{"gene":"STX7","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"YKT6 forms a SNARE complex with SNAP29 and lysosomal STX7 on autophagosomes, providing a second pathway for autophagosome-lysosome fusion that is independent of STX17; depletion of YKT6 completely blocked autophagosome-lysosome fusion in STX17 KO cells.","method":"STX17 knockout HeLa cells, SNARE screen, co-immunoprecipitation, fluorescence microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence, independent STX17 KO validation, replicated in subsequent studies","pmids":["29789439"],"is_preprint":false},{"year":2024,"finding":"YKT6 forms a priming complex with STX17 and SNAP29 on autophagosomes via its SNARE domain; VAMP8 then displaces YKT6 to form the fusogenic STX17-SNAP29-VAMP8 complex, with STX7 participating in the YKT6-SNAP29-STX7 complex at lysosomes to mediate content and lipid mixing.","method":"Co-immunoprecipitation, lipid and content mixing assays, dominant-negative constructs, autophagy flux assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution of lipid/content mixing plus co-IP, single lab with multiple orthogonal methods","pmids":["38340317"],"is_preprint":false},{"year":2011,"finding":"STX7 is required for lytic granule release from cytotoxic T lymphocytes (CTLs); it localizes preferentially to the immunological synapse and mediates trafficking of recycling TCRs through late endosomes (colocalizing with Rab7), which is a prerequisite for lytic granule accumulation and CTL-mediated killing.","method":"Dominant-negative STX7 expression, siRNA knockdown, evanescent wave microscopy, high-resolution nanoscopy, functional CTL killing assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (DN construct, siRNA, real-time imaging, nanoscopy, functional killing assay) in single study","pmids":["21438968"],"is_preprint":false},{"year":2008,"finding":"CSF-1 induces serine phosphorylation of STX7 via PKC and Akt downstream of PI3K activation; this phosphorylation, mapped to the Habc domain and/or linker region by mutagenesis, enhances STX7 binding to its SNARE partners Vti1b, STX8, and VAMP8 and upregulates STX7 expression in macrophages.","method":"Primary mouse macrophage culture, kinase inhibitor pharmacology, site-directed mutagenesis, co-immunoprecipitation, Western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus pharmacological inhibition plus co-IP in single study with multiple orthogonal methods","pmids":["18710945"],"is_preprint":false},{"year":2014,"finding":"UVRAG mediates viral endocytic transport and membrane penetration through interactions with endosomal Q-SNAREs STX7, STX8, and Vti1b, leading to assembly of a fusogenic trans-SNARE complex involving VAMP8 (but not VAMP7); inhibition of VAMP8 significantly reduces influenza A and VSV entry.","method":"Co-immunoprecipitation, viral entry assays, siRNA knockdown, VAMP8/VAMP7 inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional viral entry assays, single lab","pmids":["24550300"],"is_preprint":false},{"year":2011,"finding":"STX11 binds Vti1b and regulates the availability of Vti1b to form Q-SNARE complexes including STX6/STX7/Vti1b and STX7/STX8/Vti1b that mediate late endosome to lysosome fusion in macrophages; mutant STX11 sequesters Vti1b from these complexes.","method":"Co-immunoprecipitation, siRNA depletion, confocal microscopy, functional endosomal trafficking assays in macrophages","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus siRNA rescue plus functional phenotype, single lab","pmids":["21388490"],"is_preprint":false},{"year":2019,"finding":"SGK3 directly phosphorylates STX7 at Ser126 in a site that is inefficiently phosphorylated by Akt; IGF1-stimulated STX7 phosphorylation in HEK293 cells is blocked by SGK3 knockout or pan-SGK inhibitor, identifying STX7 as a specific endosomal substrate of SGK3.","method":"Phosphoproteomics screen, in vitro kinase assay, SGK3 knockout cells, Phos-tag gel electrophoresis, IGF1 stimulation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus genetic KO validation plus pharmacological inhibition, multiple orthogonal methods","pmids":["31665227"],"is_preprint":false},{"year":2015,"finding":"γ-SNAP mediates disassembly of endosomal STX7-containing SNARE complexes (alongside α-SNAP) and regulates endocytic trafficking of EGFR and transferrin; depletion of γ-SNAP delayed exit of EGFR and transferrin from EEA1-positive early endosomes.","method":"Immunoprecipitation, mass spectrometry, siRNA knockdown, SNARE disassembly assay, fluorescence microscopy of EGFR/transferrin trafficking","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS plus siRNA plus functional trafficking assay, single lab","pmids":["26101353"],"is_preprint":false},{"year":2017,"finding":"STX7 is required for homotypic fusion of HCV-induced phagophores to generate autophagosomes; knockdown of STX7 inhibits autophagosome formation but does not affect HCV RNA replication, which occurs on phagophore precursors.","method":"siRNA knockdown, in vitro membrane fusion assay, electron microscopy, live-cell imaging, fluorescence microscopy","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro fusion assay plus siRNA, single lab with orthogonal methods","pmids":["28931085"],"is_preprint":false},{"year":2021,"finding":"STX7 defines a rapidly replenishing synaptic vesicle (SV) recycling pool in hippocampal neurons; this Stx7-marked pool is preferentially mobilized during high-frequency stimulation and its recruitment requires actin polymerization and Ca2+/calmodulin signaling; overexpression of the STX7 N-terminal domain as a dominant negative selectively abolished this pool.","method":"Optical imaging of presynaptic SNARE proteins in cultured hippocampal neurons, dominant-negative overexpression, pharmacological inhibition (actin, Ca2+/CaM pathway), electrophysiology","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus dominant-negative functional experiments plus pharmacology, single lab","pmids":["34408265"],"is_preprint":false},{"year":2022,"finding":"STX7 localizes near invadopodia and co-traffics with MT1-MMP; STX7 depletion reduces invadopodium number and associated degradative activity; STX7 forms SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23; depletion of VAMP2, VAMP3, or STX4 phenocopies STX7 loss by abolishing invadopodia formation in MDA-MB-231 cells.","method":"siRNA knockdown, TIRF microscopy, immunoprecipitation, gelatin degradation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus TIRF imaging plus functional invasion assays, single lab, multiple orthogonal methods","pmids":["35762511"],"is_preprint":false},{"year":2021,"finding":"The trans-SNARE complex VAMP4/STX6/STX7/Vti1b regulates Golgi-to-late-endosome trafficking of MT1-MMP in LPS-activated macrophages; depletion of any complex member reduces surface MT1-MMP and gelatin degradation, while overexpression of STX6/STX7/Vti1b increases surface MT1-MMP.","method":"siRNA knockdown, overexpression, fixed and live imaging, surface protein assays, gelatin degradation assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus overexpression plus functional degradation assay, single lab","pmids":["34476885"],"is_preprint":false},{"year":2019,"finding":"UNC13D regulates late endosomal trafficking via binding to STX7; a STX7-binding-deficient mutant of UNC13D fails to rescue the defective endosomal trafficking and endocytic flux phenotype of unc13d-null cells, demonstrating that STX7 interaction is functionally required for UNC13D's role in endosomal maturation.","method":"unc13d-null cell rescue experiments with wild-type vs. STX7-binding-deficient UNC13D mutant, biochemical and microscopy assays of endocytic flux","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function rescue experiment with defined mutant, single lab","pmids":["30892133"],"is_preprint":false},{"year":2026,"finding":"Small-molecule inhibitors (ENDOtollins) of the Munc13-4–STX7 interaction block endolysosomal flux and specifically inhibit endosomal TLR signaling (ERK in neutrophils; IRF in plasmacytoid DCs) without affecting plasma membrane TLR agonists; ENDO12 reduced CpG-induced systemic inflammation in vivo.","method":"High-throughput small-molecule screening, cell-based validation of Munc13-4-STX7 interaction inhibition, functional TLR signaling assays, in vivo CpG challenge model","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based and in vivo functional validation with defined inhibitors, single lab","pmids":["41942734"],"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; mechanistically, IFITM3 disrupts assembly of the STX7-containing SNARE complex controlling homotypic late endosome fusion and accelerates trafficking of endosomal cargo to lysosomes.","method":"Co-immunoprecipitation, in vitro binding assay, mutagenesis, influenza A infection assay, endosomal cargo trafficking assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding plus mutagenesis plus functional antiviral assay, multiple orthogonal methods, single lab","pmids":["39653855"],"is_preprint":false},{"year":2024,"finding":"Chlamydia effector IncE recruits STX7-containing vesicles to the inclusion via a proximal SNARE-mimicking short linear motif (SLiM) that binds STX7 and STX12.","method":"Cell biological characterization of IncE SLiM mutants, vesicle recruitment assays, co-localization microscopy","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional vesicle recruitment assay, single lab","pmids":["39154341"],"is_preprint":false},{"year":2025,"finding":"STX7 knockdown reduces Salmonella survival in HeLa and RAW264.7 macrophages, and this is rescued by STX7 overexpression; live imaging shows STX7 is recruited to Salmonella-containing vacuoles (SCVs) at different infection stages, and BioID revealed STX7 interactions with SPI-2 effectors SifA and SopD2, indicating Salmonella hijacks STX7 to evade lysosomal fusion.","method":"STX7 siRNA knockdown and overexpression rescue, live cell imaging, BioID proximity labeling","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown/rescue plus live imaging plus proximity labeling, single lab","pmids":["40444290"],"is_preprint":false},{"year":2025,"finding":"STX7 is identified as a binding target of the anti-inflammatory compound capsazepine; STX7 siRNA knockdown phenocopied capsazepine's anti-inflammatory effects on astrocytes; interaction confirmed by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking.","method":"siRNA knockdown, DARTS, CETSA, molecular docking, astrocyte activation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays (DARTS, CETSA) plus siRNA phenocopy, single lab","pmids":["40386937"],"is_preprint":false},{"year":2023,"finding":"STX7 overexpression reduces seizure susceptibility and alleviated epileptic activity in kainic acid and pentylenetetrazole models; STX7 does not affect neuronal intrinsic excitability but affects the excitation/inhibition ratio by influencing presynaptic GABA neurotransmitter release and inhibitory vesicle density (but not inhibitory synapse density).","method":"Overexpression/knockdown in rodent epilepsy models, whole-cell patch-clamp electrophysiology, transmission electron microscopy","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression/knockdown with electrophysiology and EM, single lab","pmids":["37031804"],"is_preprint":false},{"year":2025,"finding":"STX7 knockout in hepatocellular carcinoma cells suppresses proliferation, migration, and EMT via inhibition of NF-κB signaling.","method":"CRISPR knockout, in vitro proliferation/migration assays, in vivo xenograft, Western blot for NF-κB pathway markers","journal":"BMC cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function with phenotype but pathway placement based on reporter/Western only","pmids":["40999361"],"is_preprint":false},{"year":2024,"finding":"GORASP2 depletion attenuates assembly of both STX17-SNAP29-VAMP8 and YKT6-SNAP29-STX7 SNARE complexes required for autophagosome-lysosome fusion, placing STX7 downstream of GORASP2-regulated RAB7A-HOPS machinery.","method":"Super-resolution microscopy, siRNA depletion, SNARE complex assembly assays","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — SNARE complex assembly changes observed upon GORASP2 depletion, indirect placement of STX7, single lab","pmids":["39056394"],"is_preprint":false},{"year":2020,"finding":"A trafficome-wide RNAi screen identified the late endo-/lysosomal SNARE complex STX7/STX8/VTI1B/VAMP7 or VAMP8 as required for Salmonella-induced filament (SIF) formation and intracellular Salmonella replication.","method":"Sub-genomic RNAi screen, high-resolution live cell imaging for SIF morphology and dynamics","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNAi screen hit, functional phenotype in SIF formation, no direct mechanistic follow-up on STX7 specifically","pmids":["32658937"],"is_preprint":false},{"year":2025,"finding":"STX7, STX8, and VTI1B are recruited to the Plasmodium parasitophorous vacuole membrane (PVM) ~24 h post-infection; combined knockouts with VAMP7 reveal partial redundancy; STX7/VAMP8 appear at PVM later than VAMP7/Vti1B suggesting a role in nutrient acquisition phase.","method":"CRISPR/Cas9 knockout in HeLa cells, confocal microscopy, combinatorial knockout infection assays","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO plus imaging, combinatorial analysis, single study, STX7-specific contribution difficult to isolate","pmids":["41972675"],"is_preprint":false},{"year":2025,"finding":"STX7, STX8, and VTI1B are required for crinophagy (secretory granule-lysosome fusion) in endocrine cells; siRNA screening identified these SNAREs as necessary for SG-lysosome docking/fusion alongside Munc13-4, Rab27A, VAMP2, PLEKHM1, and HOPS subunits.","method":"siRNA screen with live-cell SG-lysosome fusion assay","journal":"Research square (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA screen hit in a preprint, functional phenotype but STX7 not individually characterized beyond the screen","pmids":["40951263"],"is_preprint":true}],"current_model":"STX7 is a Qa-SNARE protein that localizes to late endosomes and lysosomes and functions as a core component of multiple endosomal SNARE complexes (including STX7/STX8/Vti1b/VAMP8, STX6/STX7/Vti1b/VAMP4, and YKT6/SNAP29/STX7) that drive late endosome-to-lysosome fusion, autophagosome-lysosome fusion, phagophore homotypic fusion, synaptic vesicle recycling, lytic granule trafficking in CTLs, invadopodia formation, and MT1-MMP trafficking; its activity is regulated by CSF-1-induced serine phosphorylation (via PKC/Akt/PI3K) that enhances SNARE partner binding, and by SGK3-mediated phosphorylation at Ser126; it is exploited by intracellular pathogens (Salmonella, Chlamydia, Plasmodium) and viruses (influenza via IFITM3) to manipulate endolysosomal trafficking, and its interaction with Munc13-4 regulates endosomal TLR signaling."},"narrative":{"mechanistic_narrative":"STX7 is a late endosomal/lysosomal Qa-SNARE that nucleates multiple endosomal SNARE complexes to drive membrane fusion across the endolysosomal and autophagic pathways [PMID:21388490, PMID:34476885]. It assembles with Vti1b and STX8 (with VAMP7 or VAMP8) to mediate late endosome-to-lysosome fusion, and with STX6/Vti1b/VAMP4 to direct Golgi-to-late-endosome trafficking of cargo such as MT1-MMP [PMID:21388490, PMID:34476885]; in the autophagy pathway it participates in a YKT6-SNAP29-STX7 complex on lysosomes that supports content and lipid mixing during autophagosome-lysosome fusion, providing a route parallel to the STX17-SNAP29-VAMP8 machinery [PMID:29789439, PMID:38340317], and it is also required for homotypic phagophore fusion [PMID:28931085]. STX7-dependent fusion supports diverse physiological outputs, including lytic granule release and recycling TCR trafficking in cytotoxic T lymphocytes [PMID:21438968], a rapidly mobilized synaptic vesicle recycling pool and presynaptic inhibitory neurotransmission [PMID:34408265, PMID:37031804], and MT1-MMP delivery driving invadopodia formation [PMID:35762511, PMID:34476885]. Its activity is regulated by phosphorylation: CSF-1 signaling through PI3K/PKC/Akt induces serine phosphorylation in the Habc/linker region that enhances binding to Vti1b, STX8, and VAMP8 [PMID:18710945], and SGK3 directly phosphorylates STX7 at Ser126 downstream of IGF1 [PMID:31665227], while disassembly of STX7 complexes is mediated by γ-SNAP [PMID:26101353]. STX7 is a recurrent target of host and pathogen factors that manipulate endolysosomal flux: it is bound by Munc13-4/UNC13D to control endosomal maturation and endosomal TLR signaling [PMID:30892133, PMID:41942734], engaged by the antiviral effector IFITM3 via a SNARE-like CD225 motif that disrupts STX7 complex assembly [PMID:39653855], and hijacked by intracellular pathogens including Chlamydia (IncE), Salmonella, and Plasmodium to evade or remodel the endolysosomal system [PMID:39154341, PMID:40444290].","teleology":[{"year":2008,"claim":"Established that STX7 SNARE-complex assembly is signal-regulated, showing how an upstream growth-factor cascade tunes endolysosomal fusion capacity.","evidence":"Kinase inhibitor pharmacology, site-directed mutagenesis, and co-IP in CSF-1-stimulated primary macrophages","pmids":["18710945"],"confidence":"High","gaps":["Precise phosphorylated residues not definitively mapped","Structural basis for enhanced partner binding unresolved"]},{"year":2011,"claim":"Defined the regulatory logic of STX7 complex formation and a physiological output, showing STX11 controls Vti1b availability for STX6/STX7/Vti1b and STX7/STX8/Vti1b complexes, and that STX7 is required for CTL lytic granule release.","evidence":"Co-IP, siRNA depletion, and functional trafficking/CTL killing assays in macrophages and cytotoxic T lymphocytes","pmids":["21388490","21438968"],"confidence":"Medium","gaps":["Stoichiometry of competing complexes not quantified","Direct fusogenic activity not reconstituted in these studies"]},{"year":2014,"claim":"Showed STX7 endosomal Q-SNARE complexes are co-opted for viral entry, linking UVRAG-organized STX7/STX8/Vti1b/VAMP8 assembly to influenza A and VSV membrane penetration.","evidence":"Reciprocal co-IP and viral entry assays with VAMP8 vs VAMP7 inhibition","pmids":["24550300"],"confidence":"Medium","gaps":["Direct role of STX7 versus other complex members in fusion not isolated","Single lab"]},{"year":2015,"claim":"Identified the disassembly arm of the STX7 cycle, showing γ-SNAP disassembles STX7 complexes and is needed for EGFR/transferrin exit from early endosomes.","evidence":"Co-IP/MS, siRNA, SNARE disassembly assay, and cargo trafficking imaging","pmids":["26101353"],"confidence":"Medium","gaps":["Whether γ-SNAP acts directly on STX7 vs partner subunits unclear","Cargo specificity mechanism not defined"]},{"year":2017,"claim":"Extended STX7 function into autophagosome biogenesis, demonstrating it drives homotypic phagophore fusion distinct from later fusion steps.","evidence":"siRNA knockdown plus in vitro membrane fusion assay and EM in HCV-induced phagophore system","pmids":["28931085"],"confidence":"Medium","gaps":["SNARE partners for homotypic phagophore fusion not specified","Generalizability beyond HCV context not tested"]},{"year":2018,"claim":"Revealed a STX17-independent autophagosome-lysosome fusion route, placing STX7 in a YKT6-SNAP29-STX7 complex.","evidence":"SNARE screen and co-IP in STX17 knockout HeLa cells with fluorescence microscopy","pmids":["29789439"],"confidence":"High","gaps":["Relative contribution of STX7 vs STX17 pathways in vivo unquantified","Membrane topology of the complex not resolved here"]},{"year":2019,"claim":"Identified a second kinase input and a functional partner, mapping SGK3 phosphorylation at STX7 Ser126 and demonstrating UNC13D-STX7 binding is required for endosomal maturation.","evidence":"In vitro kinase assay, SGK3 KO, and Phos-tag gels (Ser126); structure-function rescue with STX7-binding-deficient UNC13D mutant","pmids":["31665227","30892133"],"confidence":"High","gaps":["Functional consequence of Ser126 phosphorylation on fusion not established","Structural interface of UNC13D-STX7 not solved"]},{"year":2021,"claim":"Broadened STX7's physiological roles, defining a rapidly replenishing STX7-marked synaptic vesicle pool and a VAMP4/STX6/STX7/Vti1b complex controlling MT1-MMP trafficking.","evidence":"Presynaptic SNARE optical imaging with dominant-negative/pharmacology; siRNA, overexpression, and gelatin degradation assays in macrophages","pmids":["34408265","34476885"],"confidence":"Medium","gaps":["Mechanism coupling STX7 to actin/Ca2+/CaM-dependent SV pool recruitment unknown","How distinct STX7 complexes are spatially segregated unclear"]},{"year":2022,"claim":"Linked STX7 to cancer cell invasion, showing STX7 co-traffics with MT1-MMP and forms VAMP2/VAMP3/VAMP7/STX4/SNAP23 complexes required for invadopodia.","evidence":"siRNA, TIRF imaging, co-IP, and gelatin degradation in MDA-MB-231 cells","pmids":["35762511"],"confidence":"Medium","gaps":["Which plasma-membrane vs endosomal complex drives degradative activity not separated","Single cell line"]},{"year":2024,"claim":"Resolved sequential SNARE assembly in autophagy and defined an antiviral host mechanism, showing VAMP8 displaces YKT6 to form the fusogenic STX17 complex while STX7 mediates lysosomal mixing, and that IFITM3 binds STX7 to block its complex assembly.","evidence":"Lipid/content mixing assays and dominant-negatives; co-IP, in vitro binding, mutagenesis, and influenza A antiviral assays","pmids":["38340317","39653855"],"confidence":"High","gaps":["In vivo relevance of YKT6-STX7 mixing step not established","Structural model of IFITM3-STX7 interaction lacking"]},{"year":2025,"claim":"Documented pathogen subversion and disease-relevant phenotypes, showing Chlamydia IncE and Salmonella effectors engage STX7, and that STX7 modulates seizure susceptibility, hepatocellular carcinoma growth, and astrocyte inflammation.","evidence":"SLiM mutagenesis/recruitment assays (Chlamydia); knockdown/rescue, live imaging, and BioID (Salmonella); rodent epilepsy electrophysiology; CRISPR KO xenograft; DARTS/CETSA drug-target validation","pmids":["39154341","40444290","37031804","40999361","40386937"],"confidence":"Medium","gaps":["Direct molecular contribution of STX7 to NF-κB and inflammation not mechanistically resolved","Pathogen-effector binding interfaces not structurally defined"]},{"year":2026,"claim":"Demonstrated therapeutic targetability of the Munc13-4-STX7 interaction, showing small-molecule disruptors selectively inhibit endosomal TLR signaling and reduce systemic inflammation in vivo.","evidence":"High-throughput screening, cell-based interaction inhibition, TLR signaling assays, and in vivo CpG challenge","pmids":["41942734"],"confidence":"Medium","gaps":["Selectivity of inhibitors across STX7 complexes not fully mapped","Off-target endolysosomal consequences not characterized"]},{"year":null,"claim":"How the cell selects among the many mutually exclusive STX7-containing SNARE complexes at specific membranes and how the two characterized phosphorylation inputs alter fusion kinetics remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of any full STX7 fusogenic complex","Functional link between Ser126/Habc phosphorylation and fusion rate undefined","Spatial regulation of partner choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,11,7]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,5,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,5,7,14]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,11,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,13]}],"complexes":["STX7/STX8/Vti1b/VAMP8","STX6/STX7/Vti1b/VAMP4","YKT6/SNAP29/STX7"],"partners":["STX8","VTI1B","VAMP8","STX6","SNAP29","YKT6","UNC13D","IFITM3"],"other_free_text":[]}},"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 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co-immunoprecipitation, fluorescence microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence, independent STX17 KO validation, replicated in subsequent studies\",\n      \"pmids\": [\"29789439\"],\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 then displaces YKT6 to form the fusogenic STX17-SNAP29-VAMP8 complex, with STX7 participating in the YKT6-SNAP29-STX7 complex at lysosomes to mediate content and lipid mixing.\",\n      \"method\": \"Co-immunoprecipitation, lipid and content mixing assays, dominant-negative constructs, autophagy flux assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution of lipid/content mixing plus co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38340317\"],\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 preferentially to the immunological synapse and mediates trafficking of recycling TCRs through late endosomes (colocalizing with Rab7), which is a prerequisite for lytic granule accumulation and CTL-mediated killing.\",\n      \"method\": \"Dominant-negative STX7 expression, siRNA knockdown, evanescent wave microscopy, high-resolution nanoscopy, functional CTL killing assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (DN construct, siRNA, real-time imaging, nanoscopy, functional killing assay) in single study\",\n      \"pmids\": [\"21438968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSF-1 induces serine phosphorylation of STX7 via PKC and Akt downstream of PI3K activation; this phosphorylation, mapped to the Habc domain and/or linker region by mutagenesis, enhances STX7 binding to its SNARE partners Vti1b, STX8, and VAMP8 and upregulates STX7 expression in macrophages.\",\n      \"method\": \"Primary mouse macrophage culture, kinase inhibitor pharmacology, site-directed mutagenesis, co-immunoprecipitation, Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus pharmacological inhibition plus co-IP in single study with multiple orthogonal methods\",\n      \"pmids\": [\"18710945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UVRAG mediates viral endocytic transport and membrane penetration through interactions with endosomal Q-SNAREs STX7, STX8, and Vti1b, leading to assembly of a fusogenic trans-SNARE complex involving VAMP8 (but not VAMP7); inhibition of VAMP8 significantly reduces influenza A and VSV entry.\",\n      \"method\": \"Co-immunoprecipitation, viral entry assays, siRNA knockdown, VAMP8/VAMP7 inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional viral entry assays, single lab\",\n      \"pmids\": [\"24550300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STX11 binds Vti1b and regulates the availability of Vti1b to form Q-SNARE complexes including STX6/STX7/Vti1b and STX7/STX8/Vti1b that mediate late endosome to lysosome fusion in macrophages; mutant STX11 sequesters Vti1b from these complexes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, confocal microscopy, functional endosomal trafficking assays in macrophages\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus siRNA rescue plus functional phenotype, single lab\",\n      \"pmids\": [\"21388490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK3 directly phosphorylates STX7 at Ser126 in a site that is inefficiently phosphorylated by Akt; IGF1-stimulated STX7 phosphorylation in HEK293 cells is blocked by SGK3 knockout or pan-SGK inhibitor, identifying STX7 as a specific endosomal substrate of SGK3.\",\n      \"method\": \"Phosphoproteomics screen, in vitro kinase assay, SGK3 knockout cells, Phos-tag gel electrophoresis, IGF1 stimulation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus genetic KO validation plus pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"31665227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"γ-SNAP mediates disassembly of endosomal STX7-containing SNARE complexes (alongside α-SNAP) and regulates endocytic trafficking of EGFR and transferrin; depletion of γ-SNAP delayed exit of EGFR and transferrin from EEA1-positive early endosomes.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, siRNA knockdown, SNARE disassembly assay, fluorescence microscopy of EGFR/transferrin trafficking\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS plus siRNA plus functional trafficking assay, single lab\",\n      \"pmids\": [\"26101353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STX7 is required for homotypic fusion of HCV-induced phagophores to generate autophagosomes; knockdown of STX7 inhibits autophagosome formation but does not affect HCV RNA replication, which occurs on phagophore precursors.\",\n      \"method\": \"siRNA knockdown, in vitro membrane fusion assay, electron microscopy, live-cell imaging, fluorescence microscopy\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro fusion assay plus siRNA, single lab with orthogonal methods\",\n      \"pmids\": [\"28931085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STX7 defines a rapidly replenishing synaptic vesicle (SV) recycling pool in hippocampal neurons; this Stx7-marked pool is preferentially mobilized during high-frequency stimulation and its recruitment requires actin polymerization and Ca2+/calmodulin signaling; overexpression of the STX7 N-terminal domain as a dominant negative selectively abolished this pool.\",\n      \"method\": \"Optical imaging of presynaptic SNARE proteins in cultured hippocampal neurons, dominant-negative overexpression, pharmacological inhibition (actin, Ca2+/CaM pathway), electrophysiology\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus dominant-negative functional experiments plus pharmacology, single lab\",\n      \"pmids\": [\"34408265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STX7 localizes near invadopodia and co-traffics with MT1-MMP; STX7 depletion reduces invadopodium number and associated degradative activity; STX7 forms SNARE complexes with VAMP2, VAMP3, VAMP7, STX4, and SNAP23; depletion of VAMP2, VAMP3, or STX4 phenocopies STX7 loss by abolishing invadopodia formation in MDA-MB-231 cells.\",\n      \"method\": \"siRNA knockdown, TIRF microscopy, immunoprecipitation, gelatin degradation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus TIRF imaging plus functional invasion assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35762511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The trans-SNARE complex VAMP4/STX6/STX7/Vti1b regulates Golgi-to-late-endosome trafficking of MT1-MMP in LPS-activated macrophages; depletion of any complex member reduces surface MT1-MMP and gelatin degradation, while overexpression of STX6/STX7/Vti1b increases surface MT1-MMP.\",\n      \"method\": \"siRNA knockdown, overexpression, fixed and live imaging, surface protein assays, gelatin degradation assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus overexpression plus functional degradation assay, single lab\",\n      \"pmids\": [\"34476885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UNC13D regulates late endosomal trafficking via binding to STX7; a STX7-binding-deficient mutant of UNC13D fails to rescue the defective endosomal trafficking and endocytic flux phenotype of unc13d-null cells, demonstrating that STX7 interaction is functionally required for UNC13D's role in endosomal maturation.\",\n      \"method\": \"unc13d-null cell rescue experiments with wild-type vs. STX7-binding-deficient UNC13D mutant, biochemical and microscopy assays of endocytic flux\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function rescue experiment with defined mutant, single lab\",\n      \"pmids\": [\"30892133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Small-molecule inhibitors (ENDOtollins) of the Munc13-4–STX7 interaction block endolysosomal flux and specifically inhibit endosomal TLR signaling (ERK in neutrophils; IRF in plasmacytoid DCs) without affecting plasma membrane TLR agonists; ENDO12 reduced CpG-induced systemic inflammation in vivo.\",\n      \"method\": \"High-throughput small-molecule screening, cell-based validation of Munc13-4-STX7 interaction inhibition, functional TLR signaling assays, in vivo CpG challenge model\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based and in vivo functional validation with defined inhibitors, single lab\",\n      \"pmids\": [\"41942734\"],\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; mechanistically, IFITM3 disrupts assembly of the STX7-containing SNARE complex controlling homotypic late endosome fusion and accelerates trafficking of endosomal cargo to lysosomes.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, mutagenesis, influenza A infection assay, endosomal cargo trafficking assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding plus mutagenesis plus functional antiviral assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39653855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chlamydia effector IncE recruits STX7-containing vesicles to the inclusion via a proximal SNARE-mimicking short linear motif (SLiM) that binds STX7 and STX12.\",\n      \"method\": \"Cell biological characterization of IncE SLiM mutants, vesicle recruitment assays, co-localization microscopy\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional vesicle recruitment assay, single lab\",\n      \"pmids\": [\"39154341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7 knockdown reduces Salmonella survival in HeLa and RAW264.7 macrophages, and this is rescued by STX7 overexpression; live imaging shows STX7 is recruited to Salmonella-containing vacuoles (SCVs) at different infection stages, and BioID revealed STX7 interactions with SPI-2 effectors SifA and SopD2, indicating Salmonella hijacks STX7 to evade lysosomal fusion.\",\n      \"method\": \"STX7 siRNA knockdown and overexpression rescue, live cell imaging, BioID proximity labeling\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown/rescue plus live imaging plus proximity labeling, single lab\",\n      \"pmids\": [\"40444290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7 is identified as a binding target of the anti-inflammatory compound capsazepine; STX7 siRNA knockdown phenocopied capsazepine's anti-inflammatory effects on astrocytes; interaction confirmed by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking.\",\n      \"method\": \"siRNA knockdown, DARTS, CETSA, molecular docking, astrocyte activation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays (DARTS, CETSA) plus siRNA phenocopy, single lab\",\n      \"pmids\": [\"40386937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STX7 overexpression reduces seizure susceptibility and alleviated epileptic activity in kainic acid and pentylenetetrazole models; STX7 does not affect neuronal intrinsic excitability but affects the excitation/inhibition ratio by influencing presynaptic GABA neurotransmitter release and inhibitory vesicle density (but not inhibitory synapse density).\",\n      \"method\": \"Overexpression/knockdown in rodent epilepsy models, whole-cell patch-clamp electrophysiology, transmission electron microscopy\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression/knockdown with electrophysiology and EM, single lab\",\n      \"pmids\": [\"37031804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7 knockout in hepatocellular carcinoma cells suppresses proliferation, migration, and EMT via inhibition of NF-κB signaling.\",\n      \"method\": \"CRISPR knockout, in vitro proliferation/migration assays, in vivo xenograft, Western blot for NF-κB pathway markers\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function with phenotype but pathway placement based on reporter/Western only\",\n      \"pmids\": [\"40999361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GORASP2 depletion attenuates assembly of both STX17-SNAP29-VAMP8 and YKT6-SNAP29-STX7 SNARE complexes required for autophagosome-lysosome fusion, placing STX7 downstream of GORASP2-regulated RAB7A-HOPS machinery.\",\n      \"method\": \"Super-resolution microscopy, siRNA depletion, SNARE complex assembly assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — SNARE complex assembly changes observed upon GORASP2 depletion, indirect placement of STX7, single lab\",\n      \"pmids\": [\"39056394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A trafficome-wide RNAi screen identified the late endo-/lysosomal SNARE complex STX7/STX8/VTI1B/VAMP7 or VAMP8 as required for Salmonella-induced filament (SIF) formation and intracellular Salmonella replication.\",\n      \"method\": \"Sub-genomic RNAi screen, high-resolution live cell imaging for SIF morphology and dynamics\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNAi screen hit, functional phenotype in SIF formation, no direct mechanistic follow-up on STX7 specifically\",\n      \"pmids\": [\"32658937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7, STX8, and VTI1B are recruited to the Plasmodium parasitophorous vacuole membrane (PVM) ~24 h post-infection; combined knockouts with VAMP7 reveal partial redundancy; STX7/VAMP8 appear at PVM later than VAMP7/Vti1B suggesting a role in nutrient acquisition phase.\",\n      \"method\": \"CRISPR/Cas9 knockout in HeLa cells, confocal microscopy, combinatorial knockout infection assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO plus imaging, combinatorial analysis, single study, STX7-specific contribution difficult to isolate\",\n      \"pmids\": [\"41972675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX7, STX8, and VTI1B are required for crinophagy (secretory granule-lysosome fusion) in endocrine cells; siRNA screening identified these SNAREs as necessary for SG-lysosome docking/fusion alongside Munc13-4, Rab27A, VAMP2, PLEKHM1, and HOPS subunits.\",\n      \"method\": \"siRNA screen with live-cell SG-lysosome fusion assay\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA screen hit in a preprint, functional phenotype but STX7 not individually characterized beyond the screen\",\n      \"pmids\": [\"40951263\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"STX7 is a Qa-SNARE protein that localizes to late endosomes and lysosomes and functions as a core component of multiple endosomal SNARE complexes (including STX7/STX8/Vti1b/VAMP8, STX6/STX7/Vti1b/VAMP4, and YKT6/SNAP29/STX7) that drive late endosome-to-lysosome fusion, autophagosome-lysosome fusion, phagophore homotypic fusion, synaptic vesicle recycling, lytic granule trafficking in CTLs, invadopodia formation, and MT1-MMP trafficking; its activity is regulated by CSF-1-induced serine phosphorylation (via PKC/Akt/PI3K) that enhances SNARE partner binding, and by SGK3-mediated phosphorylation at Ser126; it is exploited by intracellular pathogens (Salmonella, Chlamydia, Plasmodium) and viruses (influenza via IFITM3) to manipulate endolysosomal trafficking, and its interaction with Munc13-4 regulates endosomal TLR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STX7 is a late endosomal/lysosomal Qa-SNARE that nucleates multiple endosomal SNARE complexes to drive membrane fusion across the endolysosomal and autophagic pathways [#5, #11]. It assembles with Vti1b and STX8 (with VAMP7 or VAMP8) to mediate late endosome-to-lysosome fusion, and with STX6/Vti1b/VAMP4 to direct Golgi-to-late-endosome trafficking of cargo such as MT1-MMP [#5, #11]; in the autophagy pathway it participates in a YKT6-SNAP29-STX7 complex on lysosomes that supports content and lipid mixing during autophagosome-lysosome fusion, providing a route parallel to the STX17-SNAP29-VAMP8 machinery [#0, #1], and it is also required for homotypic phagophore fusion [#8]. STX7-dependent fusion supports diverse physiological outputs, including lytic granule release and recycling TCR trafficking in cytotoxic T lymphocytes [#2], a rapidly mobilized synaptic vesicle recycling pool and presynaptic inhibitory neurotransmission [#9, #18], and MT1-MMP delivery driving invadopodia formation [#10, #11]. Its activity is regulated by phosphorylation: CSF-1 signaling through PI3K/PKC/Akt induces serine phosphorylation in the Habc/linker region that enhances binding to Vti1b, STX8, and VAMP8 [#3], and SGK3 directly phosphorylates STX7 at Ser126 downstream of IGF1 [#6], while disassembly of STX7 complexes is mediated by \\u03b3-SNAP [#7]. STX7 is a recurrent target of host and pathogen factors that manipulate endolysosomal flux: it is bound by Munc13-4/UNC13D to control endosomal maturation and endosomal TLR signaling [#12, #13], engaged by the antiviral effector IFITM3 via a SNARE-like CD225 motif that disrupts STX7 complex assembly [#14], and hijacked by intracellular pathogens including Chlamydia (IncE), Salmonella, and Plasmodium to evade or remodel the endolysosomal system [#15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that STX7 SNARE-complex assembly is signal-regulated, showing how an upstream growth-factor cascade tunes endolysosomal fusion capacity.\",\n      \"evidence\": \"Kinase inhibitor pharmacology, site-directed mutagenesis, and co-IP in CSF-1-stimulated primary macrophages\",\n      \"pmids\": [\"18710945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphorylated residues not definitively mapped\", \"Structural basis for enhanced partner binding unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the regulatory logic of STX7 complex formation and a physiological output, showing STX11 controls Vti1b availability for STX6/STX7/Vti1b and STX7/STX8/Vti1b complexes, and that STX7 is required for CTL lytic granule release.\",\n      \"evidence\": \"Co-IP, siRNA depletion, and functional trafficking/CTL killing assays in macrophages and cytotoxic T lymphocytes\",\n      \"pmids\": [\"21388490\", \"21438968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of competing complexes not quantified\", \"Direct fusogenic activity not reconstituted in these studies\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed STX7 endosomal Q-SNARE complexes are co-opted for viral entry, linking UVRAG-organized STX7/STX8/Vti1b/VAMP8 assembly to influenza A and VSV membrane penetration.\",\n      \"evidence\": \"Reciprocal co-IP and viral entry assays with VAMP8 vs VAMP7 inhibition\",\n      \"pmids\": [\"24550300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of STX7 versus other complex members in fusion not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the disassembly arm of the STX7 cycle, showing \\u03b3-SNAP disassembles STX7 complexes and is needed for EGFR/transferrin exit from early endosomes.\",\n      \"evidence\": \"Co-IP/MS, siRNA, SNARE disassembly assay, and cargo trafficking imaging\",\n      \"pmids\": [\"26101353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether \\u03b3-SNAP acts directly on STX7 vs partner subunits unclear\", \"Cargo specificity mechanism not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended STX7 function into autophagosome biogenesis, demonstrating it drives homotypic phagophore fusion distinct from later fusion steps.\",\n      \"evidence\": \"siRNA knockdown plus in vitro membrane fusion assay and EM in HCV-induced phagophore system\",\n      \"pmids\": [\"28931085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SNARE partners for homotypic phagophore fusion not specified\", \"Generalizability beyond HCV context not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a STX17-independent autophagosome-lysosome fusion route, placing STX7 in a YKT6-SNAP29-STX7 complex.\",\n      \"evidence\": \"SNARE screen and co-IP in STX17 knockout HeLa cells with fluorescence microscopy\",\n      \"pmids\": [\"29789439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of STX7 vs STX17 pathways in vivo unquantified\", \"Membrane topology of the complex not resolved here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a second kinase input and a functional partner, mapping SGK3 phosphorylation at STX7 Ser126 and demonstrating UNC13D-STX7 binding is required for endosomal maturation.\",\n      \"evidence\": \"In vitro kinase assay, SGK3 KO, and Phos-tag gels (Ser126); structure-function rescue with STX7-binding-deficient UNC13D mutant\",\n      \"pmids\": [\"31665227\", \"30892133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser126 phosphorylation on fusion not established\", \"Structural interface of UNC13D-STX7 not solved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened STX7's physiological roles, defining a rapidly replenishing STX7-marked synaptic vesicle pool and a VAMP4/STX6/STX7/Vti1b complex controlling MT1-MMP trafficking.\",\n      \"evidence\": \"Presynaptic SNARE optical imaging with dominant-negative/pharmacology; siRNA, overexpression, and gelatin degradation assays in macrophages\",\n      \"pmids\": [\"34408265\", \"34476885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling STX7 to actin/Ca2+/CaM-dependent SV pool recruitment unknown\", \"How distinct STX7 complexes are spatially segregated unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked STX7 to cancer cell invasion, showing STX7 co-traffics with MT1-MMP and forms VAMP2/VAMP3/VAMP7/STX4/SNAP23 complexes required for invadopodia.\",\n      \"evidence\": \"siRNA, TIRF imaging, co-IP, and gelatin degradation in MDA-MB-231 cells\",\n      \"pmids\": [\"35762511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which plasma-membrane vs endosomal complex drives degradative activity not separated\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved sequential SNARE assembly in autophagy and defined an antiviral host mechanism, showing VAMP8 displaces YKT6 to form the fusogenic STX17 complex while STX7 mediates lysosomal mixing, and that IFITM3 binds STX7 to block its complex assembly.\",\n      \"evidence\": \"Lipid/content mixing assays and dominant-negatives; co-IP, in vitro binding, mutagenesis, and influenza A antiviral assays\",\n      \"pmids\": [\"38340317\", \"39653855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of YKT6-STX7 mixing step not established\", \"Structural model of IFITM3-STX7 interaction lacking\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Documented pathogen subversion and disease-relevant phenotypes, showing Chlamydia IncE and Salmonella effectors engage STX7, and that STX7 modulates seizure susceptibility, hepatocellular carcinoma growth, and astrocyte inflammation.\",\n      \"evidence\": \"SLiM mutagenesis/recruitment assays (Chlamydia); knockdown/rescue, live imaging, and BioID (Salmonella); rodent epilepsy electrophysiology; CRISPR KO xenograft; DARTS/CETSA drug-target validation\",\n      \"pmids\": [\"39154341\", \"40444290\", \"37031804\", \"40999361\", \"40386937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular contribution of STX7 to NF-\\u03baB and inflammation not mechanistically resolved\", \"Pathogen-effector binding interfaces not structurally defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated therapeutic targetability of the Munc13-4-STX7 interaction, showing small-molecule disruptors selectively inhibit endosomal TLR signaling and reduce systemic inflammation in vivo.\",\n      \"evidence\": \"High-throughput screening, cell-based interaction inhibition, TLR signaling assays, and in vivo CpG challenge\",\n      \"pmids\": [\"41942734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of inhibitors across STX7 complexes not fully mapped\", \"Off-target endolysosomal consequences not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cell selects among the many mutually exclusive STX7-containing SNARE complexes at specific membranes and how the two characterized phosphorylation inputs alter fusion kinetics remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of any full STX7 fusogenic complex\", \"Functional link between Ser126/Habc phosphorylation and fusion rate undefined\", \"Spatial regulation of partner choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 11, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 5, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 5, 7, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 11, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"complexes\": [\n      \"STX7/STX8/Vti1b/VAMP8\",\n      \"STX6/STX7/Vti1b/VAMP4\",\n      \"YKT6/SNAP29/STX7\"\n    ],\n    \"partners\": [\n      \"STX8\",\n      \"VTI1B\",\n      \"VAMP8\",\n      \"STX6\",\n      \"SNAP29\",\n      \"YKT6\",\n      \"UNC13D\",\n      \"IFITM3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}