{"gene":"STX17","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2013,"finding":"STX17 (syntaxin 17) forms a SNARE complex with SNAP29 and the endosomal/lysosomal VAMP8 (or VAMP7 in Drosophila) to mediate autophagosome fusion with endosomes and lysosomes; this role is evolutionarily conserved from Drosophila to human cells.","method":"Genetic loss-of-function (Drosophila Syx17 mutants), cell culture knockdown, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across two independent human cell culture studies and validated in an animal (Drosophila) model with defined phenotypic readout (autophagic flux defect)","pmids":["24113031"],"is_preprint":false},{"year":2019,"finding":"STX17 dynamically shuttles between the ER and mitochondria, controlled by the outer mitochondrial membrane protein Fis1. Loss of Fis1 causes aberrant STX17 accumulation on mitochondria, exposes its N-terminus, promotes self-oligomerization, and triggers PINK1/Parkin-independent mitophagy. Mitochondrial STX17 interacts with ATG14, recruits core autophagy proteins to form the mitophagosome, and Rab7-dependent mitophagosome-lysosome fusion follows.","method":"Structured illumination microscopy (SR-SIM), proteomics, co-immunoprecipitation, loss-of-function (Fis1 depletion)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (SR-SIM, proteomics, Co-IP, KD) in a single rigorous study identifying the STX17-Fis1 interaction and downstream mitophagy pathway","pmids":["31053718"],"is_preprint":false},{"year":2020,"finding":"STX17 is acetylated at its SNARE domain by the acetyltransferase CREBBP/CBP; HDAC2 acts as the deacetylase. Upon starvation or MTORC1 inhibition, CREBBP inactivation leads to STX17 deacetylation, which promotes its interaction with SNAP29 and formation of the STX17-SNAP29-VAMP8 SNARE complex, and also enhances STX17 interaction with the HOPS tethering complex, thereby promoting autophagosome-lysosome fusion. Deacetylation does not affect STX17 recruitment to autophagosomal membranes.","method":"Mass spectrometry (PTM identification), Co-immunoprecipitation, GST pulldown, KO cell lines, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified PTM, Co-IP, GST pulldown, and KO/OE with multiple functional readouts, single lab but orthogonal methods","pmids":["32264736"],"is_preprint":false},{"year":2017,"finding":"STX17 on autophagosomes serves as an anchor for the Pacer protein, which recruits both the PI3KC3 complex and the HOPS complex to the autophagosome, enabling site-specific activation and tethering for autophagosome-lysosome fusion. Pacer antagonizes Rubicon to stimulate Vps34 kinase activity at this step.","method":"Co-immunoprecipitation, loss-of-function, autophagy flux assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and KD/KO with defined functional phenotypes, single lab with multiple orthogonal approaches","pmids":["28306502"],"is_preprint":false},{"year":2022,"finding":"STING physically interacts with STX17 and sequesters it, preventing its translocation to phagophores and mature autophagosomes. Energy crisis or TBK1-mediated phosphorylation disrupts the STING-STX17 interaction, releasing different pools of STX17 to promote autophagic flux. Loss of STING in cells and mice enhances starvation-induced autophagy.","method":"Co-immunoprecipitation, Drosophila genetic loss-of-function, STING KO mice, exercise-induced autophagy assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, fly genetics, and mouse KO all converging on same mechanism with multiple orthogonal methods","pmids":["35510944"],"is_preprint":false},{"year":2019,"finding":"DIPK2A, a late endosome- and lysosome-localized protein, binds VAMP7B (a SNARE-domain-disrupted isoform), inhibiting VAMP7B's competitive interaction with STX17. This allows STX17 to preferentially bind the functional isoform VAMP7A, thereby enhancing autophagosome-lysosome fusion.","method":"Co-immunoprecipitation, overexpression/knockdown, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays in single lab with consistent results across multiple approaches","pmids":["31251111"],"is_preprint":false},{"year":2019,"finding":"The small molecule EACC blocks autophagosome-lysosome fusion by preventing STX17 and SNAP29 loading onto autophagosomes and reducing the interaction of STX17 with HOPS subunit VPS33A and lysosomal R-SNARE VAMP8; this effect is reversible and does not impair lysosomal properties or endocytic degradation.","method":"Small molecule treatment, immunofluorescence, Co-immunoprecipitation, autophagy flux assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological tool with Co-IP and localization readouts, single lab but multiple assays","pmids":["31188703"],"is_preprint":false},{"year":2017,"finding":"STX17 carrying a deletion of the N-terminal domain (ΔNTD) or N-terminally tagged with GFP acts as a dominant-negative, causing accumulation of undegraded autophagosomes devoid of lysosomal markers. The N-terminal domain is required for STX17's function in promoting autophagosome-lysosome fusion.","method":"Dominant-negative overexpression, inducible cell line, density-gradient centrifugation, immunoprecipitation purification of autophagosomes","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis with defined functional phenotype, single lab","pmids":["28598244"],"is_preprint":false},{"year":2023,"finding":"ULK kinase phosphorylates STX17 at residue S289, which is required for STX17 localization specifically to autophagosomes. Phosphorylation of S289 promotes STX17 interaction with the actin-binding protein FLNA; FLNA acts as a linker between ATG8 family proteins and STX17 to recruit STX17 to autophagosomes and facilitate autophagosome-lysosome fusion. Disease-causing mutations in FLNA's ATG8- and STX17-binding regions disrupt these interactions and inhibit fusion.","method":"In vitro kinase assay, phospho-site mutagenesis, Co-immunoprecipitation, autophagy flux assays, disease mutation analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — kinase assay plus mutagenesis plus Co-IP and functional rescue in a single rigorous study","pmids":["37389864"],"is_preprint":false},{"year":2024,"finding":"PtdIns4P generated on autophagosomes is required for STX17 recruitment to autophagosomal membranes. Recombinant STX17 is recruited to negatively charged liposomes containing PtdIns4P, mediated by C-terminal positively charged (Lys/Arg) residues. Alanine substitution of these residues abolishes membrane binding and autophagosomal recruitment, and fails to rescue autophagosome-lysosome fusion in STX17 loss-of-function cells.","method":"In vitro liposome recruitment assay, molecular dynamics simulation, mutagenesis (Ala substitution), cell-based rescue experiments, co-localization imaging","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with liposomes, MD simulation, structure-function mutagenesis, and cellular rescue, single lab but multiple orthogonal methods","pmids":["38411137"],"is_preprint":false},{"year":2024,"finding":"YKT6 forms a priming complex with STX17 and SNAP29 on autophagosomes via its SNARE domain, enhancing autophagy flux. VAMP8 subsequently displaces YKT6 from this complex to form the fusogenic STX17-SNAP29-VAMP8 complex. The YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by the STX17-SNAP29-VAMP8 complex.","method":"Co-immunoprecipitation, in vitro lipid/content mixing assays, autophagy flux assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution (lipid/content mixing) plus Co-IP and functional assays, single lab but multiple orthogonal methods","pmids":["38340317"],"is_preprint":false},{"year":2023,"finding":"RUNDC1 negatively regulates autophagy by binding ATG14 and stimulating its homo-oligomerization to trap the ATG14-STX17-SNAP29 complex, thereby preventing VAMP8 from binding STX17-SNAP29 and blocking STX17-SNAP29-VAMP8 complex assembly and autophagosome-lysosome fusion. Phosphorylation of RUNDC1 at Ser379 is required for this inhibitory activity.","method":"Gain/loss-of-function (human cells and zebrafish model), Co-immunoprecipitation, phospho-site mutagenesis, autophagy flux assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, cross-species validation (human cells + zebrafish), multiple orthogonal methods","pmids":["37684417"],"is_preprint":false},{"year":2023,"finding":"PRRSV nonstructural protein nsp5 directly interacts with STX17 (via the N-terminal motif and SNARE motif of STX17) and inhibits STX17-SNAP29 interaction, thereby blocking autophagosome-lysosome fusion and inducing incomplete autophagy.","method":"Co-immunoprecipitation, overexpression, autophagy flux assays, domain mapping","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping and functional flux assays, single lab","pmids":["36815765"],"is_preprint":false},{"year":2019,"finding":"The ER membrane protein BAP31 interacts with STX17 to suppress autophagy induction; loss of BAP31 stimulates autophagy and tumor growth under metabolic stress, identifying the BAP31-STX17 complex as a regulatory node coupling ER stress to autophagy.","method":"Co-immunoprecipitation, KO/KD, in vivo tumor growth assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and KO with functional phenotype, single lab","pmids":["31671609"],"is_preprint":false},{"year":2023,"finding":"During Neisseria gonorrhoeae infection, IRGM directly recruits STX17 to pathogen-containing endosomes. This IRGM-STX17 interaction is enhanced by LC3, enabling STX17 tethering to lysosomes and directing bacterial degradation. Interaction was still detected at reduced levels in LC3-KO cells.","method":"Co-immunoprecipitation, LC3 KO cell line, immunofluorescence, infection assays","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and KO experiments with defined infection phenotype, single lab","pmids":["37926090"],"is_preprint":false},{"year":2022,"finding":"STX17 has different localization and function across species: fly Syx17 expressed in mammalian cells localizes to the cytosol and translocates to autophagosomes upon starvation; nematode SYX-17 localizes mainly to mitochondria and promotes mitochondrial fission but does not participate in autophagy. In vivo, fly Syx17 is not involved in mitochondrial fission and nematode SYX-17 is not involved in autophagy. The C-terminal hydrophobic domain (CHD) is conserved, but the C-terminal tail differs substantially across species.","method":"Ectopic expression in mammalian cells, in vivo genetic studies in flies and nematodes, subcellular fractionation/localization","journal":"Autophagy reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species localization and in vivo experiments, single lab","pmids":["40396044"],"is_preprint":false},{"year":2024,"finding":"STX17 interacts with STING, and reducing STX17 expression increases STING levels; further knockdown of STING enhances autophagy flux. This interaction between STX17 and STING plays a role in STX17-mediated regulation of autophagosome degradation and the inflammatory response in atherosclerosis models.","method":"Co-immunoprecipitation, shRNA knockdown, autophagy flux assays in HUVEC cells and ApoE KO mice","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and sequential KD with functional readouts, single lab","pmids":["39008328"],"is_preprint":false},{"year":2025,"finding":"STX17 colocalizes with the mitochondrial outer membrane marker TOM20; STX17 knockdown impairs mitochondrial transfer from astrocytes to dopaminergic neurons. Drp1 interacts with STX17, and LRRK2 G2019S mutation increases Drp1 Ser616 phosphorylation, reducing STX17-TOM20 colocalization and mitochondrial transfer. Inhibiting Drp1 Ser616 phosphorylation with DUSP6 restores STX17-TOM20 colocalization and mitochondrial transfer efficiency.","method":"Co-immunoprecipitation (Drp1-STX17), immunofluorescence colocalization, KD, iPSC-derived co-culture system, Drp1 phosphorylation inhibitor","journal":"Translational neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and localization with functional KD phenotype, single lab with multiple methods","pmids":["41354840"],"is_preprint":false},{"year":2024,"finding":"BMAL1 directly binds to the STX17 promoter (confirmed by luciferase assay) and upregulates STX17 transcription. Increased STX17 promotes its interaction with SNAP29 and VAMP8 (confirmed by Co-IP) to form SNARE complexes, facilitating autophagosome-lysosome fusion and autophagic clearance of amyloid-β in hippocampal neurons.","method":"Luciferase reporter assay, Co-immunoprecipitation, KD/OE, transmission electron microscopy, RT-PCR","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase and Co-IP evidence, single lab, with functional autophagy readouts","pmids":["39687016"],"is_preprint":false},{"year":2026,"finding":"Upon starvation, STX17 is acetylated at lysine 254 (K254) by the acetyltransferase GCN5, and this modification is reversed by the deacetylase SIRT1. K254 acetylation promotes autophagosomal translocation of STX17, mediated by myosin VI (an F-actin-based motor protein), and is required for subsequent autophagosome-lysosome fusion.","method":"Mass spectrometry (PTM identification), mutagenesis (K254 substitution), Co-immunoprecipitation, KD of GCN5/SIRT1/myosin VI, autophagy flux assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified PTM, mutagenesis, acetyltransferase/deacetylase identification, motor protein linkage, and functional rescue in single rigorous study","pmids":["42062288"],"is_preprint":false},{"year":2025,"finding":"Legionella SidE effectors mediate phosphoribosyl ubiquitination (PR-Ub) of STX17. PR-Ub modification of STX17 alters its interaction with ATG14L and drives recruitment of STX17+ ER membranes to Legionella-containing phagosomes in a PI3K-dependent manner, forming replicative vacuoles that do not fuse with lysosomes.","method":"Proximity labeling (BioID), mass spectrometry (identification of PR-Ub sites), mutagenesis, Legionella infection assays, biochemistry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of modification sites, mutagenesis, and infection functional assays; preprint, single lab","pmids":["bio_10.1101_2025.05.19.654886"],"is_preprint":true},{"year":2024,"finding":"SLC34A2 interacts with STX17 (identified by immunoprecipitation and mass spectrometry) and promotes autophagy and cell proliferation in esophageal squamous cell carcinoma by inhibiting the ubiquitination and degradation of STX17, thereby stabilizing STX17 protein levels.","method":"Co-immunoprecipitation, mass spectrometry, cycloheximide chase assay, ubiquitination assay","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/MS and protein stability assays, single lab","pmids":["38720472"],"is_preprint":false}],"current_model":"STX17 (syntaxin 17) is an autophagosomal Qa-SNARE that mediates autophagosome-lysosome fusion by forming a trans-SNARE complex with SNAP29 and VAMP8; its recruitment to autophagosomal membranes requires PtdIns4P binding via C-terminal basic residues, ULK-mediated phosphorylation at S289, GCN5-mediated acetylation at K254 (promoting myosin VI-dependent translocation), and FLNA as an ATG8-STX17 linker. The fusogenic activity of the STX17-SNAP29-VAMP8 complex is primed by a YKT6-STX17-SNAP29 pre-complex, regulated by HOPS and PI3KC3 complexes (recruited via Pacer), and modulated by acetylation/deacetylation (CREBBP/CBP vs. HDAC2 at the SNARE domain), while STING sequesters STX17 to suppress basal autophagy. Beyond autophagosomal fusion, STX17 dynamically shuttles between the ER and mitochondria under Fis1 control; loss of Fis1 drives STX17 accumulation on mitochondria, N-terminal exposure, self-oligomerization, and PINK1/Parkin-independent mitophagy via ATG14 recruitment. STX17 is also hijacked by pathogens (Legionella PR-ubiquitination, PRRSV nsp5 binding) to block autophagic flux, and its roles in ER-to-lysosome degradation and mitochondrial transfer have been recently identified."},"narrative":{"mechanistic_narrative":"STX17 (syntaxin 17) is an autophagosomal Qa-SNARE that drives the fusion of autophagosomes with endosomes and lysosomes by assembling a trans-SNARE complex with SNAP29 and the lysosomal R-SNARE VAMP8, a function conserved from Drosophila to human cells [PMID:24113031]. Its delivery to autophagosomal membranes is gated by multiple inputs: PtdIns4P binding through C-terminal Lys/Arg residues anchors it to the membrane [PMID:38411137], ULK-mediated phosphorylation at S289 directs autophagosomal localization and licenses interaction with the actin-binding linker FLNA that bridges STX17 to ATG8 proteins [PMID:37389864], and starvation-induced GCN5 acetylation at K254 (reversed by SIRT1) promotes myosin VI-dependent translocation [PMID:42062288]. Productive SNARE assembly is staged through a YKT6-STX17-SNAP29 priming complex that is converted to the fusogenic STX17-SNAP29-VAMP8 complex when VAMP8 displaces YKT6 [PMID:38340317], and is reinforced by deacetylation of the SNARE domain (CREBBP/CBP versus HDAC2), which enhances SNAP29 and HOPS engagement upon nutrient stress [PMID:32264736]. Tethering and lipid-kinase activity at the fusion site are coordinated by Pacer, which uses STX17 as an anchor to recruit the HOPS and PI3KC3 complexes [PMID:28306502]. This fusion step is negatively regulated by RUNDC1, which traps the ATG14-STX17-SNAP29 complex to exclude VAMP8 [PMID:37684417], and by STING, which sequesters STX17 to suppress basal and starvation-induced autophagy [PMID:35510944]. Beyond autophagosome maturation, STX17 shuttles between the ER and mitochondria under Fis1 control; loss of Fis1 drives its mitochondrial accumulation, N-terminal exposure, self-oligomerization, and ATG14-dependent, PINK1/Parkin-independent mitophagy [PMID:31053718]. STX17 is exploited by pathogens, with PRRSV nsp5 binding to block SNARE assembly and incomplete autophagy [PMID:36815765], and is transcriptionally controlled by BMAL1 to promote autophagic clearance of amyloid-beta [PMID:39687016].","teleology":[{"year":2013,"claim":"Established the core identity of STX17 as the autophagosomal SNARE that executes autophagosome-lysosome/endosome fusion, defining its central role in autophagic flux.","evidence":"Drosophila Syx17 loss-of-function, human cell knockdown, and autophagy flux assays identifying the STX17-SNAP29-VAMP8/VAMP7 complex","pmids":["24113031"],"confidence":"High","gaps":["Did not resolve how STX17 is recruited to autophagosomes","Regulatory inputs controlling complex assembly unaddressed"]},{"year":2017,"claim":"Defined functional sub-modules of STX17 — the N-terminal domain as essential for fusion and Pacer as an STX17-anchored recruiter of tethering and lipid-kinase machinery.","evidence":"Dominant-negative ΔNTD/GFP-tagged STX17 with autophagosome purification, plus Pacer Co-IP and loss-of-function flux assays","pmids":["28598244","28306502"],"confidence":"Medium","gaps":["Molecular role of the N-terminal domain at the fusion step not mechanistically resolved","How Pacer site-specificity is achieved unclear"]},{"year":2019,"claim":"Revealed STX17 functions beyond autophagosome fusion, shuttling between ER and mitochondria under Fis1 control to gate a non-canonical mitophagy pathway, and identified ER-resident regulators of its activity.","evidence":"SR-SIM, proteomics, Co-IP and Fis1 depletion for the mitochondrial pathway; BAP31 and DIPK2A Co-IP/functional assays for fusion regulation","pmids":["31053718","31671609","31251111"],"confidence":"High","gaps":["Signal triggering ER-to-mitochondria redistribution unknown","Relationship between the mitochondrial and autophagosomal pools of STX17 unresolved"]},{"year":2020,"claim":"Showed that PTM of the SNARE domain by acetylation/deacetylation (CREBBP vs HDAC2) acts as a nutrient-responsive switch controlling SNAP29 and HOPS engagement, separating recruitment from complex assembly.","evidence":"Mass spectrometry PTM mapping, Co-IP, GST pulldown, and KO cells with flux assays","pmids":["32264736"],"confidence":"High","gaps":["Quantitative stoichiometry of acetylation under physiological conditions not defined","Interplay with other STX17 PTMs unaddressed"]},{"year":2022,"claim":"Identified STING as a sequestering brake on STX17 that couples energy and innate-immune signaling to autophagy, with TBK1 phosphorylation releasing STX17 pools.","evidence":"Reciprocal Co-IP, Drosophila genetics, STING KO mice, and exercise-induced autophagy assays","pmids":["35510944"],"confidence":"High","gaps":["Structural basis of STING-STX17 sequestration not defined","Which STX17 pool is released under each stimulus incompletely resolved"]},{"year":2023,"claim":"Mapped the recruitment logic of STX17 onto kinase and adaptor control — ULK phosphorylation at S289 driving FLNA-ATG8-mediated autophagosomal targeting — and defined RUNDC1 as a negative regulator that traps the pre-fusion complex.","evidence":"In vitro kinase assay, phospho-mutagenesis, Co-IP and rescue (FLNA); reciprocal Co-IP and zebrafish/human cell validation (RUNDC1)","pmids":["37389864","37684417"],"confidence":"High","gaps":["Hierarchy among S289 phosphorylation, PtdIns4P binding, and acetylation not ordered","How RUNDC1 phosphorylation is regulated unknown"]},{"year":2024,"claim":"Provided the biophysical and staged-assembly basis of STX17 action: PtdIns4P binding via C-terminal basic residues for membrane recruitment, and a YKT6 priming complex that precedes the fusogenic VAMP8 complex.","evidence":"In vitro liposome recruitment, MD simulation, Ala-substitution rescue (PtdIns4P); Co-IP and reconstituted lipid/content-mixing assays (YKT6)","pmids":["38411137","38340317"],"confidence":"High","gaps":["How PtdIns4P generation is spatially restricted to autophagosomes unclear","Trigger for YKT6-to-VAMP8 exchange not defined"]},{"year":2024,"claim":"Connected STX17 to transcriptional and stability control and to disease contexts, with BMAL1 driving STX17 transcription for amyloid-beta clearance and SLC34A2 stabilizing STX17 against ubiquitin-mediated degradation in cancer.","evidence":"Luciferase, Co-IP, and TEM (BMAL1); Co-IP/MS, cycloheximide chase, and ubiquitination assays (SLC34A2)","pmids":["39687016","38720472"],"confidence":"Medium","gaps":["E3 ligase targeting STX17 for degradation not identified","Direct causal contribution to disease pathology beyond correlation incompletely established"]},{"year":2026,"claim":"Added GCN5/SIRT1 acetylation at K254 as a starvation-responsive PTM coupling STX17 to a myosin VI motor for autophagosomal translocation.","evidence":"Mass spectrometry PTM mapping, K254 mutagenesis, GCN5/SIRT1/myosin VI knockdown, and flux assays","pmids":["42062288"],"confidence":"High","gaps":["Relationship between K254 acetylation and SNARE-domain acetylation not integrated","Spatial coordination of myosin VI transport with PtdIns4P-dependent docking unresolved"]},{"year":null,"claim":"How the many recruitment cues (PtdIns4P, S289 phosphorylation, K254 and SNARE-domain acetylation, FLNA, myosin VI) are temporally ordered into a single coherent maturation program, and how the autophagosomal versus mitochondrial pools of STX17 are physically partitioned, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated kinetic model of STX17 recruitment","Mechanism partitioning ER/mitochondrial/autophagosomal pools undefined","Structural basis of the priming-to-fusion SNARE transition not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,17]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2,3,9,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,14,20]}],"complexes":["STX17-SNAP29-VAMP8 SNARE complex","YKT6-STX17-SNAP29 priming complex","ATG14-STX17-SNAP29 complex"],"partners":["SNAP29","VAMP8","YKT6","ATG14","FLNA","STING","FIS1","RUNDC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56962","full_name":"Syntaxin-17","aliases":[],"length_aa":302,"mass_kda":33.4,"function":"SNAREs, soluble N-ethylmaleimide-sensitive factor-attachment protein receptors, are essential proteins for fusion of cellular membranes. SNAREs localized on opposing membranes assemble to form a trans-SNARE complex, an extended, parallel four alpha-helical bundle that drives membrane fusion (PubMed:23217709, PubMed:25686604, PubMed:28306502). STX17 is a SNARE of the autophagosome involved in autophagy through the direct control of autophagosome membrane fusion with the lysosome membrane (PubMed:23217709, PubMed:25686604, PubMed:28306502, PubMed:28504273). May also play a role in the early secretory pathway where it may maintain the architecture of the endoplasmic reticulum-Golgi intermediate compartment/ERGIC and Golgi and/or regulate transport between the endoplasmic reticulum, the ERGIC and the Golgi (PubMed:21545355)","subcellular_location":"Endoplasmic reticulum membrane; Smooth endoplasmic reticulum membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane; Cytoplasmic vesicle, autophagosome membrane; Cytoplasmic vesicle, COPII-coated vesicle membrane; Cytoplasm, cytosol; Mitochondrion membrane; Autolysosome membrane","url":"https://www.uniprot.org/uniprotkb/P56962/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STX17","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STX17","total_profiled":1310},"omim":[{"mim_id":"620994","title":"RUN AND FYVE DOMAINS-CONTAINING PROTEIN 4; RUFY4","url":"https://www.omim.org/entry/620994"},{"mim_id":"620175","title":"RUBICON-LIKE AUTOPHAGY ENHANCER; RUBCNL","url":"https://www.omim.org/entry/620175"},{"mim_id":"613515","title":"AUTOPHAGY-RELATED 14; ATG14","url":"https://www.omim.org/entry/613515"},{"mim_id":"609606","title":"AUTOPHAGY-RELATED 3; ATG3","url":"https://www.omim.org/entry/609606"},{"mim_id":"604261","title":"AUTOPHAGY-RELATED 5; ATG5","url":"https://www.omim.org/entry/604261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoli","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STX17"},"hgnc":{"alias_symbol":["FLJ20651"],"prev_symbol":[]},"alphafold":{"accession":"P56962","domains":[{"cath_id":"-","chopping":"1-118_164-197","consensus_level":"medium","plddt":89.4326,"start":1,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56962","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56962-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56962-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX17","jax_strain_url":"https://www.jax.org/strain/search?query=STX17"},"sequence":{"accession":"P56962","fasta_url":"https://rest.uniprot.org/uniprotkb/P56962.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56962/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56962"}},"corpus_meta":[{"pmid":"31053718","id":"PMC_31053718","title":"STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31053718","citation_count":114,"is_preprint":false},{"pmid":"32264736","id":"PMC_32264736","title":"Acetylation of STX17 (syntaxin 17) controls autophagosome maturation.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32264736","citation_count":106,"is_preprint":false},{"pmid":"29073720","id":"PMC_29073720","title":"MALAT1 modulates the autophagy of retinoblastoma cell through miR-124-mediated stx17 regulation.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29073720","citation_count":81,"is_preprint":false},{"pmid":"28306502","id":"PMC_28306502","title":"Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17.","date":"2017","source":"Molecular 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culture knockdown, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across two independent human cell culture studies and validated in an animal (Drosophila) model with defined phenotypic readout (autophagic flux defect)\",\n      \"pmids\": [\"24113031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STX17 dynamically shuttles between the ER and mitochondria, controlled by the outer mitochondrial membrane protein Fis1. Loss of Fis1 causes aberrant STX17 accumulation on mitochondria, exposes its N-terminus, promotes self-oligomerization, and triggers PINK1/Parkin-independent mitophagy. Mitochondrial STX17 interacts with ATG14, recruits core autophagy proteins to form the mitophagosome, and Rab7-dependent mitophagosome-lysosome fusion follows.\",\n      \"method\": \"Structured illumination microscopy (SR-SIM), proteomics, co-immunoprecipitation, loss-of-function (Fis1 depletion)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (SR-SIM, proteomics, Co-IP, KD) in a single rigorous study identifying the STX17-Fis1 interaction and downstream mitophagy pathway\",\n      \"pmids\": [\"31053718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STX17 is acetylated at its SNARE domain by the acetyltransferase CREBBP/CBP; HDAC2 acts as the deacetylase. Upon starvation or MTORC1 inhibition, CREBBP inactivation leads to STX17 deacetylation, which promotes its interaction with SNAP29 and formation of the STX17-SNAP29-VAMP8 SNARE complex, and also enhances STX17 interaction with the HOPS tethering complex, thereby promoting autophagosome-lysosome fusion. Deacetylation does not affect STX17 recruitment to autophagosomal membranes.\",\n      \"method\": \"Mass spectrometry (PTM identification), Co-immunoprecipitation, GST pulldown, KO cell lines, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified PTM, Co-IP, GST pulldown, and KO/OE with multiple functional readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"32264736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STX17 on autophagosomes serves as an anchor for the Pacer protein, which recruits both the PI3KC3 complex and the HOPS complex to the autophagosome, enabling site-specific activation and tethering for autophagosome-lysosome fusion. Pacer antagonizes Rubicon to stimulate Vps34 kinase activity at this step.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function, autophagy flux assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and KD/KO with defined functional phenotypes, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"28306502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STING physically interacts with STX17 and sequesters it, preventing its translocation to phagophores and mature autophagosomes. Energy crisis or TBK1-mediated phosphorylation disrupts the STING-STX17 interaction, releasing different pools of STX17 to promote autophagic flux. Loss of STING in cells and mice enhances starvation-induced autophagy.\",\n      \"method\": \"Co-immunoprecipitation, Drosophila genetic loss-of-function, STING KO mice, exercise-induced autophagy assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, fly genetics, and mouse KO all converging on same mechanism with multiple orthogonal methods\",\n      \"pmids\": [\"35510944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DIPK2A, a late endosome- and lysosome-localized protein, binds VAMP7B (a SNARE-domain-disrupted isoform), inhibiting VAMP7B's competitive interaction with STX17. This allows STX17 to preferentially bind the functional isoform VAMP7A, thereby enhancing autophagosome-lysosome fusion.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays in single lab with consistent results across multiple approaches\",\n      \"pmids\": [\"31251111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The small molecule EACC blocks autophagosome-lysosome fusion by preventing STX17 and SNAP29 loading onto autophagosomes and reducing the interaction of STX17 with HOPS subunit VPS33A and lysosomal R-SNARE VAMP8; this effect is reversible and does not impair lysosomal properties or endocytic degradation.\",\n      \"method\": \"Small molecule treatment, immunofluorescence, Co-immunoprecipitation, autophagy flux assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological tool with Co-IP and localization readouts, single lab but multiple assays\",\n      \"pmids\": [\"31188703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STX17 carrying a deletion of the N-terminal domain (ΔNTD) or N-terminally tagged with GFP acts as a dominant-negative, causing accumulation of undegraded autophagosomes devoid of lysosomal markers. The N-terminal domain is required for STX17's function in promoting autophagosome-lysosome fusion.\",\n      \"method\": \"Dominant-negative overexpression, inducible cell line, density-gradient centrifugation, immunoprecipitation purification of autophagosomes\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis with defined functional phenotype, single lab\",\n      \"pmids\": [\"28598244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ULK kinase phosphorylates STX17 at residue S289, which is required for STX17 localization specifically to autophagosomes. Phosphorylation of S289 promotes STX17 interaction with the actin-binding protein FLNA; FLNA acts as a linker between ATG8 family proteins and STX17 to recruit STX17 to autophagosomes and facilitate autophagosome-lysosome fusion. Disease-causing mutations in FLNA's ATG8- and STX17-binding regions disrupt these interactions and inhibit fusion.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, Co-immunoprecipitation, autophagy flux assays, disease mutation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — kinase assay plus mutagenesis plus Co-IP and functional rescue in a single rigorous study\",\n      \"pmids\": [\"37389864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PtdIns4P generated on autophagosomes is required for STX17 recruitment to autophagosomal membranes. Recombinant STX17 is recruited to negatively charged liposomes containing PtdIns4P, mediated by C-terminal positively charged (Lys/Arg) residues. Alanine substitution of these residues abolishes membrane binding and autophagosomal recruitment, and fails to rescue autophagosome-lysosome fusion in STX17 loss-of-function cells.\",\n      \"method\": \"In vitro liposome recruitment assay, molecular dynamics simulation, mutagenesis (Ala substitution), cell-based rescue experiments, co-localization imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with liposomes, MD simulation, structure-function mutagenesis, and cellular rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38411137\"],\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, enhancing autophagy flux. VAMP8 subsequently displaces YKT6 from this complex to form the fusogenic STX17-SNAP29-VAMP8 complex. The YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by the STX17-SNAP29-VAMP8 complex.\",\n      \"method\": \"Co-immunoprecipitation, in vitro lipid/content mixing assays, autophagy flux assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution (lipid/content mixing) plus Co-IP and functional assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38340317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RUNDC1 negatively regulates autophagy by binding ATG14 and stimulating its homo-oligomerization to trap the ATG14-STX17-SNAP29 complex, thereby preventing VAMP8 from binding STX17-SNAP29 and blocking STX17-SNAP29-VAMP8 complex assembly and autophagosome-lysosome fusion. Phosphorylation of RUNDC1 at Ser379 is required for this inhibitory activity.\",\n      \"method\": \"Gain/loss-of-function (human cells and zebrafish model), Co-immunoprecipitation, phospho-site mutagenesis, autophagy flux assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis, cross-species validation (human cells + zebrafish), multiple orthogonal methods\",\n      \"pmids\": [\"37684417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRRSV nonstructural protein nsp5 directly interacts with STX17 (via the N-terminal motif and SNARE motif of STX17) and inhibits STX17-SNAP29 interaction, thereby blocking autophagosome-lysosome fusion and inducing incomplete autophagy.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, autophagy flux assays, domain mapping\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping and functional flux assays, single lab\",\n      \"pmids\": [\"36815765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ER membrane protein BAP31 interacts with STX17 to suppress autophagy induction; loss of BAP31 stimulates autophagy and tumor growth under metabolic stress, identifying the BAP31-STX17 complex as a regulatory node coupling ER stress to autophagy.\",\n      \"method\": \"Co-immunoprecipitation, KO/KD, in vivo tumor growth assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and KO with functional phenotype, single lab\",\n      \"pmids\": [\"31671609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During Neisseria gonorrhoeae infection, IRGM directly recruits STX17 to pathogen-containing endosomes. This IRGM-STX17 interaction is enhanced by LC3, enabling STX17 tethering to lysosomes and directing bacterial degradation. Interaction was still detected at reduced levels in LC3-KO cells.\",\n      \"method\": \"Co-immunoprecipitation, LC3 KO cell line, immunofluorescence, infection assays\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and KO experiments with defined infection phenotype, single lab\",\n      \"pmids\": [\"37926090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STX17 has different localization and function across species: fly Syx17 expressed in mammalian cells localizes to the cytosol and translocates to autophagosomes upon starvation; nematode SYX-17 localizes mainly to mitochondria and promotes mitochondrial fission but does not participate in autophagy. In vivo, fly Syx17 is not involved in mitochondrial fission and nematode SYX-17 is not involved in autophagy. The C-terminal hydrophobic domain (CHD) is conserved, but the C-terminal tail differs substantially across species.\",\n      \"method\": \"Ectopic expression in mammalian cells, in vivo genetic studies in flies and nematodes, subcellular fractionation/localization\",\n      \"journal\": \"Autophagy reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species localization and in vivo experiments, single lab\",\n      \"pmids\": [\"40396044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STX17 interacts with STING, and reducing STX17 expression increases STING levels; further knockdown of STING enhances autophagy flux. This interaction between STX17 and STING plays a role in STX17-mediated regulation of autophagosome degradation and the inflammatory response in atherosclerosis models.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, autophagy flux assays in HUVEC cells and ApoE KO mice\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and sequential KD with functional readouts, single lab\",\n      \"pmids\": [\"39008328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STX17 colocalizes with the mitochondrial outer membrane marker TOM20; STX17 knockdown impairs mitochondrial transfer from astrocytes to dopaminergic neurons. Drp1 interacts with STX17, and LRRK2 G2019S mutation increases Drp1 Ser616 phosphorylation, reducing STX17-TOM20 colocalization and mitochondrial transfer. Inhibiting Drp1 Ser616 phosphorylation with DUSP6 restores STX17-TOM20 colocalization and mitochondrial transfer efficiency.\",\n      \"method\": \"Co-immunoprecipitation (Drp1-STX17), immunofluorescence colocalization, KD, iPSC-derived co-culture system, Drp1 phosphorylation inhibitor\",\n      \"journal\": \"Translational neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and localization with functional KD phenotype, single lab with multiple methods\",\n      \"pmids\": [\"41354840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BMAL1 directly binds to the STX17 promoter (confirmed by luciferase assay) and upregulates STX17 transcription. Increased STX17 promotes its interaction with SNAP29 and VAMP8 (confirmed by Co-IP) to form SNARE complexes, facilitating autophagosome-lysosome fusion and autophagic clearance of amyloid-β in hippocampal neurons.\",\n      \"method\": \"Luciferase reporter assay, Co-immunoprecipitation, KD/OE, transmission electron microscopy, RT-PCR\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase and Co-IP evidence, single lab, with functional autophagy readouts\",\n      \"pmids\": [\"39687016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Upon starvation, STX17 is acetylated at lysine 254 (K254) by the acetyltransferase GCN5, and this modification is reversed by the deacetylase SIRT1. K254 acetylation promotes autophagosomal translocation of STX17, mediated by myosin VI (an F-actin-based motor protein), and is required for subsequent autophagosome-lysosome fusion.\",\n      \"method\": \"Mass spectrometry (PTM identification), mutagenesis (K254 substitution), Co-immunoprecipitation, KD of GCN5/SIRT1/myosin VI, autophagy flux assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified PTM, mutagenesis, acetyltransferase/deacetylase identification, motor protein linkage, and functional rescue in single rigorous study\",\n      \"pmids\": [\"42062288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Legionella SidE effectors mediate phosphoribosyl ubiquitination (PR-Ub) of STX17. PR-Ub modification of STX17 alters its interaction with ATG14L and drives recruitment of STX17+ ER membranes to Legionella-containing phagosomes in a PI3K-dependent manner, forming replicative vacuoles that do not fuse with lysosomes.\",\n      \"method\": \"Proximity labeling (BioID), mass spectrometry (identification of PR-Ub sites), mutagenesis, Legionella infection assays, biochemistry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of modification sites, mutagenesis, and infection functional assays; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.19.654886\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC34A2 interacts with STX17 (identified by immunoprecipitation and mass spectrometry) and promotes autophagy and cell proliferation in esophageal squamous cell carcinoma by inhibiting the ubiquitination and degradation of STX17, thereby stabilizing STX17 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, cycloheximide chase assay, ubiquitination assay\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/MS and protein stability assays, single lab\",\n      \"pmids\": [\"38720472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX17 (syntaxin 17) is an autophagosomal Qa-SNARE that mediates autophagosome-lysosome fusion by forming a trans-SNARE complex with SNAP29 and VAMP8; its recruitment to autophagosomal membranes requires PtdIns4P binding via C-terminal basic residues, ULK-mediated phosphorylation at S289, GCN5-mediated acetylation at K254 (promoting myosin VI-dependent translocation), and FLNA as an ATG8-STX17 linker. The fusogenic activity of the STX17-SNAP29-VAMP8 complex is primed by a YKT6-STX17-SNAP29 pre-complex, regulated by HOPS and PI3KC3 complexes (recruited via Pacer), and modulated by acetylation/deacetylation (CREBBP/CBP vs. HDAC2 at the SNARE domain), while STING sequesters STX17 to suppress basal autophagy. Beyond autophagosomal fusion, STX17 dynamically shuttles between the ER and mitochondria under Fis1 control; loss of Fis1 drives STX17 accumulation on mitochondria, N-terminal exposure, self-oligomerization, and PINK1/Parkin-independent mitophagy via ATG14 recruitment. STX17 is also hijacked by pathogens (Legionella PR-ubiquitination, PRRSV nsp5 binding) to block autophagic flux, and its roles in ER-to-lysosome degradation and mitochondrial transfer have been recently identified.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STX17 (syntaxin 17) is an autophagosomal Qa-SNARE that drives the fusion of autophagosomes with endosomes and lysosomes by assembling a trans-SNARE complex with SNAP29 and the lysosomal R-SNARE VAMP8, a function conserved from Drosophila to human cells [#0]. Its delivery to autophagosomal membranes is gated by multiple inputs: PtdIns4P binding through C-terminal Lys/Arg residues anchors it to the membrane [#9], ULK-mediated phosphorylation at S289 directs autophagosomal localization and licenses interaction with the actin-binding linker FLNA that bridges STX17 to ATG8 proteins [#8], and starvation-induced GCN5 acetylation at K254 (reversed by SIRT1) promotes myosin VI-dependent translocation [#19]. Productive SNARE assembly is staged through a YKT6-STX17-SNAP29 priming complex that is converted to the fusogenic STX17-SNAP29-VAMP8 complex when VAMP8 displaces YKT6 [#10], and is reinforced by deacetylation of the SNARE domain (CREBBP/CBP versus HDAC2), which enhances SNAP29 and HOPS engagement upon nutrient stress [#2]. Tethering and lipid-kinase activity at the fusion site are coordinated by Pacer, which uses STX17 as an anchor to recruit the HOPS and PI3KC3 complexes [#3]. This fusion step is negatively regulated by RUNDC1, which traps the ATG14-STX17-SNAP29 complex to exclude VAMP8 [#11], and by STING, which sequesters STX17 to suppress basal and starvation-induced autophagy [#4]. Beyond autophagosome maturation, STX17 shuttles between the ER and mitochondria under Fis1 control; loss of Fis1 drives its mitochondrial accumulation, N-terminal exposure, self-oligomerization, and ATG14-dependent, PINK1/Parkin-independent mitophagy [#1]. STX17 is exploited by pathogens, with PRRSV nsp5 binding to block SNARE assembly and incomplete autophagy [#12], and is transcriptionally controlled by BMAL1 to promote autophagic clearance of amyloid-beta [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the core identity of STX17 as the autophagosomal SNARE that executes autophagosome-lysosome/endosome fusion, defining its central role in autophagic flux.\",\n      \"evidence\": \"Drosophila Syx17 loss-of-function, human cell knockdown, and autophagy flux assays identifying the STX17-SNAP29-VAMP8/VAMP7 complex\",\n      \"pmids\": [\"24113031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how STX17 is recruited to autophagosomes\", \"Regulatory inputs controlling complex assembly unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined functional sub-modules of STX17 — the N-terminal domain as essential for fusion and Pacer as an STX17-anchored recruiter of tethering and lipid-kinase machinery.\",\n      \"evidence\": \"Dominant-negative ΔNTD/GFP-tagged STX17 with autophagosome purification, plus Pacer Co-IP and loss-of-function flux assays\",\n      \"pmids\": [\"28598244\", \"28306502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role of the N-terminal domain at the fusion step not mechanistically resolved\", \"How Pacer site-specificity is achieved unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed STX17 functions beyond autophagosome fusion, shuttling between ER and mitochondria under Fis1 control to gate a non-canonical mitophagy pathway, and identified ER-resident regulators of its activity.\",\n      \"evidence\": \"SR-SIM, proteomics, Co-IP and Fis1 depletion for the mitochondrial pathway; BAP31 and DIPK2A Co-IP/functional assays for fusion regulation\",\n      \"pmids\": [\"31053718\", \"31671609\", \"31251111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering ER-to-mitochondria redistribution unknown\", \"Relationship between the mitochondrial and autophagosomal pools of STX17 unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that PTM of the SNARE domain by acetylation/deacetylation (CREBBP vs HDAC2) acts as a nutrient-responsive switch controlling SNAP29 and HOPS engagement, separating recruitment from complex assembly.\",\n      \"evidence\": \"Mass spectrometry PTM mapping, Co-IP, GST pulldown, and KO cells with flux assays\",\n      \"pmids\": [\"32264736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative stoichiometry of acetylation under physiological conditions not defined\", \"Interplay with other STX17 PTMs unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified STING as a sequestering brake on STX17 that couples energy and innate-immune signaling to autophagy, with TBK1 phosphorylation releasing STX17 pools.\",\n      \"evidence\": \"Reciprocal Co-IP, Drosophila genetics, STING KO mice, and exercise-induced autophagy assays\",\n      \"pmids\": [\"35510944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STING-STX17 sequestration not defined\", \"Which STX17 pool is released under each stimulus incompletely resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped the recruitment logic of STX17 onto kinase and adaptor control — ULK phosphorylation at S289 driving FLNA-ATG8-mediated autophagosomal targeting — and defined RUNDC1 as a negative regulator that traps the pre-fusion complex.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mutagenesis, Co-IP and rescue (FLNA); reciprocal Co-IP and zebrafish/human cell validation (RUNDC1)\",\n      \"pmids\": [\"37389864\", \"37684417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among S289 phosphorylation, PtdIns4P binding, and acetylation not ordered\", \"How RUNDC1 phosphorylation is regulated unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the biophysical and staged-assembly basis of STX17 action: PtdIns4P binding via C-terminal basic residues for membrane recruitment, and a YKT6 priming complex that precedes the fusogenic VAMP8 complex.\",\n      \"evidence\": \"In vitro liposome recruitment, MD simulation, Ala-substitution rescue (PtdIns4P); Co-IP and reconstituted lipid/content-mixing assays (YKT6)\",\n      \"pmids\": [\"38411137\", \"38340317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PtdIns4P generation is spatially restricted to autophagosomes unclear\", \"Trigger for YKT6-to-VAMP8 exchange not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected STX17 to transcriptional and stability control and to disease contexts, with BMAL1 driving STX17 transcription for amyloid-beta clearance and SLC34A2 stabilizing STX17 against ubiquitin-mediated degradation in cancer.\",\n      \"evidence\": \"Luciferase, Co-IP, and TEM (BMAL1); Co-IP/MS, cycloheximide chase, and ubiquitination assays (SLC34A2)\",\n      \"pmids\": [\"39687016\", \"38720472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase targeting STX17 for degradation not identified\", \"Direct causal contribution to disease pathology beyond correlation incompletely established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added GCN5/SIRT1 acetylation at K254 as a starvation-responsive PTM coupling STX17 to a myosin VI motor for autophagosomal translocation.\",\n      \"evidence\": \"Mass spectrometry PTM mapping, K254 mutagenesis, GCN5/SIRT1/myosin VI knockdown, and flux assays\",\n      \"pmids\": [\"42062288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between K254 acetylation and SNARE-domain acetylation not integrated\", \"Spatial coordination of myosin VI transport with PtdIns4P-dependent docking unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many recruitment cues (PtdIns4P, S289 phosphorylation, K254 and SNARE-domain acetylation, FLNA, myosin VI) are temporally ordered into a single coherent maturation program, and how the autophagosomal versus mitochondrial pools of STX17 are physically partitioned, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated kinetic model of STX17 recruitment\", \"Mechanism partitioning ER/mitochondrial/autophagosomal pools undefined\", \"Structural basis of the priming-to-fusion SNARE transition not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 17]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2, 3, 9, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 20]}\n    ],\n    \"complexes\": [\n      \"STX17-SNAP29-VAMP8 SNARE complex\",\n      \"YKT6-STX17-SNAP29 priming complex\",\n      \"ATG14-STX17-SNAP29 complex\"\n    ],\n    \"partners\": [\n      \"SNAP29\",\n      \"VAMP8\",\n      \"YKT6\",\n      \"ATG14\",\n      \"FLNA\",\n      \"STING\",\n      \"Fis1\",\n      \"RUNDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}