{"gene":"STX11","run_date":"2026-06-10T10:51:54","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 in FHL-4 patients.","method":"Mutational analysis of FHL patients combined with functional characterization","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutational analysis linked to functional defect in granule exocytosis, single cohort but multiple patients","pmids":["16278825"],"is_preprint":false},{"year":2010,"finding":"A homozygous nonsense STX11 mutation (E25X) resulted in complete absence of detectable syntaxin-11 protein and abrogation of NK cell degranulation and cytotoxicity in vitro, while biallelic missense mutations (E36Q/E206K) preserved detectable syntaxin-11 and NK cell function, demonstrating that STX11 is required for NK cell degranulation.","method":"Western blot for protein expression, in vitro NK cell degranulation assay, cytotoxicity assay","journal":"Pediatric blood & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype (NK degranulation), single lab, two orthogonal functional methods","pmids":["20486178"],"is_preprint":false},{"year":2010,"finding":"A novel homozygous STX11 frameshift mutation (c.867dupG) caused absence of syntaxin-11 protein by Western blot; loss of STX11 impaired NK cell cytotoxicity, though NK cell degranulation was not impaired in one patient, indicating STX11 loss does not uniformly abrogate degranulation.","method":"Western blot (absence of protein), NK cell degranulation assay, cytotoxicity assay","journal":"Pediatric blood & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with cellular phenotype, single lab, two orthogonal functional assays","pmids":["21298754"],"is_preprint":false},{"year":2012,"finding":"Stx11-deficient (Stx11−/−) mouse lymphocytes exhibited a degranulation defect that was rescued by expression of human syntaxin-11 but not a C-terminal-truncated mutant, establishing that the C-terminal domain of syntaxin-11 is required for its function in lymphocyte degranulation.","method":"Stx11 knockout mouse model, LCMV infection-induced HLH, rescue experiment with wild-type vs. C-terminal-truncated human STX11","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO mouse model with rescue by wild-type but not mutant protein, multiple orthogonal readouts (degranulation defect, HLH phenotype), domain requirement established","pmids":["23160464"],"is_preprint":false},{"year":2014,"finding":"The STX11 missense mutation L58P (in the N-terminal Habc domain) abolished binding of syntaxin-11 to Munc18-2 in an ectopic expression system, and a separate R4A mutation at the N-terminus also abolished Munc18-2 binding, demonstrating that both the N-terminus and the Habc domain of syntaxin-11 are required for interaction with Munc18-2.","method":"Ectopic expression of mutant STX11, co-immunoprecipitation/binding assay for Munc18-2 interaction, NK cell degranulation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ectopic expression system with two distinct N-terminal mutations tested, Co-IP for binding, supported by NK cell functional defect; single lab","pmids":["24459464"],"is_preprint":false},{"year":2015,"finding":"Ectopic expression of STX11 suppressed proliferation of T-cell lines bearing genomic alterations at the STX11 locus, while a novel STX11 mutant (p.Arg78Cys) failed to exert these suppressive effects, indicating a tumor-suppressor function dependent on an intact STX11 protein.","method":"Ectopic overexpression of wild-type and mutant STX11 in T-cell lines, proliferation assays","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (proliferation assay), no pathway mechanism established beyond genomic context","pmids":["26176172"],"is_preprint":false},{"year":2022,"finding":"STX11 physically interacts with ATGL via its C-terminal domain and the patatin domain-containing segment of ATGL; STX11 overexpression prevents spatial translocation of ATGL onto lipid droplets by recruiting ATGL to the ER, inhibiting lipid droplet hydrolysis and lipophagy, while STX11 deficiency promotes lipolysis through the ATGL-SIRT1 signaling pathway.","method":"Co-IP (C-terminal STX11 / patatin domain of ATGL), subcellular localization (ER recruitment), gain-of-function and loss-of-function in hepatocytes, lipophagy assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, localization experiment linked to functional consequence, KO and OE with pathway readout; single lab","pmids":["35372814"],"is_preprint":false},{"year":2024,"finding":"STX11 interacts with SNAP25 (confirmed by Co-IP); the STX11-SNAP25 complex promotes autophagy in lung fibroblasts and inhibits TGF-β1-induced fibroblast activation via blocking the PI3K/AKT/mTOR pathway; the anti-fibrotic effect of STX11 was abolished when autophagy was blocked with chloroquine.","method":"Co-IP (STX11–SNAP25), overexpression in human lung fibroblasts, chloroquine autophagy blockade, in vivo bleomycin mouse model","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, pharmacological epistasis (autophagy blockade), in vivo and in vitro corroboration; single lab","pmids":["39523374"],"is_preprint":false},{"year":2026,"finding":"STX11 is palmitoylated, and in a palmitoylation-dependent manner suppresses AMPK signaling, attenuating ACC phosphorylation to enhance ACC enzymatic activity and stimulate de novo lipogenesis in colorectal cancer cells; genetic ablation of STX11 significantly impedes tumorigenesis in an AOM/DSS mouse model.","method":"Palmitoylation assay, AMPK pathway analysis (ACC phosphorylation), in vivo AOM/DSS mouse model with STX11 KO","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation identified as PTM, pathway placement via AMPK/ACC, in vivo KO model; single lab, abstract-level detail only","pmids":["41621610"],"is_preprint":false}],"current_model":"STX11 encodes a t-SNARE protein that is required for the final fusion of lytic granules with the plasma membrane in NK cells and cytotoxic T lymphocytes—a function that depends on its C-terminal domain and on interaction with Munc18-2 via both its N-terminus and Habc domain—while in non-immune contexts it regulates hepatic lipolysis by binding ATGL and restricting its translocation to lipid droplets, inhibits lung fibroblast activation through a SNAP25 interaction that promotes autophagy and blocks PI3K/AKT/mTOR signaling, and drives colorectal cancer lipogenesis by suppressing AMPK in a palmitoylation-dependent manner."},"narrative":{"mechanistic_narrative":"STX11 encodes a t-SNARE protein required for the final fusion of cytotoxic granules with the plasma membrane during lymphocyte killing, and loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) with defective granule exocytosis [PMID:16278825, PMID:20486178]. In NK cells and cytotoxic T lymphocytes, syntaxin-11 is required for degranulation and cytotoxicity, and its function depends on the C-terminal domain—a knockout mouse degranulation defect is rescued by full-length but not C-terminally truncated human protein [PMID:20486178, PMID:23160464]. Syntaxin-11 docks the fusion machinery through Munc18-2, an interaction that requires both its N-terminus and its Habc domain, as N-terminal (R4A) and Habc-domain (L58P) mutations each abolish binding [PMID:24459464]. Beyond immune secretion, STX11 has been assigned distinct roles in lipid and proliferative homeostasis: it binds ATGL via its C-terminal domain to retain ATGL at the ER and restrict its translocation to lipid droplets, thereby limiting lipolysis and lipophagy through the ATGL-SIRT1 axis [PMID:35372814]; it forms a complex with SNAP25 that promotes autophagy and blocks TGF-β1-driven lung fibroblast activation via the PI3K/AKT/mTOR pathway [PMID:39523374]; and it is palmitoylated, suppressing AMPK signaling to elevate ACC activity and de novo lipogenesis in colorectal cancer, where its ablation impedes tumorigenesis [PMID:41621610].","teleology":[{"year":2006,"claim":"Established STX11 as a disease gene by linking its loss-of-function to defective granule exocytosis, defining the gene's core secretory function in human disease.","evidence":"Mutational analysis of FHL patients with functional characterization of granule exocytosis","pmids":["16278825"],"confidence":"Medium","gaps":["Molecular partners and SNARE complex composition not defined","Cell type specificity of the secretory defect not resolved"]},{"year":2010,"claim":"Demonstrated that syntaxin-11 protein is required for NK cell degranulation and cytotoxicity by contrasting a null allele (E25X, absent protein, abrogated function) with missense alleles preserving protein and function.","evidence":"Western blot, in vitro NK degranulation and cytotoxicity assays on patient mutations","pmids":["20486178"],"confidence":"Medium","gaps":["Mechanism of how missense residues affect function not addressed","Direct fusion machinery interactions not tested"]},{"year":2010,"claim":"Refined the phenotype by showing STX11 loss consistently impairs NK cytotoxicity but does not uniformly abrogate degranulation, indicating context-dependence in the secretory defect.","evidence":"Western blot and functional assays on a frameshift mutation (c.867dupG)","pmids":["21298754"],"confidence":"Medium","gaps":["Basis for variable degranulation phenotype unexplained","No biochemical mechanism for cytotoxicity loss"]},{"year":2012,"claim":"Mapped the functional requirement to the C-terminal domain by rescuing the knockout degranulation defect with full-length but not C-terminally truncated human syntaxin-11, establishing a structure-function relationship in vivo.","evidence":"Stx11 knockout mouse, LCMV-induced HLH model, domain rescue experiment","pmids":["23160464"],"confidence":"High","gaps":["C-terminal binding partners not identified","SNARE pairing for granule fusion not reconstituted"]},{"year":2014,"claim":"Identified Munc18-2 as a binding partner and localized the interaction to both the N-terminus and Habc domain, explaining how disease mutations in these regions disrupt secretion.","evidence":"Ectopic expression with R4A and L58P mutants, Co-IP for Munc18-2 binding, NK degranulation assay","pmids":["24459464"],"confidence":"Medium","gaps":["Interaction shown in ectopic system, not endogenous complex","Structural basis of dual-site binding undefined"]},{"year":2015,"claim":"Proposed a tumor-suppressor function in T-cell malignancy, where ectopic wild-type but not mutant (R78C) STX11 suppresses proliferation.","evidence":"Ectopic overexpression of wild-type and mutant STX11 in T-cell lines, proliferation assays","pmids":["26176172"],"confidence":"Low","gaps":["Single method (proliferation) with no mechanistic pathway","No demonstration of endogenous loss driving proliferation"]},{"year":2022,"claim":"Extended STX11 function beyond immune cells by showing C-terminal binding to ATGL retains ATGL at the ER and restricts lipid droplet lipolysis and lipophagy via the ATGL-SIRT1 pathway.","evidence":"Co-IP, subcellular localization, gain- and loss-of-function in hepatocytes, lipophagy assay","pmids":["35372814"],"confidence":"Medium","gaps":["Whether ER retention uses SNARE fusion activity unknown","Relationship to immune secretory role not connected"]},{"year":2024,"claim":"Defined a SNAP25-dependent, autophagy-promoting anti-fibrotic role, with STX11 blocking PI3K/AKT/mTOR and TGF-β1-induced fibroblast activation.","evidence":"Co-IP, fibroblast overexpression, chloroquine autophagy blockade, in vivo bleomycin model","pmids":["39523374"],"confidence":"Medium","gaps":["Mechanism linking SNAP25 complex to autophagy induction unresolved","Direct effect on PI3K/AKT/mTOR components not shown"]},{"year":2026,"claim":"Implicated STX11 in cancer lipogenesis by showing palmitoylation-dependent suppression of AMPK that elevates ACC activity and de novo lipogenesis, with ablation impeding colorectal tumorigenesis.","evidence":"Palmitoylation assay, AMPK/ACC phosphorylation analysis, AOM/DSS mouse model with STX11 KO","pmids":["41621610"],"confidence":"Medium","gaps":["Direct AMPK substrate or binding relationship not defined","Abstract-level detail only; palmitoylation site not mapped"]},{"year":null,"claim":"How a single t-SNARE reconciles its canonical role in granule fusion with its reported regulation of lipid metabolism, autophagy, and AMPK signaling across diverse tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connects secretory and metabolic roles","Whether non-immune functions depend on SNARE fusion activity is untested","Tissue-specific partner switching not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["STXBP2","ATGL","SNAP25"],"other_free_text":[]}},"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":225,"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":73,"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":39,"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":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":38,"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":"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":20,"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":9,"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":"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":"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":"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":12598,"output_tokens":2294,"usd":0.036102,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9354,"output_tokens":3070,"usd":0.06176,"stage2_stop_reason":"end_turn"},"total_usd":0.097862,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","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 in FHL-4 patients.\",\n      \"method\": \"Mutational analysis of FHL patients combined with functional characterization\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational analysis linked to functional defect in granule exocytosis, single cohort but multiple patients\",\n      \"pmids\": [\"16278825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A homozygous nonsense STX11 mutation (E25X) resulted in complete absence of detectable syntaxin-11 protein and abrogation of NK cell degranulation and cytotoxicity in vitro, while biallelic missense mutations (E36Q/E206K) preserved detectable syntaxin-11 and NK cell function, demonstrating that STX11 is required for NK cell degranulation.\",\n      \"method\": \"Western blot for protein expression, in vitro NK cell degranulation assay, cytotoxicity assay\",\n      \"journal\": \"Pediatric blood & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype (NK degranulation), single lab, two orthogonal functional methods\",\n      \"pmids\": [\"20486178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A novel homozygous STX11 frameshift mutation (c.867dupG) caused absence of syntaxin-11 protein by Western blot; loss of STX11 impaired NK cell cytotoxicity, though NK cell degranulation was not impaired in one patient, indicating STX11 loss does not uniformly abrogate degranulation.\",\n      \"method\": \"Western blot (absence of protein), NK cell degranulation assay, cytotoxicity assay\",\n      \"journal\": \"Pediatric blood & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with cellular phenotype, single lab, two orthogonal functional assays\",\n      \"pmids\": [\"21298754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Stx11-deficient (Stx11−/−) mouse lymphocytes exhibited a degranulation defect that was rescued by expression of human syntaxin-11 but not a C-terminal-truncated mutant, establishing that the C-terminal domain of syntaxin-11 is required for its function in lymphocyte degranulation.\",\n      \"method\": \"Stx11 knockout mouse model, LCMV infection-induced HLH, rescue experiment with wild-type vs. C-terminal-truncated human STX11\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO mouse model with rescue by wild-type but not mutant protein, multiple orthogonal readouts (degranulation defect, HLH phenotype), domain requirement established\",\n      \"pmids\": [\"23160464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The STX11 missense mutation L58P (in the N-terminal Habc domain) abolished binding of syntaxin-11 to Munc18-2 in an ectopic expression system, and a separate R4A mutation at the N-terminus also abolished Munc18-2 binding, demonstrating that both the N-terminus and the Habc domain of syntaxin-11 are required for interaction with Munc18-2.\",\n      \"method\": \"Ectopic expression of mutant STX11, co-immunoprecipitation/binding assay for Munc18-2 interaction, NK cell degranulation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ectopic expression system with two distinct N-terminal mutations tested, Co-IP for binding, supported by NK cell functional defect; single lab\",\n      \"pmids\": [\"24459464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ectopic expression of STX11 suppressed proliferation of T-cell lines bearing genomic alterations at the STX11 locus, while a novel STX11 mutant (p.Arg78Cys) failed to exert these suppressive effects, indicating a tumor-suppressor function dependent on an intact STX11 protein.\",\n      \"method\": \"Ectopic overexpression of wild-type and mutant STX11 in T-cell lines, proliferation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (proliferation assay), no pathway mechanism established beyond genomic context\",\n      \"pmids\": [\"26176172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STX11 physically interacts with ATGL via its C-terminal domain and the patatin domain-containing segment of ATGL; STX11 overexpression prevents spatial translocation of ATGL onto lipid droplets by recruiting ATGL to the ER, inhibiting lipid droplet hydrolysis and lipophagy, while STX11 deficiency promotes lipolysis through the ATGL-SIRT1 signaling pathway.\",\n      \"method\": \"Co-IP (C-terminal STX11 / patatin domain of ATGL), subcellular localization (ER recruitment), gain-of-function and loss-of-function in hepatocytes, lipophagy assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, localization experiment linked to functional consequence, KO and OE with pathway readout; single lab\",\n      \"pmids\": [\"35372814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STX11 interacts with SNAP25 (confirmed by Co-IP); the STX11-SNAP25 complex promotes autophagy in lung fibroblasts and inhibits TGF-β1-induced fibroblast activation via blocking the PI3K/AKT/mTOR pathway; the anti-fibrotic effect of STX11 was abolished when autophagy was blocked with chloroquine.\",\n      \"method\": \"Co-IP (STX11–SNAP25), overexpression in human lung fibroblasts, chloroquine autophagy blockade, in vivo bleomycin mouse model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, pharmacological epistasis (autophagy blockade), in vivo and in vitro corroboration; single lab\",\n      \"pmids\": [\"39523374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STX11 is palmitoylated, and in a palmitoylation-dependent manner suppresses AMPK signaling, attenuating ACC phosphorylation to enhance ACC enzymatic activity and stimulate de novo lipogenesis in colorectal cancer cells; genetic ablation of STX11 significantly impedes tumorigenesis in an AOM/DSS mouse model.\",\n      \"method\": \"Palmitoylation assay, AMPK pathway analysis (ACC phosphorylation), in vivo AOM/DSS mouse model with STX11 KO\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation identified as PTM, pathway placement via AMPK/ACC, in vivo KO model; single lab, abstract-level detail only\",\n      \"pmids\": [\"41621610\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX11 encodes a t-SNARE protein that is required for the final fusion of lytic granules with the plasma membrane in NK cells and cytotoxic T lymphocytes—a function that depends on its C-terminal domain and on interaction with Munc18-2 via both its N-terminus and Habc domain—while in non-immune contexts it regulates hepatic lipolysis by binding ATGL and restricting its translocation to lipid droplets, inhibits lung fibroblast activation through a SNAP25 interaction that promotes autophagy and blocks PI3K/AKT/mTOR signaling, and drives colorectal cancer lipogenesis by suppressing AMPK in a palmitoylation-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STX11 encodes a t-SNARE protein required for the final fusion of cytotoxic granules with the plasma membrane during lymphocyte killing, and loss-of-function mutations cause familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) with defective granule exocytosis [#0, #1]. In NK cells and cytotoxic T lymphocytes, syntaxin-11 is required for degranulation and cytotoxicity, and its function depends on the C-terminal domain—a knockout mouse degranulation defect is rescued by full-length but not C-terminally truncated human protein [#1, #3]. Syntaxin-11 docks the fusion machinery through Munc18-2, an interaction that requires both its N-terminus and its Habc domain, as N-terminal (R4A) and Habc-domain (L58P) mutations each abolish binding [#4]. Beyond immune secretion, STX11 has been assigned distinct roles in lipid and proliferative homeostasis: it binds ATGL via its C-terminal domain to retain ATGL at the ER and restrict its translocation to lipid droplets, thereby limiting lipolysis and lipophagy through the ATGL-SIRT1 axis [#6]; it forms a complex with SNAP25 that promotes autophagy and blocks TGF-\\u03b21-driven lung fibroblast activation via the PI3K/AKT/mTOR pathway [#7]; and it is palmitoylated, suppressing AMPK signaling to elevate ACC activity and de novo lipogenesis in colorectal cancer, where its ablation impedes tumorigenesis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established STX11 as a disease gene by linking its loss-of-function to defective granule exocytosis, defining the gene's core secretory function in human disease.\",\n      \"evidence\": \"Mutational analysis of FHL patients with functional characterization of granule exocytosis\",\n      \"pmids\": [\"16278825\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular partners and SNARE complex composition not defined\", \"Cell type specificity of the secretory defect not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that syntaxin-11 protein is required for NK cell degranulation and cytotoxicity by contrasting a null allele (E25X, absent protein, abrogated function) with missense alleles preserving protein and function.\",\n      \"evidence\": \"Western blot, in vitro NK degranulation and cytotoxicity assays on patient mutations\",\n      \"pmids\": [\"20486178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of how missense residues affect function not addressed\", \"Direct fusion machinery interactions not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Refined the phenotype by showing STX11 loss consistently impairs NK cytotoxicity but does not uniformly abrogate degranulation, indicating context-dependence in the secretory defect.\",\n      \"evidence\": \"Western blot and functional assays on a frameshift mutation (c.867dupG)\",\n      \"pmids\": [\"21298754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for variable degranulation phenotype unexplained\", \"No biochemical mechanism for cytotoxicity loss\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the functional requirement to the C-terminal domain by rescuing the knockout degranulation defect with full-length but not C-terminally truncated human syntaxin-11, establishing a structure-function relationship in vivo.\",\n      \"evidence\": \"Stx11 knockout mouse, LCMV-induced HLH model, domain rescue experiment\",\n      \"pmids\": [\"23160464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C-terminal binding partners not identified\", \"SNARE pairing for granule fusion not reconstituted\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Munc18-2 as a binding partner and localized the interaction to both the N-terminus and Habc domain, explaining how disease mutations in these regions disrupt secretion.\",\n      \"evidence\": \"Ectopic expression with R4A and L58P mutants, Co-IP for Munc18-2 binding, NK degranulation assay\",\n      \"pmids\": [\"24459464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown in ectopic system, not endogenous complex\", \"Structural basis of dual-site binding undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Proposed a tumor-suppressor function in T-cell malignancy, where ectopic wild-type but not mutant (R78C) STX11 suppresses proliferation.\",\n      \"evidence\": \"Ectopic overexpression of wild-type and mutant STX11 in T-cell lines, proliferation assays\",\n      \"pmids\": [\"26176172\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (proliferation) with no mechanistic pathway\", \"No demonstration of endogenous loss driving proliferation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended STX11 function beyond immune cells by showing C-terminal binding to ATGL retains ATGL at the ER and restricts lipid droplet lipolysis and lipophagy via the ATGL-SIRT1 pathway.\",\n      \"evidence\": \"Co-IP, subcellular localization, gain- and loss-of-function in hepatocytes, lipophagy assay\",\n      \"pmids\": [\"35372814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER retention uses SNARE fusion activity unknown\", \"Relationship to immune secretory role not connected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a SNAP25-dependent, autophagy-promoting anti-fibrotic role, with STX11 blocking PI3K/AKT/mTOR and TGF-\\u03b21-induced fibroblast activation.\",\n      \"evidence\": \"Co-IP, fibroblast overexpression, chloroquine autophagy blockade, in vivo bleomycin model\",\n      \"pmids\": [\"39523374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SNAP25 complex to autophagy induction unresolved\", \"Direct effect on PI3K/AKT/mTOR components not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated STX11 in cancer lipogenesis by showing palmitoylation-dependent suppression of AMPK that elevates ACC activity and de novo lipogenesis, with ablation impeding colorectal tumorigenesis.\",\n      \"evidence\": \"Palmitoylation assay, AMPK/ACC phosphorylation analysis, AOM/DSS mouse model with STX11 KO\",\n      \"pmids\": [\"41621610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AMPK substrate or binding relationship not defined\", \"Abstract-level detail only; palmitoylation site not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single t-SNARE reconciles its canonical role in granule fusion with its reported regulation of lipid metabolism, autophagy, and AMPK signaling across diverse tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism connects secretory and metabolic roles\", \"Whether non-immune functions depend on SNARE fusion activity is untested\", \"Tissue-specific partner switching not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STXBP2\", \"ATGL\", \"SNAP25\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}