{"gene":"STX7","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":2018,"finding":"STX7 (lysosomal) forms a SNARE complex with SNAP29 and autophagosomal YKT6 to mediate autophagosome-lysosome fusion independently of STX17; YKT6 depletion completely blocked fusion in STX17-knockout cells, establishing two independent SNARE complexes for autophagosomal fusion.","method":"STX17 knockout HeLa cells, siRNA depletion of YKT6, co-immunoprecipitation of SNARE complex, fluorescence microscopy of autophagosome-lysosome fusion","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, genetic KO epistasis, replicated across two SNARE pathways with rigorous controls","pmids":["29789439"],"is_preprint":false},{"year":2011,"finding":"STX7 is required for lytic granule release from cytotoxic T lymphocytes (CTLs); it localizes to the immunological synapse and late endosomes (co-localizing with Rab7), and its loss prevents both TCR recycling through endosomes and lytic granule accumulation at the IS, without reducing total granule number.","method":"Dominant-negative STX7 expression, siRNA knockdown, evanescent wave microscopy of individual lytic granules, high-resolution STED nanoscopy, CTL killing assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (DN construct, siRNA, live imaging, nanoscopy) with defined cellular phenotype","pmids":["21438968"],"is_preprint":false},{"year":2011,"finding":"STX7 participates in SNARE complexes STX6/STX7/Vti1b and STX7/STX8/Vti1b on endosomal membranes; STX11 regulates late endosome-to-lysosome fusion by controlling availability of Vti1b to form these Q-SNARE complexes, establishing STX7 as a component of the endosomal fusion machinery in macrophages.","method":"Co-immunoprecipitation of SNARE complexes, siRNA depletion, rescue with siRNA-resistant construct, live imaging of endocytic compartments in macrophages","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA with rescue, multiple SNARE complex compositions defined","pmids":["21388490"],"is_preprint":false},{"year":2008,"finding":"CSF-1 upregulates STX7 expression in primary macrophages and induces rapid serine phosphorylation of STX7, enhancing its binding to SNARE partners Vti1b, STX8, and VAMP8; mutagenesis of serine residues in the Habc domain and/or linker region identified these as the sites through which CSF-1 regulates SNARE complex assembly.","method":"Primary mouse macrophage culture, kinase inhibitor studies, mutagenesis of STX7 serine residues, co-immunoprecipitation of SNARE partners, western blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with co-IP and pharmacological inhibition in primary cells","pmids":["18710945"],"is_preprint":false},{"year":2014,"finding":"UVRAG mediates viral endocytic transport through interaction with endosomal Q-SNAREs including STX7, STX8, and Vti1b, leading to assembly of a fusogenic trans-SNARE complex with VAMP8; inhibition of VAMP8 (but not VAMP7) significantly reduces viral entry, placing STX7 in the specific SNARE complex required for influenza A and VSV entry.","method":"Co-immunoprecipitation, siRNA depletion, viral infection assays, VAMP isoform-selective inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional viral entry assay, but STX7 role inferred as part of broader complex","pmids":["24550300"],"is_preprint":false},{"year":2015,"finding":"γ-SNAP mediates disassembly of endosomal STX7-containing SNARE complexes; immunoprecipitation combined with mass spectrometry showed γ-SNAP preferentially interacts with endosomal SNAREs, and its depletion altered endosome morphology and delayed EGFR and transferrin trafficking from early endosomes.","method":"Immunoprecipitation, mass spectrometry, siRNA depletion, overexpression, endosome morphology analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/MS with functional depletion phenotype, single lab","pmids":["26101353"],"is_preprint":false},{"year":2017,"finding":"STX7 is required for homotypic fusion of phagophores to generate HCV-induced autophagosomes; in vitro membrane fusion assay demonstrated STX7-dependent phagophore-phagophore fusion, and STX7 knockdown blocked autophagosome formation without affecting HCV RNA replication on phagophore membranes.","method":"In vitro membrane fusion assay, electron microscopy, siRNA knockdown, live-cell imaging","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of membrane fusion combined with electron microscopy and siRNA","pmids":["28931085"],"is_preprint":false},{"year":2019,"finding":"SGK3 phosphorylates STX7 at Ser126 at endosomes; phosphoproteomic screening and in vitro kinase assays confirmed STX7 Ser126 as an SGK3-specific substrate (poorly phosphorylated by Akt), and IGF1 stimulation in HEK293 cells promoted endogenous STX7 phosphorylation in an SGK3-dependent manner.","method":"Phosphoproteomic screen, in vitro kinase assay with purified SGK3 and Akt, Phos-tag gel analysis, SGK3 knockout cells, pan-SGK inhibitor treatment","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus genetic KO and pharmacological validation in cells","pmids":["31665227"],"is_preprint":false},{"year":2019,"finding":"UNC13D binds STX7 on late endosomes and regulates endosomal maturation; a STX7-binding-deficient UNC13D mutant failed to rescue defective endosomal trafficking in unc13d-null cells, establishing that the UNC13D-STX7 interaction is required for endolysosomal flux.","method":"unc13d-null cells, rescue with STX7-binding-deficient UNC13D mutant, endocytic flux assays, biochemical and microscopy methods","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis rescue experiment in KO cells with defined phenotype, single lab","pmids":["30892133"],"is_preprint":false},{"year":2020,"finding":"STX7, STX8, VTI1B, and VAMP7/8 form a complete late endo-/lysosomal SNARE fusion machinery required for Salmonella-induced filament (SIF) formation; RNAi screen showed each component is individually required for SIF morphology in conjunction with RAB7 and HOPS tethering complex.","method":"Sub-genomic RNAi screen, high-resolution live-cell imaging, SIF morphology scoring","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — systematic RNAi screen with live imaging readout, single study","pmids":["32658937"],"is_preprint":false},{"year":2021,"finding":"STX7 (endosomal Q-SNARE) defines a rapidly replenishing synaptic vesicle pool in hippocampal neurons; disruption of STX7 function by overexpressing its N-terminal domain selectively abolished this pool, and recruitment of STX7-marked vesicles requires actin polymerization and Ca2+/calmodulin signaling.","method":"Optical imaging of presynaptic endosomal SNARE proteins, dominant-negative N-terminal domain overexpression, pharmacological inhibition of actin polymerization and Ca2+/calmodulin signaling in cultured hippocampal neurons","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — dominant-negative with defined neuronal phenotype and pathway placement, single lab","pmids":["34408265"],"is_preprint":false},{"year":2021,"finding":"The trans-SNARE complex VAMP4/STX6/STX7/Vti1b mediates Golgi-to-late-endosome trafficking of MT1-MMP in macrophages; depletion of any SNARE in this complex reduced surface MT1-MMP and gelatin degradation, while overexpression of STX6/STX7/Vti1b increased surface MT1-MMP.","method":"Fixed and live imaging, siRNA depletion, overexpression, gelatin degradation assay in LPS-activated macrophages","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA depletion with gain-of-function and functional readout, single lab","pmids":["34476885"],"is_preprint":false},{"year":2022,"finding":"STX7 promotes invadopodia formation and breast cancer cell invasion by forming distinct SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23; STX7 depletion reduced invadopodia number and associated MT1-MMP at invadopodia, while increasing non-invadosomal MT1-MMP pools.","method":"siRNA screening of 13 SNAREs, TIRF microscopy, co-trafficking with MT1-MMP, immunoprecipitation, invasion assays in MDA-MB-231 cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of multiple SNARE complexes, TIRF imaging, siRNA with functional invasion readout","pmids":["35762511"],"is_preprint":false},{"year":2023,"finding":"STX7 modulates seizure susceptibility by regulating presynaptic GABA release; overexpression of STX7 reduced seizure susceptibility in kainic acid and PTZ kindling models, affecting excitation/inhibition ratio and inhibitory vesicle density without changing intrinsic neuronal excitability or inhibitory synapse density.","method":"Kainic acid and PTZ kindling mouse models, STX7 overexpression and knockdown, whole-cell patch-clamp recordings, transmission electron microscopy","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain/loss-of-function with electrophysiology and EM, single lab","pmids":["37031804"],"is_preprint":false},{"year":2024,"finding":"YKT6 forms a priming complex with STX17 and SNAP29 on autophagosomes via its SNARE domain; VAMP8 displaces YKT6 from this complex to form the fusogenic STX17-SNAP29-VAMP8 complex, with the YKT6-SNAP29-STX17 complex facilitating both lipid and content mixing to promote autophagy flux. STX7 (lysosomal) participates in the parallel STX7-SNAP29-YKT6 fusogenic complex.","method":"Co-immunoprecipitation, lipid mixing assay, content mixing assay, autophagy flux measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro membrane mixing assays combined with co-IP defining complex hierarchy","pmids":["38340317"],"is_preprint":false},{"year":2024,"finding":"IFITM3 binds STX7 in cells and in vitro via a SNARE-like motif in its CD225 domain; mutations that abrogate STX7 binding cause loss of antiviral activity against influenza A virus, and mechanistically IFITM3 disrupts assembly of the STX7-containing SNARE complex controlling homotypic late endosome fusion, accelerating cargo trafficking to lysosomes.","method":"Co-immunoprecipitation in cells, in vitro binding assay, mutagenesis of SNARE-like motif, influenza A virus infection assay, endosomal cargo trafficking assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding plus mutagenesis plus functional antiviral assay","pmids":["39653855"],"is_preprint":false},{"year":2024,"finding":"Chlamydia effector IncE binds STX7- and STX12-containing vesicles via a proximal SNARE-mimetic short linear motif (SLiM) in its C-terminus, recruiting these vesicles to the Chlamydia inclusion to facilitate intracellular bacterial development.","method":"SLiM mutagenesis, vesicle recruitment assays, co-localization microscopy, functional bacterial development assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with functional bacterial development readout, single lab","pmids":["39154341"],"is_preprint":false},{"year":2025,"finding":"Munc13-4 specifically interacts with STX7 to regulate endolysosomal flux and endosomal TLR signaling; small-molecule ENDOtollins inhibiting the Munc13-4-STX7 interaction blocked endolysosomal cargo degradation and reduced TLR3/7/9-driven inflammatory cytokine production in dendritic cells and neutrophils without affecting plasma membrane TLR responses.","method":"High-throughput small-molecule screening, orthogonal cell-based validation, endolysosomal flux assay, TLR ligand stimulation assays, in vivo CpG-induced inflammation model","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — HTS with orthogonal validation, chemical probes, in vivo model, mechanistic specificity demonstrated","pmids":["41942734"],"is_preprint":false},{"year":2025,"finding":"Salmonella Typhimurium hijacks STX7 to evade lysosomal fusion and maintain its intracellular vacuolar niche; STX7 knockdown reduced bacterial survival rescued by STX7 overexpression, STX7 is recruited to SCVs with altered distribution at late infection stages, and SPI-2 effectors SifA and SopD2 interact with STX7 by BioID proximity labeling.","method":"BioID proximity labeling, siRNA knockdown, overexpression rescue, live cell imaging, bacterial survival assay in HeLa and RAW264.7 cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling plus KD/rescue with functional bacterial survival readout, single lab","pmids":["40444290"],"is_preprint":false},{"year":2025,"finding":"STX7 is identified as a direct binding target of capsazepine in astrocytes; drug affinity responsive target stability (DARTS) analysis, cellular thermal shift assay, and molecular docking demonstrated capsazepine binding to STX7, and STX7 siRNA knockdown phenocopied capsazepine's anti-inflammatory effects on astrocyte activation.","method":"DARTS analysis, cellular thermal shift assay (CETSA), molecular docking, siRNA knockdown, in vitro and in vivo astrocyte inflammation models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple target engagement methods (DARTS, CETSA, docking) with siRNA phenocopy, single lab","pmids":["40386937"],"is_preprint":false},{"year":2025,"finding":"STX7, VAMP8, VTI1B, and VAMP7 are recruited to the Plasmodium parasitophorous vacuole membrane (PVM) with distinct temporal profiles; combinatorial CRISPR knockouts showed VAMP7-VAMP8 and VAMP7-VTI1B double KOs significantly reduced parasite infection and growth, with STX7 appearing at PVM ~24 hpi during nutrient acquisition, indicating host SNARE machinery is co-opted for lysosome-PVM fusion.","method":"CRISPR/Cas9 knockout in HeLa cells, advanced fluorescence microscopy of P. berghei-infected cells, combinatorial knockout analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with combinatorial genetics and imaging, single study","pmids":["41972675"],"is_preprint":false},{"year":2025,"finding":"siRNA screening identified STX7, STX8, and VTI1B as components of the lysosomal SNARE machinery required for secretory granule-lysosome fusion (crinophagy); Munc13-4 associates with these SNAREs and regulates docking and fusion of secretory granules with lysosomes in a calcium-dependent manner.","method":"siRNA screening with live-cell SG-lysosome fusion assay, co-immunoprecipitation of Munc13-4 with SNARE partners, calcium manipulation experiments","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — systematic siRNA screen with functional fusion assay, preprint status reduces confidence","pmids":["40951263"],"is_preprint":true}],"current_model":"STX7 is a Qa-SNARE (endosomal/lysosomal syntaxin) that functions as a core component of multiple late endosomal and lysosomal SNARE complexes — including STX7/STX8/Vti1b/VAMP8, STX7/SNAP29/YKT6, STX6/STX7/Vti1b/VAMP4, and VAMP4/STX6/STX7/Vti1b — mediating membrane fusion events in autophagosome-lysosome fusion, late endosome-to-lysosome trafficking, secretory granule turnover (crinophagy), synaptic vesicle recycling, phagophore homotypic fusion, and immune cell effector functions (lytic granule release, TLR endosomal signaling via Munc13-4 interaction), and is subject to regulatory phosphorylation by SGK3 (at Ser126) and by CSF-1-activated PKC/Akt at Habc-domain serines that modulate SNARE partner binding."},"narrative":{"teleology":[{"year":2008,"claim":"The question of how extracellular signals regulate endosomal SNARE complex assembly was addressed by showing that CSF-1 induces serine phosphorylation of STX7's Habc domain, directly enhancing its binding to Vti1b, STX8, and VAMP8 in primary macrophages.","evidence":"Serine mutagenesis, co-IP of SNARE partners, kinase inhibitors in primary mouse macrophages","pmids":["18710945"],"confidence":"High","gaps":["Identity of the specific kinase(s) directly phosphorylating the Habc domain serines not definitively established","Functional consequence of phosphorylation on membrane fusion rates not measured directly"]},{"year":2011,"claim":"Two studies established STX7 as a core Qa-SNARE of multiple endosomal fusion complexes and revealed its requirement in immune cell effector function: STX7 participates in STX6/STX7/Vti1b and STX7/STX8/Vti1b complexes in macrophages, and is required for lytic granule delivery to the immunological synapse in CTLs.","evidence":"Reciprocal co-IP with siRNA rescue in macrophages; dominant-negative STX7, siRNA, STED nanoscopy, and killing assays in CTLs","pmids":["21388490","21438968"],"confidence":"High","gaps":["Whether STX7 loss phenocopies the complete SNARE complex disruption or whether compensatory SNAREs exist in CTLs","Structural basis of STX7 selectivity for different R-SNARE partners not resolved"]},{"year":2014,"claim":"STX7 was placed in a specific fusogenic complex (STX7/STX8/Vti1b/VAMP8) recruited by UVRAG to mediate viral endocytic entry, linking the canonical endosomal SNARE machinery to virus-host interactions.","evidence":"Co-IP, siRNA depletion, influenza A and VSV infection assays","pmids":["24550300"],"confidence":"Medium","gaps":["STX7's individual contribution versus collective complex requirement not separated","Whether UVRAG directly activates STX7 or acts upstream through tethering"]},{"year":2015,"claim":"The recycling of STX7-containing SNARE complexes was shown to require γ-SNAP-mediated disassembly, establishing the first regulatory step for SNARE complex turnover at endosomes.","evidence":"IP-MS, siRNA depletion, endosome morphology and EGFR/transferrin trafficking assays","pmids":["26101353"],"confidence":"Medium","gaps":["Whether γ-SNAP acts directly on assembled STX7 complexes or on individual SNAREs post-disassembly","Quantitative kinetics of SNARE disassembly not determined"]},{"year":2017,"claim":"A reconstituted in vitro fusion assay demonstrated that STX7 mediates homotypic phagophore-phagophore fusion, revealing a role upstream of autophagosome-lysosome fusion in autophagosome biogenesis itself.","evidence":"In vitro membrane fusion assay, electron microscopy, siRNA in HCV-infected cells","pmids":["28931085"],"confidence":"High","gaps":["SNARE partners for the phagophore fusion event not fully defined","Whether this mechanism operates outside HCV-induced autophagy"]},{"year":2018,"claim":"The discovery that STX7 forms a SNAP29/YKT6 complex on lysosomes to mediate autophagosome-lysosome fusion independently of STX17 resolved how autophagy can proceed when the canonical STX17 pathway is absent.","evidence":"STX17-KO HeLa cells, reciprocal co-IP, fluorescence microscopy of autophagosome-lysosome fusion","pmids":["29789439"],"confidence":"High","gaps":["Relative contribution of STX7 versus STX17 pathway under physiological conditions unknown","How selectivity between the two parallel pathways is achieved"]},{"year":2019,"claim":"Two independent findings defined kinase-level and effector-level regulation of STX7: SGK3 phosphorylates STX7 at Ser126 specifically at endosomes, and the Munc13-4 (UNC13D) interaction with STX7 is required for endolysosomal maturation.","evidence":"In vitro kinase assay with SGK3/Akt, SGK3-KO cells, Phos-tag gels; UNC13D-null cell rescue with STX7-binding-deficient mutant","pmids":["31665227","30892133"],"confidence":"High","gaps":["Functional consequence of Ser126 phosphorylation on STX7 SNARE complex assembly or fusion not shown","Whether SGK3 and Munc13-4 act on the same or different STX7 complexes"]},{"year":2020,"claim":"A systematic RNAi screen confirmed STX7, STX8, VTI1B, and VAMP7/8 as a complete late endosomal SNARE machinery acting in conjunction with the RAB7/HOPS tethering system, using Salmonella-induced filament formation as a readout for endolysosomal membrane dynamics.","evidence":"Sub-genomic RNAi screen with high-resolution live-cell imaging in Salmonella-infected cells","pmids":["32658937"],"confidence":"Medium","gaps":["Whether STX7 is rate-limiting within this complex or exchangeable","HOPS-STX7 direct interaction not demonstrated"]},{"year":2021,"claim":"Two studies extended STX7 function to neuronal and macrophage trafficking: STX7 defines a rapidly replenishing presynaptic vesicle pool dependent on actin and Ca²⁺/calmodulin, and the VAMP4/STX6/STX7/Vti1b complex mediates Golgi-to-late endosome trafficking of MT1-MMP for macrophage invasion.","evidence":"Dominant-negative STX7 N-terminal domain in hippocampal neurons with pharmacology; siRNA and overexpression with gelatin degradation in macrophages","pmids":["34408265","34476885"],"confidence":"Medium","gaps":["Whether STX7 marks a molecularly distinct vesicle subpopulation or labels general endosomal vesicles entering the presynaptic pool","Direct Ca²⁺/calmodulin binding to STX7 not tested"]},{"year":2022,"claim":"STX7 was shown to form non-canonical SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23 to drive invadopodia formation and MT1-MMP delivery in breast cancer cells, expanding its partner repertoire beyond canonical endolysosomal SNAREs.","evidence":"siRNA screen of 13 SNAREs, TIRF microscopy, co-IP, invasion assays in MDA-MB-231 cells","pmids":["35762511"],"confidence":"Medium","gaps":["Whether these non-canonical complexes are unique to cancer cell invasion or occur broadly","Structural basis for STX7 promiscuity in partner selection unknown"]},{"year":2023,"claim":"STX7 was linked to seizure susceptibility through regulation of presynaptic GABA release and inhibitory vesicle density, establishing a neurophysiological function beyond vesicle pool definition.","evidence":"STX7 overexpression and knockdown in kainic acid and PTZ kindling mouse models, patch-clamp electrophysiology, transmission EM","pmids":["37031804"],"confidence":"Medium","gaps":["Which SNARE partners mediate the inhibitory vesicle phenotype in neurons","Whether STX7 loss in specific neuronal subtypes is sufficient for the seizure phenotype"]},{"year":2024,"claim":"Multiple discoveries in 2024 refined the mechanistic hierarchy of autophagosomal SNARE complexes and revealed pathogen exploitation of STX7: YKT6 primes a complex with STX17/SNAP29 that is displaced by VAMP8 for fusion, while the parallel STX7/SNAP29/YKT6 complex independently promotes fusion; IFITM3 inhibits STX7-containing SNARE complex assembly via a SNARE-like motif to restrict viral entry; and Chlamydia effector IncE recruits STX7-containing vesicles via a SNARE-mimetic SLiM.","evidence":"In vitro lipid/content mixing assays with co-IP for complex hierarchy; in vitro binding, mutagenesis, and IAV infection for IFITM3; SLiM mutagenesis with bacterial development assays for Chlamydia","pmids":["38340317","39653855","39154341"],"confidence":"High","gaps":["How IFITM3's inhibition of STX7 is regulated during infection","Whether Chlamydia IncE competes with cellular STX7 partners or captures a distinct pool"]},{"year":2025,"claim":"Chemical biology and pathogen studies converged to establish the Munc13-4–STX7 interaction as a druggable node controlling endosomal TLR signaling, and revealed that Salmonella and Plasmodium both exploit host STX7-containing SNARE machinery for intracellular survival.","evidence":"HTS-derived ENDOtollin inhibitors of Munc13-4–STX7, endolysosomal flux and TLR assays, in vivo CpG model; BioID, siRNA/rescue, bacterial survival for Salmonella; combinatorial CRISPR KO and imaging for Plasmodium","pmids":["41942734","40444290","41972675"],"confidence":"High","gaps":["Structural basis of Munc13-4–STX7 interaction not resolved at atomic level","Whether ENDOtollins affect all STX7-dependent fusion events or are pathway-selective","Relative contribution of STX7 versus other SNAREs at the parasitophorous vacuole"]},{"year":null,"claim":"No high-resolution structure of STX7 alone or in a SNARE complex exists, the mechanism by which STX7 selects among its diverse R-SNARE partners in different cellular contexts is unresolved, and the functional consequences of Ser126 phosphorylation by SGK3 on SNARE complex dynamics remain untested.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of STX7 or STX7-containing SNARE complex","Partner selectivity mechanism unknown","SGK3 phosphorylation functional output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,4,9]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,5,7,8]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,9,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,6,14]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4,5,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7]}],"complexes":["STX7/STX8/Vti1b/VAMP8","STX7/SNAP29/YKT6","STX6/STX7/Vti1b/VAMP4"],"partners":["VTI1B","STX8","VAMP8","SNAP29","YKT6","STX6","UNC13D","IFITM3"],"other_free_text":[]},"mechanistic_narrative":"STX7 is a Qa-SNARE protein that functions as a central organizer of membrane fusion events at late endosomes and lysosomes, participating in multiple distinct SNARE complexes to control endolysosomal trafficking, autophagosome–lysosome fusion, and regulated secretion. On endosomal membranes, STX7 assembles with STX8, Vti1b, and VAMP8 to drive late endosome-to-lysosome fusion [PMID:21388490, PMID:32658937], and independently pairs with SNAP29 and autophagosomal YKT6 to mediate autophagosome–lysosome fusion in a pathway parallel to the STX17-dependent route [PMID:29789439, PMID:38340317]. STX7 is subject to regulatory phosphorylation by SGK3 at Ser126 and by CSF-1-activated kinases at Habc-domain serines that modulate SNARE complex assembly [PMID:18710945, PMID:31665227], and its interaction with Munc13-4 (UNC13D) is required for endolysosomal maturation, endosomal TLR signaling, and lytic granule release from cytotoxic T lymphocytes [PMID:30892133, PMID:21438968, PMID:41942734]. Beyond canonical endolysosomal roles, STX7 defines a rapidly replenishing synaptic vesicle pool in hippocampal neurons that modulates presynaptic GABA release and seizure susceptibility [PMID:34408265, PMID:37031804], and is co-opted by intracellular pathogens including influenza A virus, Salmonella, Chlamydia, and Plasmodium to facilitate infection [PMID:39653855, PMID:40444290, PMID:39154341, PMID:41972675]."},"prefetch_data":{"uniprot":{"accession":"O15400","full_name":"Syntaxin-7","aliases":[],"length_aa":261,"mass_kda":29.8,"function":"May be involved in protein trafficking from the plasma membrane to the early endosome (EE) as well as in homotypic fusion of endocytic organelles. Mediates the endocytic trafficking from early endosomes to late endosomes and lysosomes","subcellular_location":"Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/O15400/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STX7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000079950","cell_line_id":"CID000765","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"VAMP8","stoichiometry":4.0},{"gene":"NSF","stoichiometry":4.0},{"gene":"ATP6AP2","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"SLC35F2","stoichiometry":0.2},{"gene":"STX10","stoichiometry":0.2},{"gene":"AP1AR","stoichiometry":0.2},{"gene":"VAMP3;VAMP2","stoichiometry":0.2},{"gene":"RAB11B","stoichiometry":0.2},{"gene":"WDFY1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000765","total_profiled":1310},"omim":[{"mim_id":"613401","title":"VPS33B-INTERACTING PROTEIN, APICAL-BASOLATERAL POLARITY REGULATOR, SPE39 HOMOLOG; VIPAS39","url":"https://www.omim.org/entry/613401"},{"mim_id":"611438","title":"TAXILIN, BETA; TXLNB","url":"https://www.omim.org/entry/611438"},{"mim_id":"608923","title":"TRACE AMINE-ASSOCIATED RECEPTOR 6; TAAR6","url":"https://www.omim.org/entry/608923"},{"mim_id":"607405","title":"TRACE AMINE-ASSOCIATED RECEPTOR 5; TAAR5","url":"https://www.omim.org/entry/607405"},{"mim_id":"606892","title":"SYNTAXIN 12; STX12","url":"https://www.omim.org/entry/606892"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Lysosomes","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STX7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O15400","domains":[{"cath_id":"1.20.58.70","chopping":"10-129_164-201","consensus_level":"high","plddt":89.028,"start":10,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15400","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15400-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15400-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX7","jax_strain_url":"https://www.jax.org/strain/search?query=STX7"},"sequence":{"accession":"O15400","fasta_url":"https://rest.uniprot.org/uniprotkb/O15400.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15400/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15400"}},"corpus_meta":[{"pmid":"18198266","id":"PMC_18198266","title":"No significant association of 14 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fluorescence microscopy of autophagosome-lysosome fusion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, genetic KO epistasis, replicated across two SNARE pathways with rigorous controls\",\n      \"pmids\": [\"29789439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STX7 is required for lytic granule release from cytotoxic T lymphocytes (CTLs); it localizes to the immunological synapse and late endosomes (co-localizing with Rab7), and its loss prevents both TCR recycling through endosomes and lytic granule accumulation at the IS, without reducing total granule number.\",\n      \"method\": \"Dominant-negative STX7 expression, siRNA knockdown, evanescent wave microscopy of individual lytic granules, high-resolution STED nanoscopy, CTL killing assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (DN construct, siRNA, live imaging, nanoscopy) with defined cellular phenotype\",\n      \"pmids\": [\"21438968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STX7 participates in SNARE complexes STX6/STX7/Vti1b and STX7/STX8/Vti1b on endosomal membranes; STX11 regulates late endosome-to-lysosome fusion by controlling availability of Vti1b to form these Q-SNARE complexes, establishing STX7 as a component of the endosomal fusion machinery in macrophages.\",\n      \"method\": \"Co-immunoprecipitation of SNARE complexes, siRNA depletion, rescue with siRNA-resistant construct, live imaging of endocytic compartments in macrophages\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA with rescue, multiple SNARE complex compositions defined\",\n      \"pmids\": [\"21388490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSF-1 upregulates STX7 expression in primary macrophages and induces rapid serine phosphorylation of STX7, enhancing its binding to SNARE partners Vti1b, STX8, and VAMP8; mutagenesis of serine residues in the Habc domain and/or linker region identified these as the sites through which CSF-1 regulates SNARE complex assembly.\",\n      \"method\": \"Primary mouse macrophage culture, kinase inhibitor studies, mutagenesis of STX7 serine residues, co-immunoprecipitation of SNARE partners, western blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with co-IP and pharmacological inhibition in primary cells\",\n      \"pmids\": [\"18710945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UVRAG mediates viral endocytic transport through interaction with endosomal Q-SNAREs including STX7, STX8, and Vti1b, leading to assembly of a fusogenic trans-SNARE complex with VAMP8; inhibition of VAMP8 (but not VAMP7) significantly reduces viral entry, placing STX7 in the specific SNARE complex required for influenza A and VSV entry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, viral infection assays, VAMP isoform-selective inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional viral entry assay, but STX7 role inferred as part of broader complex\",\n      \"pmids\": [\"24550300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"γ-SNAP mediates disassembly of endosomal STX7-containing SNARE complexes; immunoprecipitation combined with mass spectrometry showed γ-SNAP preferentially interacts with endosomal SNAREs, and its depletion altered endosome morphology and delayed EGFR and transferrin trafficking from early endosomes.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, siRNA depletion, overexpression, endosome morphology analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS with functional depletion phenotype, single lab\",\n      \"pmids\": [\"26101353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STX7 is required for homotypic fusion of phagophores to generate HCV-induced autophagosomes; in vitro membrane fusion assay demonstrated STX7-dependent phagophore-phagophore fusion, and STX7 knockdown blocked autophagosome formation without affecting HCV RNA replication on phagophore membranes.\",\n      \"method\": \"In vitro membrane fusion assay, electron microscopy, siRNA knockdown, live-cell imaging\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of membrane fusion combined with electron microscopy and siRNA\",\n      \"pmids\": [\"28931085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK3 phosphorylates STX7 at Ser126 at endosomes; phosphoproteomic screening and in vitro kinase assays confirmed STX7 Ser126 as an SGK3-specific substrate (poorly phosphorylated by Akt), and IGF1 stimulation in HEK293 cells promoted endogenous STX7 phosphorylation in an SGK3-dependent manner.\",\n      \"method\": \"Phosphoproteomic screen, in vitro kinase assay with purified SGK3 and Akt, Phos-tag gel analysis, SGK3 knockout cells, pan-SGK inhibitor treatment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus genetic KO and pharmacological validation in cells\",\n      \"pmids\": [\"31665227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UNC13D binds STX7 on late endosomes and regulates endosomal maturation; a STX7-binding-deficient UNC13D mutant failed to rescue defective endosomal trafficking in unc13d-null cells, establishing that the UNC13D-STX7 interaction is required for endolysosomal flux.\",\n      \"method\": \"unc13d-null cells, rescue with STX7-binding-deficient UNC13D mutant, endocytic flux assays, biochemical and microscopy methods\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis rescue experiment in KO cells with defined phenotype, single lab\",\n      \"pmids\": [\"30892133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STX7, STX8, VTI1B, and VAMP7/8 form a complete late endo-/lysosomal SNARE fusion machinery required for Salmonella-induced filament (SIF) formation; RNAi screen showed each component is individually required for SIF morphology in conjunction with RAB7 and HOPS tethering complex.\",\n      \"method\": \"Sub-genomic RNAi screen, high-resolution live-cell imaging, SIF morphology scoring\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic RNAi screen with live imaging readout, single study\",\n      \"pmids\": [\"32658937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STX7 (endosomal Q-SNARE) defines a rapidly replenishing synaptic vesicle pool in hippocampal neurons; disruption of STX7 function by overexpressing its N-terminal domain selectively abolished this pool, and recruitment of STX7-marked vesicles requires actin polymerization and Ca2+/calmodulin signaling.\",\n      \"method\": \"Optical imaging of presynaptic endosomal SNARE proteins, dominant-negative N-terminal domain overexpression, pharmacological inhibition of actin polymerization and Ca2+/calmodulin signaling in cultured hippocampal neurons\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative with defined neuronal phenotype and pathway placement, single lab\",\n      \"pmids\": [\"34408265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The trans-SNARE complex VAMP4/STX6/STX7/Vti1b mediates Golgi-to-late-endosome trafficking of MT1-MMP in macrophages; depletion of any SNARE in this complex reduced surface MT1-MMP and gelatin degradation, while overexpression of STX6/STX7/Vti1b increased surface MT1-MMP.\",\n      \"method\": \"Fixed and live imaging, siRNA depletion, overexpression, gelatin degradation assay in LPS-activated macrophages\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA depletion with gain-of-function and functional readout, single lab\",\n      \"pmids\": [\"34476885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STX7 promotes invadopodia formation and breast cancer cell invasion by forming distinct SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23; STX7 depletion reduced invadopodia number and associated MT1-MMP at invadopodia, while increasing non-invadosomal MT1-MMP pools.\",\n      \"method\": \"siRNA screening of 13 SNAREs, TIRF microscopy, co-trafficking with MT1-MMP, immunoprecipitation, invasion assays in MDA-MB-231 cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of multiple SNARE complexes, TIRF imaging, siRNA with functional invasion readout\",\n      \"pmids\": [\"35762511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STX7 modulates seizure susceptibility by regulating presynaptic GABA release; overexpression of STX7 reduced seizure susceptibility in kainic acid and PTZ kindling models, affecting excitation/inhibition ratio and inhibitory vesicle density without changing intrinsic neuronal excitability or inhibitory synapse density.\",\n      \"method\": \"Kainic acid and PTZ kindling mouse models, STX7 overexpression and knockdown, whole-cell patch-clamp recordings, transmission electron microscopy\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain/loss-of-function with electrophysiology and EM, single lab\",\n      \"pmids\": [\"37031804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YKT6 forms a priming complex with STX17 and SNAP29 on autophagosomes via its SNARE domain; VAMP8 displaces YKT6 from this complex to form the fusogenic STX17-SNAP29-VAMP8 complex, with the YKT6-SNAP29-STX17 complex facilitating both lipid and content mixing to promote autophagy flux. STX7 (lysosomal) participates in the parallel STX7-SNAP29-YKT6 fusogenic complex.\",\n      \"method\": \"Co-immunoprecipitation, lipid mixing assay, content mixing assay, autophagy flux measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro membrane mixing assays combined with co-IP defining complex hierarchy\",\n      \"pmids\": [\"38340317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFITM3 binds STX7 in cells and in vitro via a SNARE-like motif in its CD225 domain; mutations that abrogate STX7 binding cause loss of antiviral activity against influenza A virus, and mechanistically IFITM3 disrupts assembly of the STX7-containing SNARE complex controlling homotypic late endosome fusion, accelerating cargo trafficking to lysosomes.\",\n      \"method\": \"Co-immunoprecipitation in cells, in vitro binding assay, mutagenesis of SNARE-like motif, influenza A virus infection assay, endosomal cargo trafficking assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding plus mutagenesis plus functional antiviral assay\",\n      \"pmids\": [\"39653855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chlamydia effector IncE binds STX7- and STX12-containing vesicles via a proximal SNARE-mimetic short linear motif (SLiM) in its C-terminus, recruiting these vesicles to the Chlamydia inclusion to facilitate intracellular bacterial development.\",\n      \"method\": \"SLiM mutagenesis, vesicle recruitment assays, co-localization microscopy, functional bacterial development assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with functional bacterial development readout, single lab\",\n      \"pmids\": [\"39154341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Munc13-4 specifically interacts with STX7 to regulate endolysosomal flux and endosomal TLR signaling; small-molecule ENDOtollins inhibiting the Munc13-4-STX7 interaction blocked endolysosomal cargo degradation and reduced TLR3/7/9-driven inflammatory cytokine production in dendritic cells and neutrophils without affecting plasma membrane TLR responses.\",\n      \"method\": \"High-throughput small-molecule screening, orthogonal cell-based validation, endolysosomal flux assay, TLR ligand stimulation assays, in vivo CpG-induced inflammation model\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — HTS with orthogonal validation, chemical probes, in vivo model, mechanistic specificity demonstrated\",\n      \"pmids\": [\"41942734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Salmonella Typhimurium hijacks STX7 to evade lysosomal fusion and maintain its intracellular vacuolar niche; STX7 knockdown reduced bacterial survival rescued by STX7 overexpression, STX7 is recruited to SCVs with altered distribution at late infection stages, and SPI-2 effectors SifA and SopD2 interact with STX7 by BioID proximity labeling.\",\n      \"method\": \"BioID proximity labeling, siRNA knockdown, overexpression rescue, live cell imaging, bacterial survival assay in HeLa and RAW264.7 cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling plus KD/rescue with functional bacterial survival readout, single lab\",\n      \"pmids\": [\"40444290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7 is identified as a direct binding target of capsazepine in astrocytes; drug affinity responsive target stability (DARTS) analysis, cellular thermal shift assay, and molecular docking demonstrated capsazepine binding to STX7, and STX7 siRNA knockdown phenocopied capsazepine's anti-inflammatory effects on astrocyte activation.\",\n      \"method\": \"DARTS analysis, cellular thermal shift assay (CETSA), molecular docking, siRNA knockdown, in vitro and in vivo astrocyte inflammation models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple target engagement methods (DARTS, CETSA, docking) with siRNA phenocopy, single lab\",\n      \"pmids\": [\"40386937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7, VAMP8, VTI1B, and VAMP7 are recruited to the Plasmodium parasitophorous vacuole membrane (PVM) with distinct temporal profiles; combinatorial CRISPR knockouts showed VAMP7-VAMP8 and VAMP7-VTI1B double KOs significantly reduced parasite infection and growth, with STX7 appearing at PVM ~24 hpi during nutrient acquisition, indicating host SNARE machinery is co-opted for lysosome-PVM fusion.\",\n      \"method\": \"CRISPR/Cas9 knockout in HeLa cells, advanced fluorescence microscopy of P. berghei-infected cells, combinatorial knockout analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with combinatorial genetics and imaging, single study\",\n      \"pmids\": [\"41972675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA screening identified STX7, STX8, and VTI1B as components of the lysosomal SNARE machinery required for secretory granule-lysosome fusion (crinophagy); Munc13-4 associates with these SNAREs and regulates docking and fusion of secretory granules with lysosomes in a calcium-dependent manner.\",\n      \"method\": \"siRNA screening with live-cell SG-lysosome fusion assay, co-immunoprecipitation of Munc13-4 with SNARE partners, calcium manipulation experiments\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic siRNA screen with functional fusion assay, preprint status reduces confidence\",\n      \"pmids\": [\"40951263\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"STX7 is a Qa-SNARE (endosomal/lysosomal syntaxin) that functions as a core component of multiple late endosomal and lysosomal SNARE complexes — including STX7/STX8/Vti1b/VAMP8, STX7/SNAP29/YKT6, STX6/STX7/Vti1b/VAMP4, and VAMP4/STX6/STX7/Vti1b — mediating membrane fusion events in autophagosome-lysosome fusion, late endosome-to-lysosome trafficking, secretory granule turnover (crinophagy), synaptic vesicle recycling, phagophore homotypic fusion, and immune cell effector functions (lytic granule release, TLR endosomal signaling via Munc13-4 interaction), and is subject to regulatory phosphorylation by SGK3 (at Ser126) and by CSF-1-activated PKC/Akt at Habc-domain serines that modulate SNARE partner binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"STX7 is a Qa-SNARE protein that functions as a central organizer of membrane fusion events at late endosomes and lysosomes, participating in multiple distinct SNARE complexes to control endolysosomal trafficking, autophagosome–lysosome fusion, and regulated secretion. On endosomal membranes, STX7 assembles with STX8, Vti1b, and VAMP8 to drive late endosome-to-lysosome fusion [PMID:21388490, PMID:32658937], and independently pairs with SNAP29 and autophagosomal YKT6 to mediate autophagosome–lysosome fusion in a pathway parallel to the STX17-dependent route [PMID:29789439, PMID:38340317]. STX7 is subject to regulatory phosphorylation by SGK3 at Ser126 and by CSF-1-activated kinases at Habc-domain serines that modulate SNARE complex assembly [PMID:18710945, PMID:31665227], and its interaction with Munc13-4 (UNC13D) is required for endolysosomal maturation, endosomal TLR signaling, and lytic granule release from cytotoxic T lymphocytes [PMID:30892133, PMID:21438968, PMID:41942734]. Beyond canonical endolysosomal roles, STX7 defines a rapidly replenishing synaptic vesicle pool in hippocampal neurons that modulates presynaptic GABA release and seizure susceptibility [PMID:34408265, PMID:37031804], and is co-opted by intracellular pathogens including influenza A virus, Salmonella, Chlamydia, and Plasmodium to facilitate infection [PMID:39653855, PMID:40444290, PMID:39154341, PMID:41972675].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of how extracellular signals regulate endosomal SNARE complex assembly was addressed by showing that CSF-1 induces serine phosphorylation of STX7's Habc domain, directly enhancing its binding to Vti1b, STX8, and VAMP8 in primary macrophages.\",\n      \"evidence\": \"Serine mutagenesis, co-IP of SNARE partners, kinase inhibitors in primary mouse macrophages\",\n      \"pmids\": [\"18710945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific kinase(s) directly phosphorylating the Habc domain serines not definitively established\", \"Functional consequence of phosphorylation on membrane fusion rates not measured directly\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two studies established STX7 as a core Qa-SNARE of multiple endosomal fusion complexes and revealed its requirement in immune cell effector function: STX7 participates in STX6/STX7/Vti1b and STX7/STX8/Vti1b complexes in macrophages, and is required for lytic granule delivery to the immunological synapse in CTLs.\",\n      \"evidence\": \"Reciprocal co-IP with siRNA rescue in macrophages; dominant-negative STX7, siRNA, STED nanoscopy, and killing assays in CTLs\",\n      \"pmids\": [\"21388490\", \"21438968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STX7 loss phenocopies the complete SNARE complex disruption or whether compensatory SNAREs exist in CTLs\", \"Structural basis of STX7 selectivity for different R-SNARE partners not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"STX7 was placed in a specific fusogenic complex (STX7/STX8/Vti1b/VAMP8) recruited by UVRAG to mediate viral endocytic entry, linking the canonical endosomal SNARE machinery to virus-host interactions.\",\n      \"evidence\": \"Co-IP, siRNA depletion, influenza A and VSV infection assays\",\n      \"pmids\": [\"24550300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STX7's individual contribution versus collective complex requirement not separated\", \"Whether UVRAG directly activates STX7 or acts upstream through tethering\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The recycling of STX7-containing SNARE complexes was shown to require γ-SNAP-mediated disassembly, establishing the first regulatory step for SNARE complex turnover at endosomes.\",\n      \"evidence\": \"IP-MS, siRNA depletion, endosome morphology and EGFR/transferrin trafficking assays\",\n      \"pmids\": [\"26101353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether γ-SNAP acts directly on assembled STX7 complexes or on individual SNAREs post-disassembly\", \"Quantitative kinetics of SNARE disassembly not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A reconstituted in vitro fusion assay demonstrated that STX7 mediates homotypic phagophore-phagophore fusion, revealing a role upstream of autophagosome-lysosome fusion in autophagosome biogenesis itself.\",\n      \"evidence\": \"In vitro membrane fusion assay, electron microscopy, siRNA in HCV-infected cells\",\n      \"pmids\": [\"28931085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SNARE partners for the phagophore fusion event not fully defined\", \"Whether this mechanism operates outside HCV-induced autophagy\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The discovery that STX7 forms a SNAP29/YKT6 complex on lysosomes to mediate autophagosome-lysosome fusion independently of STX17 resolved how autophagy can proceed when the canonical STX17 pathway is absent.\",\n      \"evidence\": \"STX17-KO HeLa cells, reciprocal co-IP, fluorescence microscopy of autophagosome-lysosome fusion\",\n      \"pmids\": [\"29789439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of STX7 versus STX17 pathway under physiological conditions unknown\", \"How selectivity between the two parallel pathways is achieved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two independent findings defined kinase-level and effector-level regulation of STX7: SGK3 phosphorylates STX7 at Ser126 specifically at endosomes, and the Munc13-4 (UNC13D) interaction with STX7 is required for endolysosomal maturation.\",\n      \"evidence\": \"In vitro kinase assay with SGK3/Akt, SGK3-KO cells, Phos-tag gels; UNC13D-null cell rescue with STX7-binding-deficient mutant\",\n      \"pmids\": [\"31665227\", \"30892133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser126 phosphorylation on STX7 SNARE complex assembly or fusion not shown\", \"Whether SGK3 and Munc13-4 act on the same or different STX7 complexes\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A systematic RNAi screen confirmed STX7, STX8, VTI1B, and VAMP7/8 as a complete late endosomal SNARE machinery acting in conjunction with the RAB7/HOPS tethering system, using Salmonella-induced filament formation as a readout for endolysosomal membrane dynamics.\",\n      \"evidence\": \"Sub-genomic RNAi screen with high-resolution live-cell imaging in Salmonella-infected cells\",\n      \"pmids\": [\"32658937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STX7 is rate-limiting within this complex or exchangeable\", \"HOPS-STX7 direct interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies extended STX7 function to neuronal and macrophage trafficking: STX7 defines a rapidly replenishing presynaptic vesicle pool dependent on actin and Ca²⁺/calmodulin, and the VAMP4/STX6/STX7/Vti1b complex mediates Golgi-to-late endosome trafficking of MT1-MMP for macrophage invasion.\",\n      \"evidence\": \"Dominant-negative STX7 N-terminal domain in hippocampal neurons with pharmacology; siRNA and overexpression with gelatin degradation in macrophages\",\n      \"pmids\": [\"34408265\", \"34476885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STX7 marks a molecularly distinct vesicle subpopulation or labels general endosomal vesicles entering the presynaptic pool\", \"Direct Ca²⁺/calmodulin binding to STX7 not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"STX7 was shown to form non-canonical SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23 to drive invadopodia formation and MT1-MMP delivery in breast cancer cells, expanding its partner repertoire beyond canonical endolysosomal SNAREs.\",\n      \"evidence\": \"siRNA screen of 13 SNAREs, TIRF microscopy, co-IP, invasion assays in MDA-MB-231 cells\",\n      \"pmids\": [\"35762511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these non-canonical complexes are unique to cancer cell invasion or occur broadly\", \"Structural basis for STX7 promiscuity in partner selection unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"STX7 was linked to seizure susceptibility through regulation of presynaptic GABA release and inhibitory vesicle density, establishing a neurophysiological function beyond vesicle pool definition.\",\n      \"evidence\": \"STX7 overexpression and knockdown in kainic acid and PTZ kindling mouse models, patch-clamp electrophysiology, transmission EM\",\n      \"pmids\": [\"37031804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which SNARE partners mediate the inhibitory vesicle phenotype in neurons\", \"Whether STX7 loss in specific neuronal subtypes is sufficient for the seizure phenotype\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple discoveries in 2024 refined the mechanistic hierarchy of autophagosomal SNARE complexes and revealed pathogen exploitation of STX7: YKT6 primes a complex with STX17/SNAP29 that is displaced by VAMP8 for fusion, while the parallel STX7/SNAP29/YKT6 complex independently promotes fusion; IFITM3 inhibits STX7-containing SNARE complex assembly via a SNARE-like motif to restrict viral entry; and Chlamydia effector IncE recruits STX7-containing vesicles via a SNARE-mimetic SLiM.\",\n      \"evidence\": \"In vitro lipid/content mixing assays with co-IP for complex hierarchy; in vitro binding, mutagenesis, and IAV infection for IFITM3; SLiM mutagenesis with bacterial development assays for Chlamydia\",\n      \"pmids\": [\"38340317\", \"39653855\", \"39154341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IFITM3's inhibition of STX7 is regulated during infection\", \"Whether Chlamydia IncE competes with cellular STX7 partners or captures a distinct pool\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Chemical biology and pathogen studies converged to establish the Munc13-4–STX7 interaction as a druggable node controlling endosomal TLR signaling, and revealed that Salmonella and Plasmodium both exploit host STX7-containing SNARE machinery for intracellular survival.\",\n      \"evidence\": \"HTS-derived ENDOtollin inhibitors of Munc13-4–STX7, endolysosomal flux and TLR assays, in vivo CpG model; BioID, siRNA/rescue, bacterial survival for Salmonella; combinatorial CRISPR KO and imaging for Plasmodium\",\n      \"pmids\": [\"41942734\", \"40444290\", \"41972675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Munc13-4–STX7 interaction not resolved at atomic level\", \"Whether ENDOtollins affect all STX7-dependent fusion events or are pathway-selective\", \"Relative contribution of STX7 versus other SNAREs at the parasitophorous vacuole\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of STX7 alone or in a SNARE complex exists, the mechanism by which STX7 selects among its diverse R-SNARE partners in different cellular contexts is unresolved, and the functional consequences of Ser126 phosphorylation by SGK3 on SNARE complex dynamics remain untested.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of STX7 or STX7-containing SNARE complex\", \"Partner selectivity mechanism unknown\", \"SGK3 phosphorylation functional output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 5, 7, 8]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 9, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 6, 14]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4, 5, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\n      \"STX7/STX8/Vti1b/VAMP8\",\n      \"STX7/SNAP29/YKT6\",\n      \"STX6/STX7/Vti1b/VAMP4\"\n    ],\n    \"partners\": [\n      \"VTI1B\",\n      \"STX8\",\n      \"VAMP8\",\n      \"SNAP29\",\n      \"YKT6\",\n      \"STX6\",\n      \"UNC13D\",\n      \"IFITM3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}