Affinage

STX11

Syntaxin-11 · UniProt O75558

Length
287 aa
Mass
33.2 kDa
Annotated
2026-06-10
21 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2006 Medium

    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

    PMID:16278825

    Open questions at the time
    • Molecular partners and SNARE complex composition not defined
    • Cell type specificity of the secretory defect not resolved
  2. 2010 Medium

    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

    PMID:20486178

    Open questions at the time
    • Mechanism of how missense residues affect function not addressed
    • Direct fusion machinery interactions not tested
  3. 2010 Medium

    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)

    PMID:21298754

    Open questions at the time
    • Basis for variable degranulation phenotype unexplained
    • No biochemical mechanism for cytotoxicity loss
  4. 2012 High

    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

    PMID:23160464

    Open questions at the time
    • C-terminal binding partners not identified
    • SNARE pairing for granule fusion not reconstituted
  5. 2014 Medium

    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

    PMID:24459464

    Open questions at the time
    • Interaction shown in ectopic system, not endogenous complex
    • Structural basis of dual-site binding undefined
  6. 2015 Low

    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

    PMID:26176172

    Open questions at the time
    • Single method (proliferation) with no mechanistic pathway
    • No demonstration of endogenous loss driving proliferation
  7. 2022 Medium

    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

    PMID:35372814

    Open questions at the time
    • Whether ER retention uses SNARE fusion activity unknown
    • Relationship to immune secretory role not connected
  8. 2024 Medium

    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

    PMID:39523374

    Open questions at the time
    • Mechanism linking SNAP25 complex to autophagy induction unresolved
    • Direct effect on PI3K/AKT/mTOR components not shown
  9. 2026 Medium

    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

    PMID:41621610

    Open questions at the time
    • Direct AMPK substrate or binding relationship not defined
    • Abstract-level detail only; palmitoylation site not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 2
Partners
ATGLSNAP25STXBP2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 STX11 encodes a t-SNARE protein involved in intracellular trafficking; loss-of-function mutations in STX11 cause defective granule exocytosis in FHL-4 patients. Mutational analysis of FHL patients combined with functional characterization Human mutation Medium 16278825
2010 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. Western blot for protein expression, in vitro NK cell degranulation assay, cytotoxicity assay Pediatric blood & cancer Medium 20486178
2010 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. Western blot (absence of protein), NK cell degranulation assay, cytotoxicity assay Pediatric blood & cancer Medium 21298754
2012 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. Stx11 knockout mouse model, LCMV infection-induced HLH, rescue experiment with wild-type vs. C-terminal-truncated human STX11 Blood High 23160464
2014 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. Ectopic expression of mutant STX11, co-immunoprecipitation/binding assay for Munc18-2 interaction, NK cell degranulation assay Frontiers in immunology Medium 24459464
2015 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. Ectopic overexpression of wild-type and mutant STX11 in T-cell lines, proliferation assays Cancer science Low 26176172
2022 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. Co-IP (C-terminal STX11 / patatin domain of ATGL), subcellular localization (ER recruitment), gain-of-function and loss-of-function in hepatocytes, lipophagy assay iScience Medium 35372814
2024 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. Co-IP (STX11–SNAP25), overexpression in human lung fibroblasts, chloroquine autophagy blockade, in vivo bleomycin mouse model Signal transduction and targeted therapy Medium 39523374
2026 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. Palmitoylation assay, AMPK pathway analysis (ACC phosphorylation), in vivo AOM/DSS mouse model with STX11 KO Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 41621610

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Human mutation 225 16278825
2008 Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. British journal of haematology 73 18710388
2012 Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. Blood 72 23160464
2018 Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. Clinical genetics 39 29665027
2024 Overexpression of STX11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the PI3K/AKT/mTOR pathway. Signal transduction and targeted therapy 38 39523374
2011 Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatric blood & cancer 38 21674762
2010 STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatric blood & cancer 33 20486178
2022 The vesicular transporter STX11 governs ATGL-mediated hepatic lipolysis and lipophagy. iScience 23 35372814
2014 An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2. Frontiers in immunology 20 24459464
2015 STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas. Cancer science 15 26176172
2010 Unusual functional manifestations of a novel STX11 frameshift mutation in two infants with familial hemophagocytic lymphohistiocytosis type 4 (FHL4). Pediatric blood & cancer 12 21298754
2009 Novel syntaxin 11 gene (STX11) mutation in three Argentinean patients with hemophagocytic lymphohistiocytosis. Journal of clinical immunology 11 19967551
2021 Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis. International journal of laboratory hematology 9 34339548
2019 Familial hemophagocytic lymphohistiocytosis in a girl with a novel homozygous mutation of STX11: A case report. Medicine 2 31770233
2016 A Novel Syntaxin 11 Gene (STX11) Mutation c.650T>C, p.Leu217Pro, in a Korean Child With Familial Hemophagocytic Lymphohistiocytosis. Annals of laboratory medicine 2 26709266
2009 Developmental methylation program and concerted expression of Stx11 in mouse tissues. Mammalian genome : official journal of the International Mammalian Genome Society 1 19169743
2026 Palmitoylated STX11 suppresses AMPK to drive lipogenesis and colorectal cancer. Biochimica et biophysica acta. Molecular and cell biology of lipids 0 41621610
2025 T and NK cell functionality in a patient harboring heterozygous novel BCL11B p.Asp632fsAla∗91 and STX11 p.R129P mutations. Heliyon 0 40066033
2025 Late-onset hemophagocytic lymphohistiocytosis associated with monoallelic STX11 mutation in an adult: a case report and rationale for early allogeneic hematopoietic cell transplantation. Annals of hematology 0 40970921
2025 Hemophagocytic lymphohistiocytosis caused by dual mutations in UNC13D and STX11 induced by HHV-7: a case report and review of the literature. Annals of hematology 0 41028446
2023 The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity. The Journal of allergy and clinical immunology 0 37595757

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