{"gene":"STX11","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2006,"finding":"STX11 encodes a t-SNARE protein involved in intracellular trafficking; loss-of-function mutations in STX11 cause defective granule exocytosis (FHL-4) in NK cells and cytotoxic T lymphocytes","method":"Mutational analysis in FHL patients; functional characterization of STX11 as a t-SNARE","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — patient mutation data with functional context, replicated across multiple cohorts","pmids":["16278825"],"is_preprint":false},{"year":2010,"finding":"Nonsense mutation in STX11 (E25X) results in absence of detectable syntaxin-11 protein and abrogation of NK cell degranulation and cytotoxicity in vitro, while biallelic heterozygous missense mutations (E36Q/E206K) preserve detectable syntaxin-11 and NK cell degranulation and cytotoxicity","method":"Western blot for protein expression; in vitro NK cell degranulation and cytotoxicity assays","journal":"Pediatric blood & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assays correlating protein expression with NK cell degranulation defect, single lab","pmids":["20486178"],"is_preprint":false},{"year":2012,"finding":"Syntaxin-11 deficiency in mice (Stx11−/−) causes a degranulation defect in lymphocytes that can be rescued by expression of human syntaxin-11 but not by a C-terminal-truncated mutant, demonstrating the C-terminus is required for degranulation function","method":"Stx11-knockout mouse model; LCMV infection-induced HLH; rescue experiments with wild-type and truncated human STX11","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — genetic KO with defined cellular phenotype, rescue by WT but not mutant, replicated in vivo","pmids":["23160464"],"is_preprint":false},{"year":2014,"finding":"The N-terminal Habc domain of syntaxin-11 is required for binding to Munc18-2 (STXBP2); missense mutations L58P (Habc domain) and R4A (N-terminus) each abolish syntaxin-11 binding to Munc18-2 and impair NK cell degranulation","method":"Co-immunoprecipitation in ectopic expression system; NK cell degranulation assay; Western blot for protein expression","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays with multiple mutants, functional NK cell assay, clear mechanistic finding","pmids":["24459464"],"is_preprint":false},{"year":2022,"finding":"STX11 physically interacts with ATGL (adipose triglyceride lipase) via its C-terminus binding to the patatin domain of ATGL; STX11 overexpression prevents translocation of ATGL onto lipid droplets by recruiting ATGL to the ER, thereby inhibiting lipid droplet degradation and lipophagy in hepatocytes; STX11 deficiency promotes ATGL-SIRT1 signaling and enhances lipophagy","method":"Co-immunoprecipitation; domain mapping; subcellular localization by imaging; STX11 overexpression and knockdown in hepatocytes; lipid droplet and lipophagy assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping, localization imaging, KO/OE with defined lipid phenotype; single lab","pmids":["35372814"],"is_preprint":false},{"year":2024,"finding":"STX11 interacts with SNAP25 (Co-IP), and together they promote fibroblast autophagy and inhibit TGF-β1-induced fibroblast activation via blocking the PI3K/AKT/mTOR pathway; STX11 overexpression in vivo protects against bleomycin-induced pulmonary fibrosis","method":"Co-immunoprecipitation; autophagy assays (with chloroquine blockade); PI3K/AKT/mTOR pathway analysis; bleomycin mouse model; fibroblast proliferation and migration assays","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, in vivo rescue, pathway inhibitor validation; single lab","pmids":["39523374"],"is_preprint":false},{"year":2026,"finding":"STX11 modulates the AMPK signaling pathway in a palmitoylation-dependent manner, attenuating ACC phosphorylation to enhance its enzymatic activity and stimulate de novo lipogenesis in colorectal cancer; genetic ablation of STX11 impedes tumorigenesis in an AOM/DSS mouse model","method":"STX11 genetic ablation (AOM/DSS CRC mouse model); AMPK pathway and ACC phosphorylation assays; palmitoylation-dependent mechanism; in vitro and in vivo studies","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with defined metabolic phenotype and pathway analysis; palmitoylation mechanism; single lab","pmids":["41621610"],"is_preprint":false},{"year":2009,"finding":"STX11 CpG island undergoes de novo methylation from E18 onwards in mouse tissues with tissue-specific kinetics; alleles of Stx11 are unequally expressed in F1 mice, reflecting cis-regulatory factors and suggesting epigenetic/imprinting control of expression","method":"DNA methylation analysis; allele-specific expression in F1 mice; developmental tissue expression profiling","journal":"Mammalian genome","confidence":"Low","confidence_rationale":"Tier 3 — single lab, methylation and expression profiling without direct functional manipulation of the methylation","pmids":["19169743"],"is_preprint":false},{"year":2025,"finding":"Structural analysis indicates that an STX11 R129P mutation disrupts key interactions with Munc18-2; patient cells with this heterozygous mutation exhibit decreased NK cell degranulation and cytotoxicity, and diminished CD8+ T cell degranulation, which can be restored by in vitro IL-2 treatment","method":"Structural modeling; NK and CD8+ T cell degranulation assays; IL-2 rescue experiments; Western blot for STX11 expression","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3 — structural analysis is computational; functional assays in single patient, single lab","pmids":["40066033"],"is_preprint":false}],"current_model":"STX11 encodes a t-SNARE protein that mediates the final fusion of lytic granules with the plasma membrane in NK cells and cytotoxic T lymphocytes, functioning through an N-terminal Habc domain and C-terminus required for binding to Munc18-2 (STXBP2) and for degranulation; loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4, while in non-immune contexts STX11 also interacts with ATGL to regulate hepatic lipolysis/lipophagy and with SNAP25 to modulate fibroblast autophagy via the PI3K/AKT/mTOR pathway, and regulates lipogenesis in colorectal cancer via palmitoylation-dependent AMPK suppression."},"narrative":{"teleology":[{"year":2006,"claim":"Identifying STX11 as a t-SNARE whose loss-of-function mutations cause defective granule exocytosis in NK cells and CTLs established the gene's causal role in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4).","evidence":"Mutational analysis in FHL patient cohorts combined with classification of STX11 as a t-SNARE","pmids":["16278825"],"confidence":"Medium","gaps":["Precise membrane fusion step mediated by STX11 not defined","Domain requirements for degranulation function unknown","Binding partners in the SNARE complex not identified"]},{"year":2010,"claim":"Demonstrating that a nonsense mutation (E25X) abolishes STX11 protein expression and NK cell degranulation while certain missense mutations preserve both linked protein abundance to functional output.","evidence":"Western blot for protein expression and in vitro NK cell degranulation/cytotoxicity assays on patient-derived cells","pmids":["20486178"],"confidence":"Medium","gaps":["Mechanism by which residual protein maintains function not characterized","Contribution of specific STX11 domains to degranulation not tested"]},{"year":2012,"claim":"Using a knockout mouse model with rescue experiments resolved that the C-terminus of syntaxin-11 is essential for degranulation, since wild-type but not C-terminally truncated human STX11 rescued the lymphocyte defect.","evidence":"Stx11-knockout mice with LCMV-induced HLH; rescue by WT vs. truncated human STX11 constructs","pmids":["23160464"],"confidence":"High","gaps":["Identity of the C-terminal binding partner(s) not yet determined","Structural basis for C-terminal requirement unknown"]},{"year":2014,"claim":"Mapping the STX11–Munc18-2 (STXBP2) interaction to the N-terminal Habc domain and showing that point mutations L58P and R4A abolish binding and impair degranulation defined the molecular interface required for effector function.","evidence":"Co-immunoprecipitation with domain and point mutants; NK cell degranulation assays","pmids":["24459464"],"confidence":"High","gaps":["Atomic-resolution structure of the STX11–Munc18-2 complex not solved","Other SNARE partners forming the fusogenic complex with STX11 not identified","How Munc18-2 binding enables membrane fusion mechanistically remains open"]},{"year":2022,"claim":"Discovery of a non-immune role: STX11 physically sequesters ATGL at the ER via a C-terminal interaction with ATGL's patatin domain, preventing ATGL translocation to lipid droplets and inhibiting lipophagy in hepatocytes.","evidence":"Co-IP with domain mapping; subcellular localization imaging; STX11 overexpression/knockdown in hepatocytes with lipid droplet and lipophagy quantification","pmids":["35372814"],"confidence":"Medium","gaps":["Physiological triggers controlling STX11-ATGL interaction not identified","Whether SNARE activity is required for ATGL sequestration is unclear","In vivo hepatic phenotype of STX11 loss not fully characterized"]},{"year":2024,"claim":"STX11 forms a complex with SNAP25 to promote fibroblast autophagy and block PI3K/AKT/mTOR signaling, revealing a SNARE-dependent anti-fibrotic mechanism validated in a bleomycin pulmonary fibrosis model.","evidence":"Co-IP of STX11–SNAP25; autophagy flux assays; PI3K/AKT/mTOR pathway analysis; bleomycin mouse model with STX11 overexpression","pmids":["39523374"],"confidence":"Medium","gaps":["Whether STX11–SNAP25 interaction mediates autophagosome fusion or upstream signaling is unresolved","Specificity of STX11 vs. other syntaxins in this pathway not tested"]},{"year":2026,"claim":"STX11 promotes de novo lipogenesis in colorectal cancer by suppressing AMPK-mediated ACC phosphorylation in a palmitoylation-dependent manner, and its ablation impedes tumorigenesis in vivo.","evidence":"AOM/DSS colorectal cancer mouse model with STX11 genetic ablation; AMPK/ACC signaling and palmitoylation assays","pmids":["41621610"],"confidence":"Medium","gaps":["How palmitoylation alters STX11's ability to modulate AMPK is mechanistically undefined","Whether this lipogenic function is generalizable beyond colorectal cancer is unknown","Independent replication in a second CRC model not reported"]},{"year":null,"claim":"A complete structural model of STX11 in complex with Munc18-2 and other SNARE partners is lacking, and the mechanistic relationship between its immune degranulation function and its non-immune roles in lipid metabolism and autophagy remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of STX11 or its complexes","Whether STX11's SNARE fusogenic activity is required for its metabolic and autophagic roles is untested","The full set of v-SNARE partners for STX11-mediated lytic granule fusion is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["STXBP2","SNAP25","PNPLA2"],"other_free_text":[]},"mechanistic_narrative":"STX11 encodes a SNARE protein that mediates lytic granule exocytosis in NK cells and cytotoxic T lymphocytes, and loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) [PMID:16278825, PMID:20486178]. Syntaxin-11 binds Munc18-2 (STXBP2) through its N-terminal Habc domain and requires its C-terminus for degranulation function, as shown by rescue experiments in Stx11-knockout mice and mutagenesis of critical residues (L58P, R4A) that abolish the interaction and impair NK cell degranulation [PMID:23160464, PMID:24459464]. Beyond immune cell degranulation, STX11 physically interacts with ATGL via its C-terminus to sequester ATGL at the endoplasmic reticulum, thereby inhibiting lipid droplet degradation and lipophagy in hepatocytes, and interacts with SNAP25 to promote autophagy and suppress the PI3K/AKT/mTOR pathway in fibroblasts [PMID:35372814, PMID:39523374]. STX11 also promotes de novo lipogenesis in colorectal cancer through palmitoylation-dependent suppression of AMPK-mediated ACC phosphorylation [PMID:41621610]."},"prefetch_data":{"uniprot":{"accession":"O75558","full_name":"Syntaxin-11","aliases":[],"length_aa":287,"mass_kda":33.2,"function":"SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network","subcellular_location":"Membrane; Golgi apparatus, trans-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/O75558/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STX11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STX11","total_profiled":1310},"omim":[{"mim_id":"613101","title":"HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE; FHL5","url":"https://www.omim.org/entry/613101"},{"mim_id":"608898","title":"HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 3; FHL3","url":"https://www.omim.org/entry/608898"},{"mim_id":"608897","title":"UNC13 HOMOLOG D; UNC13D","url":"https://www.omim.org/entry/608897"},{"mim_id":"605014","title":"SYNTAXIN 11; STX11","url":"https://www.omim.org/entry/605014"},{"mim_id":"603868","title":"RAS-ASSOCIATED PROTEIN RAB27A; RAB27A","url":"https://www.omim.org/entry/603868"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":141.4}],"url":"https://www.proteinatlas.org/search/STX11"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75558","domains":[{"cath_id":"1.20.58.70","chopping":"45-236","consensus_level":"medium","plddt":85.8445,"start":45,"end":236}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75558","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75558-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75558-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX11","jax_strain_url":"https://www.jax.org/strain/search?query=STX11"},"sequence":{"accession":"O75558","fasta_url":"https://rest.uniprot.org/uniprotkb/O75558.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75558/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75558"}},"corpus_meta":[{"pmid":"16278825","id":"PMC_16278825","title":"Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16278825","citation_count":222,"is_preprint":false},{"pmid":"18710388","id":"PMC_18710388","title":"Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis.","date":"2008","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/18710388","citation_count":72,"is_preprint":false},{"pmid":"23160464","id":"PMC_23160464","title":"Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23160464","citation_count":72,"is_preprint":false},{"pmid":"29665027","id":"PMC_29665027","title":"Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29665027","citation_count":38,"is_preprint":false},{"pmid":"21674762","id":"PMC_21674762","title":"Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.","date":"2011","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21674762","citation_count":36,"is_preprint":false},{"pmid":"20486178","id":"PMC_20486178","title":"STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America.","date":"2010","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20486178","citation_count":33,"is_preprint":false},{"pmid":"39523374","id":"PMC_39523374","title":"Overexpression of STX11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the PI3K/AKT/mTOR pathway.","date":"2024","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39523374","citation_count":32,"is_preprint":false},{"pmid":"35372814","id":"PMC_35372814","title":"The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35372814","citation_count":23,"is_preprint":false},{"pmid":"24459464","id":"PMC_24459464","title":"An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24459464","citation_count":19,"is_preprint":false},{"pmid":"26176172","id":"PMC_26176172","title":"STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas.","date":"2015","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/26176172","citation_count":15,"is_preprint":false},{"pmid":"21298754","id":"PMC_21298754","title":"Unusual functional manifestations of a novel STX11 frameshift mutation in two infants with familial hemophagocytic lymphohistiocytosis type 4 (FHL4).","date":"2010","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21298754","citation_count":12,"is_preprint":false},{"pmid":"19967551","id":"PMC_19967551","title":"Novel syntaxin 11 gene (STX11) mutation in three Argentinean patients with hemophagocytic lymphohistiocytosis.","date":"2009","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19967551","citation_count":11,"is_preprint":false},{"pmid":"34339548","id":"PMC_34339548","title":"Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis.","date":"2021","source":"International journal of laboratory hematology","url":"https://pubmed.ncbi.nlm.nih.gov/34339548","citation_count":8,"is_preprint":false},{"pmid":"26709266","id":"PMC_26709266","title":"A Novel Syntaxin 11 Gene (STX11) Mutation c.650T>C, p.Leu217Pro, in a Korean Child With Familial Hemophagocytic Lymphohistiocytosis.","date":"2016","source":"Annals of laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26709266","citation_count":2,"is_preprint":false},{"pmid":"31770233","id":"PMC_31770233","title":"Familial hemophagocytic lymphohistiocytosis in a girl with a novel homozygous mutation of STX11: A case report.","date":"2019","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31770233","citation_count":2,"is_preprint":false},{"pmid":"19169743","id":"PMC_19169743","title":"Developmental methylation program and concerted expression of Stx11 in mouse tissues.","date":"2009","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/19169743","citation_count":1,"is_preprint":false},{"pmid":"37595757","id":"PMC_37595757","title":"The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37595757","citation_count":0,"is_preprint":false},{"pmid":"41028446","id":"PMC_41028446","title":"Hemophagocytic lymphohistiocytosis caused by dual mutations in UNC13D and STX11 induced by HHV-7: a case report and review of the literature.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41028446","citation_count":0,"is_preprint":false},{"pmid":"41621610","id":"PMC_41621610","title":"Palmitoylated STX11 suppresses AMPK to drive lipogenesis and colorectal cancer.","date":"2026","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/41621610","citation_count":0,"is_preprint":false},{"pmid":"40066033","id":"PMC_40066033","title":"T and NK cell functionality in a patient harboring heterozygous novel BCL11B p.Asp632fsAla∗91 and STX11 p.R129P mutations.","date":"2025","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/40066033","citation_count":0,"is_preprint":false},{"pmid":"40970921","id":"PMC_40970921","title":"Late-onset hemophagocytic lymphohistiocytosis associated with monoallelic STX11 mutation in an adult: a case report and rationale for early allogeneic hematopoietic cell transplantation.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/40970921","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11879,"output_tokens":2176,"usd":0.034139},"stage2":{"model":"claude-opus-4-6","input_tokens":5475,"output_tokens":2268,"usd":0.126112},"total_usd":0.160251,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"STX11 encodes a t-SNARE protein involved in intracellular trafficking; loss-of-function mutations in STX11 cause defective granule exocytosis (FHL-4) in NK cells and cytotoxic T lymphocytes\",\n      \"method\": \"Mutational analysis in FHL patients; functional characterization of STX11 as a t-SNARE\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient mutation data with functional context, replicated across multiple cohorts\",\n      \"pmids\": [\"16278825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nonsense mutation in STX11 (E25X) results in absence of detectable syntaxin-11 protein and abrogation of NK cell degranulation and cytotoxicity in vitro, while biallelic heterozygous missense mutations (E36Q/E206K) preserve detectable syntaxin-11 and NK cell degranulation and cytotoxicity\",\n      \"method\": \"Western blot for protein expression; in vitro NK cell degranulation and cytotoxicity assays\",\n      \"journal\": \"Pediatric blood & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assays correlating protein expression with NK cell degranulation defect, single lab\",\n      \"pmids\": [\"20486178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Syntaxin-11 deficiency in mice (Stx11−/−) causes a degranulation defect in lymphocytes that can be rescued by expression of human syntaxin-11 but not by a C-terminal-truncated mutant, demonstrating the C-terminus is required for degranulation function\",\n      \"method\": \"Stx11-knockout mouse model; LCMV infection-induced HLH; rescue experiments with wild-type and truncated human STX11\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO with defined cellular phenotype, rescue by WT but not mutant, replicated in vivo\",\n      \"pmids\": [\"23160464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminal Habc domain of syntaxin-11 is required for binding to Munc18-2 (STXBP2); missense mutations L58P (Habc domain) and R4A (N-terminus) each abolish syntaxin-11 binding to Munc18-2 and impair NK cell degranulation\",\n      \"method\": \"Co-immunoprecipitation in ectopic expression system; NK cell degranulation assay; Western blot for protein expression\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with multiple mutants, functional NK cell assay, clear mechanistic finding\",\n      \"pmids\": [\"24459464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STX11 physically interacts with ATGL (adipose triglyceride lipase) via its C-terminus binding to the patatin domain of ATGL; STX11 overexpression prevents translocation of ATGL onto lipid droplets by recruiting ATGL to the ER, thereby inhibiting lipid droplet degradation and lipophagy in hepatocytes; STX11 deficiency promotes ATGL-SIRT1 signaling and enhances lipophagy\",\n      \"method\": \"Co-immunoprecipitation; domain mapping; subcellular localization by imaging; STX11 overexpression and knockdown in hepatocytes; lipid droplet and lipophagy assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, localization imaging, KO/OE with defined lipid phenotype; single lab\",\n      \"pmids\": [\"35372814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STX11 interacts with SNAP25 (Co-IP), and together they promote fibroblast autophagy and inhibit TGF-β1-induced fibroblast activation via blocking the PI3K/AKT/mTOR pathway; STX11 overexpression in vivo protects against bleomycin-induced pulmonary fibrosis\",\n      \"method\": \"Co-immunoprecipitation; autophagy assays (with chloroquine blockade); PI3K/AKT/mTOR pathway analysis; bleomycin mouse model; fibroblast proliferation and migration assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, in vivo rescue, pathway inhibitor validation; single lab\",\n      \"pmids\": [\"39523374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STX11 modulates the AMPK signaling pathway in a palmitoylation-dependent manner, attenuating ACC phosphorylation to enhance its enzymatic activity and stimulate de novo lipogenesis in colorectal cancer; genetic ablation of STX11 impedes tumorigenesis in an AOM/DSS mouse model\",\n      \"method\": \"STX11 genetic ablation (AOM/DSS CRC mouse model); AMPK pathway and ACC phosphorylation assays; palmitoylation-dependent mechanism; in vitro and in vivo studies\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined metabolic phenotype and pathway analysis; palmitoylation mechanism; single lab\",\n      \"pmids\": [\"41621610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STX11 CpG island undergoes de novo methylation from E18 onwards in mouse tissues with tissue-specific kinetics; alleles of Stx11 are unequally expressed in F1 mice, reflecting cis-regulatory factors and suggesting epigenetic/imprinting control of expression\",\n      \"method\": \"DNA methylation analysis; allele-specific expression in F1 mice; developmental tissue expression profiling\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, methylation and expression profiling without direct functional manipulation of the methylation\",\n      \"pmids\": [\"19169743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Structural analysis indicates that an STX11 R129P mutation disrupts key interactions with Munc18-2; patient cells with this heterozygous mutation exhibit decreased NK cell degranulation and cytotoxicity, and diminished CD8+ T cell degranulation, which can be restored by in vitro IL-2 treatment\",\n      \"method\": \"Structural modeling; NK and CD8+ T cell degranulation assays; IL-2 rescue experiments; Western blot for STX11 expression\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — structural analysis is computational; functional assays in single patient, single lab\",\n      \"pmids\": [\"40066033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX11 encodes a t-SNARE protein that mediates the final fusion of lytic granules with the plasma membrane in NK cells and cytotoxic T lymphocytes, functioning through an N-terminal Habc domain and C-terminus required for binding to Munc18-2 (STXBP2) and for degranulation; loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4, while in non-immune contexts STX11 also interacts with ATGL to regulate hepatic lipolysis/lipophagy and with SNAP25 to modulate fibroblast autophagy via the PI3K/AKT/mTOR pathway, and regulates lipogenesis in colorectal cancer via palmitoylation-dependent AMPK suppression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STX11 encodes a SNARE protein that mediates lytic granule exocytosis in NK cells and cytotoxic T lymphocytes, and loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) [PMID:16278825, PMID:20486178]. Syntaxin-11 binds Munc18-2 (STXBP2) through its N-terminal Habc domain and requires its C-terminus for degranulation function, as shown by rescue experiments in Stx11-knockout mice and mutagenesis of critical residues (L58P, R4A) that abolish the interaction and impair NK cell degranulation [PMID:23160464, PMID:24459464]. Beyond immune cell degranulation, STX11 physically interacts with ATGL via its C-terminus to sequester ATGL at the endoplasmic reticulum, thereby inhibiting lipid droplet degradation and lipophagy in hepatocytes, and interacts with SNAP25 to promote autophagy and suppress the PI3K/AKT/mTOR pathway in fibroblasts [PMID:35372814, PMID:39523374]. STX11 also promotes de novo lipogenesis in colorectal cancer through palmitoylation-dependent suppression of AMPK-mediated ACC phosphorylation [PMID:41621610].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying STX11 as a t-SNARE whose loss-of-function mutations cause defective granule exocytosis in NK cells and CTLs established the gene's causal role in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4).\",\n      \"evidence\": \"Mutational analysis in FHL patient cohorts combined with classification of STX11 as a t-SNARE\",\n      \"pmids\": [\"16278825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Precise membrane fusion step mediated by STX11 not defined\",\n        \"Domain requirements for degranulation function unknown\",\n        \"Binding partners in the SNARE complex not identified\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that a nonsense mutation (E25X) abolishes STX11 protein expression and NK cell degranulation while certain missense mutations preserve both linked protein abundance to functional output.\",\n      \"evidence\": \"Western blot for protein expression and in vitro NK cell degranulation/cytotoxicity assays on patient-derived cells\",\n      \"pmids\": [\"20486178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which residual protein maintains function not characterized\",\n        \"Contribution of specific STX11 domains to degranulation not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Using a knockout mouse model with rescue experiments resolved that the C-terminus of syntaxin-11 is essential for degranulation, since wild-type but not C-terminally truncated human STX11 rescued the lymphocyte defect.\",\n      \"evidence\": \"Stx11-knockout mice with LCMV-induced HLH; rescue by WT vs. truncated human STX11 constructs\",\n      \"pmids\": [\"23160464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the C-terminal binding partner(s) not yet determined\",\n        \"Structural basis for C-terminal requirement unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the STX11–Munc18-2 (STXBP2) interaction to the N-terminal Habc domain and showing that point mutations L58P and R4A abolish binding and impair degranulation defined the molecular interface required for effector function.\",\n      \"evidence\": \"Co-immunoprecipitation with domain and point mutants; NK cell degranulation assays\",\n      \"pmids\": [\"24459464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the STX11–Munc18-2 complex not solved\",\n        \"Other SNARE partners forming the fusogenic complex with STX11 not identified\",\n        \"How Munc18-2 binding enables membrane fusion mechanistically remains open\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of a non-immune role: STX11 physically sequesters ATGL at the ER via a C-terminal interaction with ATGL's patatin domain, preventing ATGL translocation to lipid droplets and inhibiting lipophagy in hepatocytes.\",\n      \"evidence\": \"Co-IP with domain mapping; subcellular localization imaging; STX11 overexpression/knockdown in hepatocytes with lipid droplet and lipophagy quantification\",\n      \"pmids\": [\"35372814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological triggers controlling STX11-ATGL interaction not identified\",\n        \"Whether SNARE activity is required for ATGL sequestration is unclear\",\n        \"In vivo hepatic phenotype of STX11 loss not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"STX11 forms a complex with SNAP25 to promote fibroblast autophagy and block PI3K/AKT/mTOR signaling, revealing a SNARE-dependent anti-fibrotic mechanism validated in a bleomycin pulmonary fibrosis model.\",\n      \"evidence\": \"Co-IP of STX11–SNAP25; autophagy flux assays; PI3K/AKT/mTOR pathway analysis; bleomycin mouse model with STX11 overexpression\",\n      \"pmids\": [\"39523374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether STX11–SNAP25 interaction mediates autophagosome fusion or upstream signaling is unresolved\",\n        \"Specificity of STX11 vs. other syntaxins in this pathway not tested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"STX11 promotes de novo lipogenesis in colorectal cancer by suppressing AMPK-mediated ACC phosphorylation in a palmitoylation-dependent manner, and its ablation impedes tumorigenesis in vivo.\",\n      \"evidence\": \"AOM/DSS colorectal cancer mouse model with STX11 genetic ablation; AMPK/ACC signaling and palmitoylation assays\",\n      \"pmids\": [\"41621610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How palmitoylation alters STX11's ability to modulate AMPK is mechanistically undefined\",\n        \"Whether this lipogenic function is generalizable beyond colorectal cancer is unknown\",\n        \"Independent replication in a second CRC model not reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete structural model of STX11 in complex with Munc18-2 and other SNARE partners is lacking, and the mechanistic relationship between its immune degranulation function and its non-immune roles in lipid metabolism and autophagy remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of STX11 or its complexes\",\n        \"Whether STX11's SNARE fusogenic activity is required for its metabolic and autophagic roles is untested\",\n        \"The full set of v-SNARE partners for STX11-mediated lytic granule fusion is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"STXBP2\",\n      \"SNAP25\",\n      \"PNPLA2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}