"https://www.jax.org/strain/search?query=SNX8"},"sequence":{"accession":"Q9Y5X2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5X2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5X2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X2"}},"corpus_meta":[{"pmid":"7862158","id":"PMC_7862158","title":"The Saccharomyces cerevisiae MVP1 gene interacts with VPS1 and is required for vacuolar protein sorting.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7862158","citation_count":70,"is_preprint":false},{"pmid":"30321235","id":"PMC_30321235","title":"SNX8 modulates innate immune response to DNA virus by mediating trafficking and activation of MITA.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/30321235","citation_count":39,"is_preprint":false},{"pmid":"34524084","id":"PMC_34524084","title":"A PX-BAR protein Mvp1/SNX8 and a dynamin-like GTPase Vps1 drive endosomal recycling.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34524084","citation_count":31,"is_preprint":false},{"pmid":"29180417","id":"PMC_29180417","title":"SNX8 mediates IFNγ-triggered noncanonical signaling pathway and host defense against Listeria monocytogenes.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29180417","citation_count":26,"is_preprint":false},{"pmid":"31511639","id":"PMC_31511639","title":"SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA.","date":"2019","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31511639","citation_count":26,"is_preprint":false},{"pmid":"32198400","id":"PMC_32198400","title":"The cryo-EM structure of the SNX-BAR Mvp1 tetramer.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32198400","citation_count":21,"is_preprint":false},{"pmid":"24330158","id":"PMC_24330158","title":"Trafficking of the myrosinase-associated protein GLL23 requires NUC/MVP1/GOLD36/ERMO3 and the p24 protein CYB.","date":"2014","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24330158","citation_count":16,"is_preprint":false},{"pmid":"24362679","id":"PMC_24362679","title":"The expression of neuronal sorting nexin 8 (SNX8) exacerbates abnormal cholesterol levels.","date":"2013","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/24362679","citation_count":15,"is_preprint":false},{"pmid":"31568860","id":"PMC_31568860","title":"Small 7p22.3 microdeletion: Case report of Snx8 haploinsufficiency and neurological findings.","date":"2019","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31568860","citation_count":11,"is_preprint":false},{"pmid":"38519472","id":"PMC_38519472","title":"SNX8 enables lysosome reformation and reverses lysosomal storage disorder.","date":"2024","source":"Nature 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HIGH GRADE SEROUS OVARIAN CANCER","date":"2024-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.21.619446","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9017,"output_tokens":2838,"usd":0.034811,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10167,"output_tokens":3481,"usd":0.06893,"stage2_stop_reason":"end_turn"},"total_usd":0.103741,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Mvp1p (SNX8 ortholog) genetically interacts with the dynamin-like GTPase Vps1p and is required for vacuolar protein sorting; overproduction of Mvp1p suppresses dominant-negative vps1 alleles in a manner dependent on wild-type Vps1p, and Mvp1p colocalizes with Vps1p in vps1Δ and vps27Δ cells, indicating they act in concert to promote membrane traffic to the vacuole.\",\n      \"method\": \"Multicopy suppressor genetic screen, epistasis analysis, fluorescence colocalization in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus colocalization, single lab, two orthogonal methods\",\n      \"pmids\": [\"7862158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Full-length Mvp1 (yeast SNX8 ortholog) forms an autoinhibited tetramer (dimer-of-dimers) in which the membrane-interacting BAR surfaces are sequestered and PX lipid-binding sites are occluded; the N-terminal low-complexity region is essential for tetramerization, and deletion of this region produces a dimer with enhanced membrane association and remodeling activity, revealing an autoinhibitory mechanism for membrane binding.\",\n      \"method\": \"Cryo-EM structure of full-length Mvp1, deletion mutagenesis, membrane-binding/remodeling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with mutagenesis and functional membrane-binding assays in one rigorous study\",\n      \"pmids\": [\"32198400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mvp1/SNX8 deforms the endosomal membrane, sorts cargos containing a specific sorting motif into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze membrane scission and tubule release, defining a retromer-independent endosomal recycling pathway conserved from yeast to humans; human SNX8 likewise mediates formation of endosomal recycling tubules.\",\n      \"method\": \"Live-cell fluorescence microscopy, cargo-sorting assays, genetic and biochemical reconstitution in yeast, human SNX8 functional complementation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, cargo sorting, tubule formation, Vps1 recruitment assays) replicated in two organisms\",\n      \"pmids\": [\"34524084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Recycling of the endosomal protein Vps68 in yeast depends on both retromer and Mvp1/SNX8; a tyrosine-based recycling signal in the cytosolic tail of Vps68 is required for Mvp1-dependent recycling, and co-immunoprecipitation detected a physical association between Mvp1 and the retromer subunit Vps26, indicating Mvp1 can cooperate with retromer.\",\n      \"method\": \"Genetic deletion analysis, vacuolar degradation assays, identification of tyrosine recycling signal by mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"41883240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX8 interacts with JAK1 and IKKβ, promotes their association, and acts as a scaffold in the IFNγ-triggered noncanonical signaling pathway; IFNγ induces JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promotes IKKβ recruitment to the JAK1 complex and is required for IKKβ oligomerization and autophosphorylation at Ser177, selectively inducing downstream effector genes important for defense against Listeria monocytogenes.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-site mutagenesis, Snx8-/- mouse infection model, downstream gene induction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phosphosite mutagenesis, and in vivo KO model with defined molecular phenotype in one study\",\n      \"pmids\": [\"29180417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX8 recruits the class III phosphatidylinositol 3-kinase VPS34 to the innate immune adaptor MITA/STING, and this recruitment is required for trafficking of MITA from the ER to perinuclear microsomes after DNA virus infection, which is critical for MITA activation and induction of antiviral genes; Snx8-/- mice show impaired antiviral cytokine responses and higher HSV-1 lethality.\",\n      \"method\": \"Co-immunoprecipitation, Snx8-/- mouse infection model, subcellular trafficking assays, downstream gene induction assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying VPS34-SNX8-MITA complex, trafficking assay, and in vivo KO validation with multiple readouts\",\n      \"pmids\": [\"30321235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Upon RNA virus infection SNX8 translocates from the cytosol to mitochondria, increases its association with the mitochondrial antiviral signaling adaptor VISA/MAVS, and promotes VISA aggregation, which is required for recruitment of downstream signaling components and induction of antiviral genes; Snx8-/- mice show impaired RNA virus-triggered cytokine responses and higher lethality.\",\n      \"method\": \"Subcellular fractionation/translocation assay, co-immunoprecipitation, VISA aggregation assay, Snx8-/- mouse infection model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — translocation assay, Co-IP, aggregation assay, and in vivo KO model with multiple readouts in one study\",\n      \"pmids\": [\"31511639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX8 localizes predominantly to early and late endosomes; SNX8 overexpression enhances total APP levels, cell-surface APP distribution, and non-amyloidogenic soluble APPα cleavage, while SNX8 depletion elevates Aβ levels; overexpression of SNX8 reduces Aβ accumulation and rescues cognitive impairment in APP/PS1 AD mice, implicating SNX8 in non-amyloidogenic APP trafficking through the endosomal pathway.\",\n      \"method\": \"Subcellular localization by fluorescence microscopy, SNX8 overexpression and siRNA knockdown in cells, APP cleavage and Aβ ELISA, APP/PS1 mouse behavioral rescue\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell fractionation/localization, gain- and loss-of-function with defined molecular readouts, and in vivo mouse model, single lab\",\n      \"pmids\": [\"31551717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX8 promotes lysosome tubulation required for lysosome reformation; loss of SNX8 causes enlarged lysosomes and defective lysosomal storage characteristic of Lysosomal Storage Disorders (LSDs), while SNX8 overexpression or AAV-mediated SNX8 delivery to the brain rescues LSD phenotypes in human cells and mice; small molecules that enhance SNX8-lysosome binding similarly reverse LSD phenotypes.\",\n      \"method\": \"SNX8 KO in human cells (lysosome morphology and storage assays), SNX8 overexpression rescue, AAV delivery in LSD mouse model, small-molecule screen with SNX8-lysosome binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, gain-of-function rescue in cells and in vivo, pharmacological enhancement with binding assay) in one rigorous study\",\n      \"pmids\": [\"38519472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX8 is expressed in neurons (soma) but not astrocytes or microglia; overexpression of GFP-SNX8 under moderately high cholesterol conditions caused redistribution of cholesterol within neurons, creating a phenotype similar to lysosomal cholesterol accumulation, suggesting SNX8 modulates intraneuronal cholesterol trafficking.\",\n      \"method\": \"Immunofluorescence localization in primary CNS cells, GFP-SNX8 lentiviral overexpression, filipin cholesterol staining\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression method with morphological readout, no direct mechanistic pathway defined\",\n      \"pmids\": [\"24362679\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX8 (Mvp1 in yeast) is a PX-BAR sorting nexin that, in its autoinhibited tetrameric state, requires unmasking of its PX and BAR domains to bind membranes; once active it deforms endosomal membranes into recycling tubules, recruits the dynamin-like GTPase Vps1 for tubule scission, and thereby drives a retromer-independent endosomal recycling pathway; in mammals, SNX8 additionally functions as a signaling scaffold that recruits VPS34 to the innate immune adaptor STING to enable its ER-to-perinuclear trafficking after DNA virus infection, promotes VISA/MAVS aggregation during RNA virus infection, and acts as a JAK1/IKKβ scaffold in the IFNγ non-canonical pathway, while also facilitating non-amyloidogenic APP trafficking and lysosome reformation by promoting lysosomal tubulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX8 (yeast Mvp1) is a PX-BAR sorting nexin that drives a retromer-independent endosomal membrane-remodeling and recycling pathway conserved from yeast to humans [#2]. In its resting state the full-length protein adopts an autoinhibited tetramer (dimer-of-dimers) in which the membrane-engaging BAR surfaces and PX lipid-binding sites are occluded; the N-terminal low-complexity region mediates tetramerization, and its removal yields an active dimer with enhanced membrane association and remodeling [#1]. Once active, SNX8/Mvp1 deforms the endosomal membrane, captures cargo bearing defined sorting motifs into recycling tubules, and recruits the dynamin-like GTPase Vps1 to catalyze scission and tubule release [#0, #2]; it can also cooperate with retromer via association with the Vps26 subunit to recycle tyrosine-motif cargo such as Vps68 [#3]. The same tubulating activity supports lysosome reformation, where loss of SNX8 produces enlarged lysosomes and storage defects modeling Lysosomal Storage Disorders that are rescued by SNX8 restoration or small molecules enhancing SNX8-lysosome binding [#8], and it promotes non-amyloidogenic APP trafficking through the endosomal pathway, reducing Aβ accumulation [#7]. In mammals SNX8 additionally serves as a signaling scaffold in antiviral and inflammatory responses: it recruits the PI3-kinase VPS34 to the adaptor MITA/STING to enable ER-to-perinuclear trafficking and activation after DNA virus infection [#5], translocates to mitochondria to promote VISA/MAVS aggregation during RNA virus infection [#6], and bridges JAK1 and IKKβ as a phosphorylation-dependent scaffold in the noncanonical IFNγ pathway [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the first functional link for the SNX8 ortholog, showing Mvp1 acts together with a dynamin-like GTPase to drive traffic to the vacuole, framing it as a membrane-trafficking factor.\",\n      \"evidence\": \"Multicopy suppressor genetic screen, epistasis, and colocalization with Vps1p in yeast\",\n      \"pmids\": [\"7862158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define direct membrane-binding or scission mechanism\", \"No structural basis for Mvp1-Vps1 cooperation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-trafficking scaffold role, showing SNX8 bridges JAK1 and IKKβ and must itself be tyrosine-phosphorylated to organize the noncanonical IFNγ signaling complex against intracellular bacteria.\",\n      \"evidence\": \"Reciprocal Co-IP, phosphosite mutagenesis (Tyr95/Tyr126), and Snx8-/- Listeria infection model\",\n      \"pmids\": [\"29180417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of JAK1/IKKβ scaffolding unknown\", \"Relationship to its endosomal PX-BAR function unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SNX8 functions as an antiviral adaptor by recruiting VPS34 to STING to license its ER-to-perinuclear trafficking, connecting SNX8's trafficking biology to innate immune adaptor activation.\",\n      \"evidence\": \"Co-IP of VPS34-SNX8-MITA complex, trafficking assays, and Snx8-/- HSV-1 infection model\",\n      \"pmids\": [\"30321235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PX/BAR membrane-deforming activity is required for STING trafficking not dissected\", \"Direct binding interfaces not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SNX8's antiviral scaffolding to RNA virus sensing, showing it relocates to mitochondria and promotes aggregation of the adaptor VISA/MAVS to enable downstream signaling.\",\n      \"evidence\": \"Translocation/fractionation assay, Co-IP, VISA aggregation assay, and Snx8-/- RNA virus infection model\",\n      \"pmids\": [\"31511639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for cytosol-to-mitochondria translocation unknown\", \"Mechanism by which SNX8 nucleates VISA aggregation undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked SNX8 to disease-relevant endosomal cargo handling by showing it promotes non-amyloidogenic APP processing and limits Aβ accumulation.\",\n      \"evidence\": \"Endosomal localization, overexpression/knockdown with APP cleavage and Aβ ELISA, and APP/PS1 mouse behavioral rescue\",\n      \"pmids\": [\"31551717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SNX8-APP interaction not demonstrated\", \"Sorting motif on APP recognized by SNX8 not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the regulatory switch for SNX8 membrane engagement, showing full-length Mvp1 is an autoinhibited tetramer whose PX and BAR surfaces must be unmasked for activity.\",\n      \"evidence\": \"Cryo-EM of full-length Mvp1 with deletion mutagenesis and membrane-binding/remodeling assays\",\n      \"pmids\": [\"32198400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signal that relieves autoinhibition unknown\", \"Whether mammalian SNX8 uses identical autoinhibition not directly shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the core endosomal mechanism, showing SNX8/Mvp1 deforms membranes, sorts motif-bearing cargo into tubules, and recruits Vps1 for scission in a retromer-independent recycling pathway conserved to human SNX8.\",\n      \"evidence\": \"Live-cell imaging, cargo-sorting and tubule assays, reconstitution in yeast, and human SNX8 complementation\",\n      \"pmids\": [\"34524084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full cargo repertoire incompletely defined\", \"Coordination between Vps1 recruitment and autoinhibition release unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected SNX8 tubulation to organelle homeostasis and human disease, showing it drives lysosome reformation and that restoring its activity reverses lysosomal storage phenotypes.\",\n      \"evidence\": \"SNX8 KO lysosome morphology/storage assays, overexpression and AAV rescue in LSD mouse model, and small-molecule SNX8-lysosome binding screen\",\n      \"pmids\": [\"38519472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo and scission machinery for lysosomal tubulation not specified\", \"Mechanism of small-molecule enhancement of SNX8 binding undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed SNX8 is not strictly retromer-independent, demonstrating cooperation with retromer (Vps26) for recycling of tyrosine-motif cargo Vps68.\",\n      \"evidence\": \"Genetic deletion, vacuolar degradation assays, sorting-signal mutagenesis, and Mvp1-Vps26 co-IP in yeast\",\n      \"pmids\": [\"41883240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal/structural validation of the Mvp1-Vps26 interface\", \"Generality of retromer cooperation beyond Vps68 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single PX-BAR protein partitions between autoinhibited membrane remodeling and its distinct cytosolic/mitochondrial signaling-scaffold roles, and what signals dictate each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking autoinhibition release to immune-scaffold activation\", \"Structural basis of mammalian signaling complexes (STING/VPS34, VISA, JAK1/IKKβ) not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"retromer (via Vps26 association)\"],\n    \"partners\": [\"VPS1\", \"VPS26\", \"VPS34\", \"STING/MITA\", \"VISA/MAVS\", \"JAK1\", \"IKKB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}