{"gene":"SNX11","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structures of truncated human SNX11 revealed a novel extended PX (PXe) domain with two additional α-helices at the C terminus beyond the canonical three-stranded β-sheet/three α-helix PX domain fold; mutagenesis showed these α-helices are indispensable for SNX11's in vitro functions, including inhibition of SNX10-induced vacuolation.","method":"X-ray crystallography of truncated human SNX11; structure-guided mutagenesis; in vitro vacuolation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination combined with mutagenesis and functional in vitro assay in a single rigorous study","pmids":["23615901"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of SNX11 bound to PI(3,5)P2 (open PPII-C loop conformation) and a potential PI3P-binding model (closed conformation) established SNX11 as a PI(3,5)P2 effector; SNX11 was shown by co-immunoprecipitation to interact with the V1D subunit of vacuolar H+-ATPase (V-ATPase), linking PI(3,5)P2 signaling to V-ATPase and endosome homeostasis; molecular dynamics simulations indicated the α5 helix can unfold from the PX domain upon membrane targeting or partner interaction.","method":"X-ray crystallography (PI(3,5)P2-bound and apo structures); co-immunoprecipitation; molecular dynamics simulations","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — crystal structures with ligand, Co-IP interaction, and MD simulations, multiple orthogonal methods in one study","pmids":["32561432"],"is_preprint":false},{"year":2016,"finding":"SNX11 interacts with TRPV3 and targets it from the plasma membrane to lysosomes for degradation; overexpression of SNX11 decreased TRPV3 plasma membrane levels and current amplitude in HEK293T cells, while knockdown of SNX11 increased native TRPV3 protein and Ca2+ influx in HaCaT keratinocytes; lysosomal inhibitors chloroquine and leupeptin blocked this degradation.","method":"Co-immunoprecipitation; subcellular fractionation/colocalization; overexpression and siRNA knockdown; patch-clamp electrophysiology; lysosomal inhibitor treatment","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction, functional KD/OE with defined electrophysiological readout, pharmacological rescue, multiple orthogonal methods","pmids":["26818531"],"is_preprint":false},{"year":2019,"finding":"Snx11-knockout mice displayed enhanced thermosensing behaviour (stronger preference for mild temperatures, increased sensitivity to noxious heat); keratinocytes from knockout mice exhibited larger TRPV3-mediated membrane currents and elevated TRPV3 plasma membrane expression, establishing SNX11 as a regulator of thermal perception through control of TRPV3 surface levels.","method":"Snx11 germline knockout mouse; thermal preference/avoidance behavioural assays; patch-clamp electrophysiology on primary keratinocytes; western blot; immunofluorescence","journal":"Genes, brain, and behavior","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined in vivo phenotype replicated at cellular level with electrophysiology and protein quantification","pmids":["31730264"],"is_preprint":false},{"year":2014,"finding":"SNX11 was identified as a required component of the microtubule-dependent shuttle that translocates the GPCR F2rl1 (PAR2) from the plasma membrane to the nucleus in retinal ganglion cells after receptor stimulation; nuclear F2rl1 then recruits transcription factor Sp1 to the Vegfa promoter to drive neovascularization.","method":"Live cell imaging; subcellular fractionation; loss-of-function experiments; in vivo retinal vascular development assays","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, localization and trafficking functional link established but SNX11-specific mechanistic details are limited within the abstract","pmids":["25216639"],"is_preprint":false},{"year":2019,"finding":"Genome-wide CRISPR knockout screening identified SNX11 as an essential host factor for SFTSV (Dabie bandavirus) infection; SNX11-KO HeLa cells showed significantly reduced viral replication, retention of viral glycoproteins in late endosomal compartments rather than ER/Golgi, increased endosomal pH, and elevated LAMP1 expression, indicating that SNX11 is required for viral penetration from endolysosomes into the cytoplasm.","method":"Genome-wide CRISPR-Cas9 knockout screen; SNX11-KO cell line generation; viral replication assay; immunofluorescence for viral glycoproteins; endosomal pH measurement; western blot for LAMP1","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal cellular readouts in a single lab study","pmids":["31215001"],"is_preprint":false},{"year":2025,"finding":"SNX11 interacts with the V1 subunit of V-ATPase on the endosomal membrane, regulates its expression level on that membrane, and thereby controls V-ATPase assembly and endosomal pH; SNX11 deletion disrupts V-ATPase assembly, raises endosomal pH, and inhibits replication of Dabie bandavirus, dengue virus, hantavirus, and influenza virus.","method":"Co-immunoprecipitation (SNX11 with V-ATPase V1 subunit); SNX11-KO cell lines; viral replication assays; endosomal pH measurement; western blot for V-ATPase subunits on endosomal fractions","journal":"Pathogens (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional KO phenotype in multiple viral models, single lab","pmids":["40732723"],"is_preprint":false}],"current_model":"SNX11 is an endosomal sorting nexin containing a structurally unique extended PX (PXe) domain that binds PI(3,5)P2 and interacts with the V1 subunit of V-ATPase to regulate endosomal pH and membrane homeostasis; it promotes lysosomal degradation of plasma membrane cargo (notably the thermosensor TRPV3) through direct protein–protein interactions, thereby modulating thermal perception in vivo, and also participates in nuclear trafficking of GPCRs (F2rl1/PAR2) to control Vegfa-driven angiogenesis, while its endosomal trafficking function makes it an essential host factor exploited by multiple enveloped viruses for endolysosomal escape."},"narrative":{"mechanistic_narrative":"SNX11 is an endosomal sorting nexin that regulates endolysosomal membrane homeostasis and the surface levels of plasma-membrane cargo through a structurally distinct lipid- and protein-binding module [PMID:23615901, PMID:26818531]. Its defining feature is an extended PX (PXe) domain in which two C-terminal α-helices augment the canonical PX fold and are indispensable for SNX11 function, including suppression of SNX10-induced vacuolation [PMID:23615901]; this domain binds PI(3,5)P2, establishing SNX11 as a phosphoinositide effector on endosomal membranes [PMID:32561432]. SNX11 couples this lipid recognition to the vacuolar H+-ATPase by interacting with the V1 subunit, controlling V-ATPase assembly and thereby endosomal pH [PMID:32561432, PMID:40732723]. Functionally, SNX11 directs cargo toward lysosomal degradation: it binds the thermosensor TRPV3 and routes it from the plasma membrane to lysosomes, lowering TRPV3 surface levels and current, so that loss of SNX11 elevates TRPV3 and sharpens thermal perception in vivo [PMID:26818531, PMID:31730264]. SNX11 is also a required component of a microtubule-dependent pathway that translocates the GPCR F2rl1 (PAR2) from the plasma membrane to the nucleus, where PAR2 recruits Sp1 to the Vegfa promoter to drive neovascularization [PMID:25216639]. Through its control of endosomal pH and V-ATPase function, SNX11 acts as an essential host factor that multiple enveloped viruses exploit for endolysosomal escape [PMID:31215001, PMID:40732723].","teleology":[{"year":2013,"claim":"Defined the structural basis of SNX11 by revealing an extended PX (PXe) domain, answering whether SNX11 is a conventional PX-domain protein and which features carry its activity.","evidence":"X-ray crystallography of truncated human SNX11 with structure-guided mutagenesis and an in vitro vacuolation assay","pmids":["23615901"],"confidence":"High","gaps":["Did not identify the physiological lipid ligand","No full-length structure or membrane-bound conformation","Cellular role beyond SNX10-vacuolation suppression not addressed"]},{"year":2014,"claim":"Placed SNX11 in a nuclear-trafficking pathway for a GPCR, showing it is required to shuttle F2rl1/PAR2 to the nucleus to activate Vegfa transcription and angiogenesis.","evidence":"Live-cell imaging, subcellular fractionation, loss-of-function, and in vivo retinal vascular assays","pmids":["25216639"],"confidence":"Medium","gaps":["SNX11-specific molecular mechanism within the shuttle not resolved","Direct SNX11–PAR2 interaction not established","Single-lab finding"]},{"year":2016,"claim":"Established SNX11 as a degradative sorting factor by identifying TRPV3 as cargo it routes from the plasma membrane to lysosomes, linking SNX11 to control of an ion channel's surface abundance.","evidence":"Co-IP, colocalization/fractionation, OE and siRNA knockdown, patch-clamp, and lysosomal inhibitor rescue in HEK293T and HaCaT cells","pmids":["26818531"],"confidence":"High","gaps":["Did not define the recognition motif on TRPV3","Lysosomal targeting machinery downstream of SNX11 unspecified","Generality across other channel cargo unknown"]},{"year":2019,"claim":"Demonstrated the in vivo physiological consequence of SNX11-mediated TRPV3 control, showing it tunes thermal perception in the whole animal.","evidence":"Snx11 germline knockout mice with thermal behavioural assays, plus keratinocyte patch-clamp and protein quantification","pmids":["31730264"],"confidence":"High","gaps":["Tissue-specific contributions not dissected","Whether other thermosensors are co-regulated unknown"]},{"year":2019,"claim":"Identified SNX11 as an essential host factor for viral infection, connecting its endosomal role to endolysosomal escape of an enveloped virus.","evidence":"Genome-wide CRISPR-Cas9 screen, SNX11-KO HeLa cells, viral replication and glycoprotein localization assays, endosomal pH and LAMP1 measurement","pmids":["31215001"],"confidence":"Medium","gaps":["Molecular basis of the pH/escape defect not mechanistically resolved at this stage","Single virus tested","Single-lab study"]},{"year":2020,"claim":"Defined SNX11 as a PI(3,5)P2 effector and linked its lipid binding to V-ATPase, providing a mechanistic bridge from phosphoinositide signaling to endosome homeostasis.","evidence":"Crystal structures of PI(3,5)P2-bound and apo SNX11, Co-IP with V-ATPase V1D subunit, and molecular dynamics simulations","pmids":["32561432"],"confidence":"High","gaps":["Functional consequence of V-ATPase binding not tested in cells here","α5 helix unfolding upon membrane targeting inferred from simulation, not measured","Direct binding to V-ATPase not validated reciprocally in vivo"]},{"year":2025,"claim":"Unified the endosomal and antiviral roles by showing SNX11 controls V-ATPase assembly and endosomal pH, explaining how its loss blocks escape of multiple enveloped viruses.","evidence":"Co-IP with V-ATPase V1 subunit, SNX11-KO cell lines, endosomal pH measurement, V-ATPase subunit western blots, and replication assays for SFTSV, dengue, hantavirus, and influenza","pmids":["40732723"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of the SNX11–V1 interaction not resolved","How PI(3,5)P2 binding and V-ATPase regulation are mechanistically coupled unclear","Single-lab study"]},{"year":null,"claim":"How SNX11's PI(3,5)P2 binding, V-ATPase regulation, and selective cargo recognition are mechanistically integrated into one degradative/sorting machine remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined cargo-recognition determinant linking lipid binding to substrate selection","No full-length membrane-bound structural model","Relationship between nuclear GPCR trafficking and endosomal V-ATPase roles unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,5,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["TRPV3","F2RL1","ATP6V1D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5W9","full_name":"Sorting nexin-11","aliases":[],"length_aa":270,"mass_kda":30.4,"function":"Phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes (PubMed:23615901). Regulates the levels of TRPV3 by promoting its trafficking from the cell membrane to lysosome for degradation (PubMed:26818531)","subcellular_location":"Cell membrane; Endosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y5W9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX11","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000002919","cell_line_id":"CID000686","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"FANCL","stoichiometry":10.0},{"gene":"PKMYT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000686","total_profiled":1310},"omim":[{"mim_id":"614906","title":"SORTING NEXIN 11; SNX11","url":"https://www.omim.org/entry/614906"},{"mim_id":"609194","title":"CDK5 AND ABL ENZYME SUBSTRATE 1; CABLES1","url":"https://www.omim.org/entry/609194"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX11"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5W9","domains":[{"cath_id":"3.30.1520.10","chopping":"18-164","consensus_level":"medium","plddt":94.4664,"start":18,"end":164}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5W9-F1-predicted_aligned_error_v6.png","plddt_mean":75.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX11","jax_strain_url":"https://www.jax.org/strain/search?query=SNX11"},"sequence":{"accession":"Q9Y5W9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5W9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5W9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5W9"}},"corpus_meta":[{"pmid":"25216639","id":"PMC_25216639","title":"Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis.","date":"2014","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25216639","citation_count":68,"is_preprint":false},{"pmid":"31561579","id":"PMC_31561579","title":"Analysis of Promoter-Associated Chromatin Interactions Reveals Biologically Relevant Candidate Target Genes at Endometrial Cancer Risk Loci.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31561579","citation_count":34,"is_preprint":false},{"pmid":"23615901","id":"PMC_23615901","title":"Structure of sorting nexin 11 (SNX11) reveals a novel extended phox homology (PX) domain critical for inhibition of SNX10-induced vacuolation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23615901","citation_count":23,"is_preprint":false},{"pmid":"31215001","id":"PMC_31215001","title":"SNX11 Identified as an Essential Host Factor for SFTS Virus Infection by CRISPR Knockout Screening.","date":"2019","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/31215001","citation_count":21,"is_preprint":false},{"pmid":"32561432","id":"PMC_32561432","title":"Molecular Basis for PI(3,5)P2 Recognition by SNX11, a Protein Involved in Lysosomal Degradation and Endosome Homeostasis Regulation.","date":"2020","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32561432","citation_count":18,"is_preprint":false},{"pmid":"26818531","id":"PMC_26818531","title":"Sorting Nexin 11 Regulates Lysosomal Degradation of Plasma Membrane TRPV3.","date":"2016","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/26818531","citation_count":18,"is_preprint":false},{"pmid":"31730264","id":"PMC_31730264","title":"Sorting nexin 11 knockout mice exhibit enhanced thermosensing behaviour.","date":"2019","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/31730264","citation_count":5,"is_preprint":false},{"pmid":"39401154","id":"PMC_39401154","title":"Identification of candidate genes for endometrial cancer in multi-omics: a Mendelian randomization analysis.","date":"2024","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39401154","citation_count":3,"is_preprint":false},{"pmid":"40732723","id":"PMC_40732723","title":"SNX11 Deletion Inhibits Dabie bandavirus Infection by Interfering with the Assembly of V-ATPase.","date":"2025","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40732723","citation_count":0,"is_preprint":false},{"pmid":"41377584","id":"PMC_41377584","title":"Enhanced oral nanomedicine utilizing biomineralized oncolytic virus for synergistic gastrointestinal cancer therapy.","date":"2025","source":"Materials today. Bio","url":"https://pubmed.ncbi.nlm.nih.gov/41377584","citation_count":0,"is_preprint":false},{"pmid":"41789074","id":"PMC_41789074","title":"Multi-dimensional evidence establishing the causal association between metabolic syndrome and gout and the molecular mechanisms of comorbidity.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41789074","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7445,"output_tokens":2023,"usd":0.02634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8990,"output_tokens":2890,"usd":0.0586,"stage2_stop_reason":"end_turn"},"total_usd":0.08494,"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\": 2013,\n      \"finding\": \"Crystal structures of truncated human SNX11 revealed a novel extended PX (PXe) domain with two additional α-helices at the C terminus beyond the canonical three-stranded β-sheet/three α-helix PX domain fold; mutagenesis showed these α-helices are indispensable for SNX11's in vitro functions, including inhibition of SNX10-induced vacuolation.\",\n      \"method\": \"X-ray crystallography of truncated human SNX11; structure-guided mutagenesis; in vitro vacuolation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination combined with mutagenesis and functional in vitro assay in a single rigorous study\",\n      \"pmids\": [\"23615901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of SNX11 bound to PI(3,5)P2 (open PPII-C loop conformation) and a potential PI3P-binding model (closed conformation) established SNX11 as a PI(3,5)P2 effector; SNX11 was shown by co-immunoprecipitation to interact with the V1D subunit of vacuolar H+-ATPase (V-ATPase), linking PI(3,5)P2 signaling to V-ATPase and endosome homeostasis; molecular dynamics simulations indicated the α5 helix can unfold from the PX domain upon membrane targeting or partner interaction.\",\n      \"method\": \"X-ray crystallography (PI(3,5)P2-bound and apo structures); co-immunoprecipitation; molecular dynamics simulations\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — crystal structures with ligand, Co-IP interaction, and MD simulations, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32561432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SNX11 interacts with TRPV3 and targets it from the plasma membrane to lysosomes for degradation; overexpression of SNX11 decreased TRPV3 plasma membrane levels and current amplitude in HEK293T cells, while knockdown of SNX11 increased native TRPV3 protein and Ca2+ influx in HaCaT keratinocytes; lysosomal inhibitors chloroquine and leupeptin blocked this degradation.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation/colocalization; overexpression and siRNA knockdown; patch-clamp electrophysiology; lysosomal inhibitor treatment\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction, functional KD/OE with defined electrophysiological readout, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26818531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Snx11-knockout mice displayed enhanced thermosensing behaviour (stronger preference for mild temperatures, increased sensitivity to noxious heat); keratinocytes from knockout mice exhibited larger TRPV3-mediated membrane currents and elevated TRPV3 plasma membrane expression, establishing SNX11 as a regulator of thermal perception through control of TRPV3 surface levels.\",\n      \"method\": \"Snx11 germline knockout mouse; thermal preference/avoidance behavioural assays; patch-clamp electrophysiology on primary keratinocytes; western blot; immunofluorescence\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined in vivo phenotype replicated at cellular level with electrophysiology and protein quantification\",\n      \"pmids\": [\"31730264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX11 was identified as a required component of the microtubule-dependent shuttle that translocates the GPCR F2rl1 (PAR2) from the plasma membrane to the nucleus in retinal ganglion cells after receptor stimulation; nuclear F2rl1 then recruits transcription factor Sp1 to the Vegfa promoter to drive neovascularization.\",\n      \"method\": \"Live cell imaging; subcellular fractionation; loss-of-function experiments; in vivo retinal vascular development assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, localization and trafficking functional link established but SNX11-specific mechanistic details are limited within the abstract\",\n      \"pmids\": [\"25216639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genome-wide CRISPR knockout screening identified SNX11 as an essential host factor for SFTSV (Dabie bandavirus) infection; SNX11-KO HeLa cells showed significantly reduced viral replication, retention of viral glycoproteins in late endosomal compartments rather than ER/Golgi, increased endosomal pH, and elevated LAMP1 expression, indicating that SNX11 is required for viral penetration from endolysosomes into the cytoplasm.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen; SNX11-KO cell line generation; viral replication assay; immunofluorescence for viral glycoproteins; endosomal pH measurement; western blot for LAMP1\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal cellular readouts in a single lab study\",\n      \"pmids\": [\"31215001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX11 interacts with the V1 subunit of V-ATPase on the endosomal membrane, regulates its expression level on that membrane, and thereby controls V-ATPase assembly and endosomal pH; SNX11 deletion disrupts V-ATPase assembly, raises endosomal pH, and inhibits replication of Dabie bandavirus, dengue virus, hantavirus, and influenza virus.\",\n      \"method\": \"Co-immunoprecipitation (SNX11 with V-ATPase V1 subunit); SNX11-KO cell lines; viral replication assays; endosomal pH measurement; western blot for V-ATPase subunits on endosomal fractions\",\n      \"journal\": \"Pathogens (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional KO phenotype in multiple viral models, single lab\",\n      \"pmids\": [\"40732723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX11 is an endosomal sorting nexin containing a structurally unique extended PX (PXe) domain that binds PI(3,5)P2 and interacts with the V1 subunit of V-ATPase to regulate endosomal pH and membrane homeostasis; it promotes lysosomal degradation of plasma membrane cargo (notably the thermosensor TRPV3) through direct protein–protein interactions, thereby modulating thermal perception in vivo, and also participates in nuclear trafficking of GPCRs (F2rl1/PAR2) to control Vegfa-driven angiogenesis, while its endosomal trafficking function makes it an essential host factor exploited by multiple enveloped viruses for endolysosomal escape.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX11 is an endosomal sorting nexin that regulates endolysosomal membrane homeostasis and the surface levels of plasma-membrane cargo through a structurally distinct lipid- and protein-binding module [#0, #2]. Its defining feature is an extended PX (PXe) domain in which two C-terminal α-helices augment the canonical PX fold and are indispensable for SNX11 function, including suppression of SNX10-induced vacuolation [#0]; this domain binds PI(3,5)P2, establishing SNX11 as a phosphoinositide effector on endosomal membranes [#1]. SNX11 couples this lipid recognition to the vacuolar H+-ATPase by interacting with the V1 subunit, controlling V-ATPase assembly and thereby endosomal pH [#1, #6]. Functionally, SNX11 directs cargo toward lysosomal degradation: it binds the thermosensor TRPV3 and routes it from the plasma membrane to lysosomes, lowering TRPV3 surface levels and current, so that loss of SNX11 elevates TRPV3 and sharpens thermal perception in vivo [#2, #3]. SNX11 is also a required component of a microtubule-dependent pathway that translocates the GPCR F2rl1 (PAR2) from the plasma membrane to the nucleus, where PAR2 recruits Sp1 to the Vegfa promoter to drive neovascularization [#4]. Through its control of endosomal pH and V-ATPase function, SNX11 acts as an essential host factor that multiple enveloped viruses exploit for endolysosomal escape [#5, #6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis of SNX11 by revealing an extended PX (PXe) domain, answering whether SNX11 is a conventional PX-domain protein and which features carry its activity.\",\n      \"evidence\": \"X-ray crystallography of truncated human SNX11 with structure-guided mutagenesis and an in vitro vacuolation assay\",\n      \"pmids\": [\"23615901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological lipid ligand\", \"No full-length structure or membrane-bound conformation\", \"Cellular role beyond SNX10-vacuolation suppression not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SNX11 in a nuclear-trafficking pathway for a GPCR, showing it is required to shuttle F2rl1/PAR2 to the nucleus to activate Vegfa transcription and angiogenesis.\",\n      \"evidence\": \"Live-cell imaging, subcellular fractionation, loss-of-function, and in vivo retinal vascular assays\",\n      \"pmids\": [\"25216639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SNX11-specific molecular mechanism within the shuttle not resolved\", \"Direct SNX11–PAR2 interaction not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SNX11 as a degradative sorting factor by identifying TRPV3 as cargo it routes from the plasma membrane to lysosomes, linking SNX11 to control of an ion channel's surface abundance.\",\n      \"evidence\": \"Co-IP, colocalization/fractionation, OE and siRNA knockdown, patch-clamp, and lysosomal inhibitor rescue in HEK293T and HaCaT cells\",\n      \"pmids\": [\"26818531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the recognition motif on TRPV3\", \"Lysosomal targeting machinery downstream of SNX11 unspecified\", \"Generality across other channel cargo unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated the in vivo physiological consequence of SNX11-mediated TRPV3 control, showing it tunes thermal perception in the whole animal.\",\n      \"evidence\": \"Snx11 germline knockout mice with thermal behavioural assays, plus keratinocyte patch-clamp and protein quantification\",\n      \"pmids\": [\"31730264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not dissected\", \"Whether other thermosensors are co-regulated unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SNX11 as an essential host factor for viral infection, connecting its endosomal role to endolysosomal escape of an enveloped virus.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen, SNX11-KO HeLa cells, viral replication and glycoprotein localization assays, endosomal pH and LAMP1 measurement\",\n      \"pmids\": [\"31215001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the pH/escape defect not mechanistically resolved at this stage\", \"Single virus tested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined SNX11 as a PI(3,5)P2 effector and linked its lipid binding to V-ATPase, providing a mechanistic bridge from phosphoinositide signaling to endosome homeostasis.\",\n      \"evidence\": \"Crystal structures of PI(3,5)P2-bound and apo SNX11, Co-IP with V-ATPase V1D subunit, and molecular dynamics simulations\",\n      \"pmids\": [\"32561432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of V-ATPase binding not tested in cells here\", \"α5 helix unfolding upon membrane targeting inferred from simulation, not measured\", \"Direct binding to V-ATPase not validated reciprocally in vivo\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Unified the endosomal and antiviral roles by showing SNX11 controls V-ATPase assembly and endosomal pH, explaining how its loss blocks escape of multiple enveloped viruses.\",\n      \"evidence\": \"Co-IP with V-ATPase V1 subunit, SNX11-KO cell lines, endosomal pH measurement, V-ATPase subunit western blots, and replication assays for SFTSV, dengue, hantavirus, and influenza\",\n      \"pmids\": [\"40732723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of the SNX11–V1 interaction not resolved\", \"How PI(3,5)P2 binding and V-ATPase regulation are mechanistically coupled unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX11's PI(3,5)P2 binding, V-ATPase regulation, and selective cargo recognition are mechanistically integrated into one degradative/sorting machine remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined cargo-recognition determinant linking lipid binding to substrate selection\", \"No full-length membrane-bound structural model\", \"Relationship between nuclear GPCR trafficking and endosomal V-ATPase roles unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRPV3\", \"F2rl1\", \"ATP6V1D\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}