{"gene":"STX18","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1996,"finding":"UFE1 (STX18 ortholog in S. cerevisiae) is an essential gene required for both spore germination and vegetative growth, with sequence similarity to SED5 and the coiled-coil region of USO1, suggesting involvement in the secretory pathway.","method":"Gene disruption experiments, sequence analysis","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined growth phenotype, single lab, single method","pmids":["8929391"],"is_preprint":false},{"year":1997,"finding":"Ufe1p (yeast STX18 ortholog) functions as an ER t-SNARE mediating retrograde transport from the Golgi to the ER. It forms a functional SNARE complex with Sec20p, Tip20p, and the v-SNARE Sec22p. A growth-inhibiting mutation in Ufe1p is compensated by a mutation in Sec20p, and SEC22 acts as an allele-specific multicopy suppressor of a temperature-sensitive ufe1 mutation.","method":"Co-precipitation, genetic suppressor analysis, allele-specific multicopy suppressor screen","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-precipitation plus genetic epistasis (suppressor screen), replicated across multiple orthogonal methods in one study, foundational paper with 119 citations","pmids":["9214619"],"is_preprint":false},{"year":1998,"finding":"Ufe1p (yeast STX18 ortholog) is required for ER membrane fusion in a process that does not require Sec18p/NSF or Sec17p but instead requires the NSF-related ATPase Cdc48p. Ufe1p acts as a t-SNARE undergoing direct t-t-SNARE and Cdc48p interactions during organelle (ER) membrane fusion, in addition to its role as a t-SNARE for vesicular traffic.","method":"In vitro ER membrane fusion assay, protein interaction studies, genetic analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of ER membrane fusion combined with protein interaction studies, 134 citations, foundational mechanistic study","pmids":["9506516"],"is_preprint":false},{"year":1998,"finding":"The v-SNARE Sec22p recycles from the Golgi back to the ER via retrograde COPI vesicles, and this recycling requires functional Ufe1p (yeast STX18 ortholog) as well as Sec20p, Sec21p, and Sec27p. Ufe1-1 mutant cells show mislocalization of Sec22p to Golgi structures rather than ER.","method":"Immunofluorescence microscopy, subcellular fractionation, alpha-factor-tagged Sec22 reporter assay in yeast mutants","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (reporter assay and immunofluorescence), single lab","pmids":["9580559"],"is_preprint":false},{"year":1998,"finding":"Temperature-sensitive tip20 mutants are synthetic lethal with ufe1-1 and ret2-1 (delta-COP), indicating Tip20p and Ufe1p (yeast STX18 ortholog) function together in ER-Golgi retrograde transport, likely as part of the docking complex for Golgi-derived retrograde transport vesicles.","method":"Synthetic lethality / genetic epistasis analysis","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, single lab","pmids":["9639310"],"is_preprint":false},{"year":2002,"finding":"Candida albicans Ufe1p (ortholog of STX18) functionally complements a thermosensitive ufe1 mutation in S. cerevisiae, demonstrating functional conservation of the ER t-SNARE activity across fungal species. CaUfe1p interacts with CaSec20p and CaTip20p as part of an ER-tSNARE complex.","method":"Complementation assay, two-hybrid analysis, co-immunoprecipitation","journal":"Molecular genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation plus two-hybrid and co-IP, single lab","pmids":["12471444"],"is_preprint":false},{"year":2003,"finding":"Slt1 (a previously uncharacterized ER-localized SNARE) forms a SNARE complex with Sec22 and the ER syntaxin Ufe1 (yeast STX18 ortholog) and is required for retrograde traffic to the ER. Down-regulation of Slt1 leads to improper secretion of proteins normally resident in the ER. Sec20 likely contributes the fourth SNARE to this SNAREpin.","method":"Sequence analysis, localization studies, functional knockdown, complex assembly assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SNARE complex assembly plus functional knockdown showing ER retention defects, single lab","pmids":["12893879"],"is_preprint":false},{"year":2007,"finding":"Yeast Ufe1 (STX18 ortholog) is subject to ERAD-like degradation by the ubiquitin-proteasome system, and is protected from this degradation by binding to the SM protein Sly1. This SM-protein-controlled stabilization is specific to Ufe1 and does not apply to the Golgi Qa-SNARE Sed5, despite both being Sly1 partners.","method":"Protein stability assays, genetic manipulation of ERAD components, interaction studies","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein stability measurements with multiple genetic backgrounds, single lab","pmids":["18007658"],"is_preprint":false},{"year":2011,"finding":"The Dsl1 tethering complex (Dsl1, Dsl3/Sec39, Tip20) forms a stable complex with the ER SNAREs Ufe1, Use1, and Sec20 to mediate fusion of COPI vesicles with the ER. Among R-SNAREs, Sec22 is preferred over Ykt6 in the Dsl-SNARE complex. NSF/Sec18 can displace Ykt6 but not Sec22, suggesting a regulatory role for Ykt6. Ufe1 and Sec20 are ER-resident proteins that do not enter COPII vesicles.","method":"In vitro binding assays, in vivo co-immunoprecipitation, subcellular fractionation (COPII vesicle analysis)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro and in vivo orthogonal methods, reconstitution of complex interactions with defined subunit preferences, single lab with multiple methods","pmids":["21550981"],"is_preprint":false},{"year":2016,"finding":"During starvation in yeast, Ufe1 (STX18 ortholog) is increasingly exported from the ER in specific COPII vesicles (dependent on Sec23) and targeted to autophagosome formation sites containing Atg8 and Atg9. Ufe1 interacts with non-ER SNARE proteins implicated in autophagosome formation. Loss of Ufe1 function impairs autophagy, resulting in fewer and smaller autophagosomes.","method":"Fluorescence microscopy (co-localization with autophagy markers), genetic loss-of-function, COPII mutant analysis (sec23-1), starvation sensitivity assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (live imaging, genetic LOF, COPII mutant), single lab","pmids":["26876173"],"is_preprint":false},{"year":2016,"finding":"STX18 (human) is required for ER to Golgi transport of type II collagen during chondrogenesis. Loss of STX18 or its partner SCFD1 (SLY1) severely impairs transport of type II collagen in mammalian chondrocytes, establishing a specific ER export pathway for large ECM proteins during chondrogenesis.","method":"Loss-of-function (knockdown) in mammalian chondrocytes, co-localization/transport assay for type II collagen","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mammalian cell loss-of-function with specific cargo readout, single lab, supported by zebrafish genetic model","pmids":["27851892"],"is_preprint":false},{"year":2016,"finding":"STX18 knockdown in antigen-presenting cells decreases surface translocation of MR1 and impairs MR1-dependent MAIT cell recognition of Mycobacterium tuberculosis-infected cells, indicating STX18 regulates MR1 trafficking and loading of intracellular mycobacterially-derived ligands.","method":"Lentiviral shRNA screen, surface MR1 quantification, MAIT cell activation assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral shRNA knockdown with functional cell-based readout, single lab","pmids":["27031111"],"is_preprint":false},{"year":2018,"finding":"The ER-resident SNARE Ufe1 (STX18 ortholog) is co-opted by Tomato bushy stunt virus (TBSV) into the viral replication compartment. The viral p33 replication protein physically interacts with both Ufe1p and Use1p, and depletion of Ufe1 causes mislocalization of the p33 protein to the ER membrane, reduces viral RNA accumulation, and impairs formation of membrane contact sites, sterol enrichment at replication sites, and recruitment of pro-viral host factors.","method":"Co-immunoprecipitation (p33-Ufe1 interaction), cell-free replicase assay, fluorescence microscopy (localization of p33), dominant-negative overexpression, genetic depletion of Ufe1","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, cell-free assay, imaging, dominant-negative), single lab","pmids":["29746582"],"is_preprint":false},{"year":2023,"finding":"STX18 is required for cartilage and bone development in vivo. A homozygous p.Arg10Pro substitution in STX18 is associated with severe osteochondrodysplasia in a human fetus. CRISPR/Cas9-mediated Stx18 deficiency in zebrafish causes defects in cartilage and bone development. Stx18 deficiency is accompanied by increased expression of multiple SNARE complex components (Ufe1 complex) and COPI/COPII proteins, suggesting impairment of both anterograde and retrograde vesicular transport.","method":"Human genetics (homozygous variant identification), CRISPR/Cas9 zebrafish loss-of-function, expression analysis of SNARE and coat proteins","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR zebrafish model with defined skeletal phenotype plus human genetic variant, single lab","pmids":["37718532"],"is_preprint":false},{"year":2024,"finding":"STX18 acts as a negative regulator of lipophagy by binding ATG14, disrupting ATG14 interactions with ATG8-family members and subverting PI3KC3-C1 complex formation. Knockdown of STX18 activates ATG14-dependent lipophagy, leading to degradation of lipid droplet-associated anti-viral protein Viperin (RSAD2). Coronavirus M protein binds STX18 and disrupts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production.","method":"Co-immunoprecipitation (STX18-ATG14 interaction), siRNA knockdown, lipid droplet degradation assay, Viperin/RSAD2 protein level measurement, virus production assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with multiple orthogonal readouts (lipophagy, protein degradation, viral production), single lab with multiple methods","pmids":["38245527"],"is_preprint":false}],"current_model":"STX18 (Ufe1 in yeast) is an ER-resident Qa/t-SNARE that mediates retrograde vesicular transport from the Golgi to the ER by forming a SNAREpin with Sec20/Use1, Tip20, and the v-SNARE Sec22, is stabilized by the SM protein Sly1/SCFD1, participates in ER membrane fusion via interaction with the AAA-ATPase Cdc48p/p97, is required for ER-to-Golgi export of large ECM proteins (e.g., collagen II) during chondrogenesis, regulates MR1 antigen-presenting molecule trafficking, can be exported in COPII vesicles to autophagosome formation sites during starvation, and acts as a negative regulator of lipophagy by binding ATG14 to suppress PI3KC3-C1 complex formation and ATG14-ATG8 interactions—a mechanism exploited by coronavirus M protein to degrade the anti-viral protein Viperin."},"narrative":{"mechanistic_narrative":"STX18 (yeast Ufe1) is an ER-resident Qa/t-SNARE that drives retrograde vesicular transport from the Golgi to the endoplasmic reticulum [PMID:9214619]. It assembles a functional SNARE complex with Sec20, Tip20, and the v-SNARE Sec22, an arrangement confirmed by reciprocal co-precipitation and allele-specific genetic suppression and conserved across fungal species [PMID:9214619, PMID:12471444]; this t-SNARE machinery operates as the docking apparatus for Golgi-derived COPI retrograde vesicles together with the Dsl1 tethering complex, while STX18 itself remains an ER-resident protein that does not enter COPII vesicles under normal conditions [PMID:9639310, PMID:21550981]. Beyond vesicular fusion, STX18 mediates homotypic ER membrane fusion through direct t-t-SNARE and AAA-ATPase Cdc48p/p97 interactions, a fusion route independent of NSF/Sec18 [PMID:9506516], and its stability is controlled by the SM protein Sly1/SCFD1, which protects it from ERAD-mediated proteasomal degradation [PMID:18007658]. In mammals STX18 supports ER-to-Golgi export of large extracellular-matrix cargo such as type II collagen during chondrogenesis and is required for cartilage and bone development, with a homozygous p.Arg10Pro substitution associated with severe osteochondrodysplasia [PMID:27851892, PMID:37718532]. STX18 additionally functions outside its canonical transport role: it can be exported in COPII vesicles to autophagosome formation sites during starvation [PMID:26876173], regulates surface trafficking of the MR1 antigen-presenting molecule [PMID:27031111], and acts as a negative regulator of lipophagy by binding ATG14 to block PI3KC3-C1 complex assembly and ATG14-ATG8 interactions—a brake that coronavirus M protein subverts to degrade the antiviral protein Viperin [PMID:38245527].","teleology":[{"year":1996,"claim":"Established that the STX18 ortholog UFE1 is an essential gene whose sequence ties it to the secretory pathway, motivating its mechanistic characterization.","evidence":"Gene disruption and sequence analysis in S. cerevisiae","pmids":["8929391"],"confidence":"Medium","gaps":["No molecular function assigned","Secretory-pathway role inferred only from sequence similarity"]},{"year":1997,"claim":"Defined STX18/Ufe1 as the ER t-SNARE for Golgi-to-ER retrograde transport and identified its core SNARE partners, resolving the directionality and machinery of the pathway.","evidence":"Co-precipitation plus allele-specific multicopy suppressor screen in yeast (Sec20p, Tip20p, Sec22p)","pmids":["9214619"],"confidence":"High","gaps":["Stoichiometry of the SNAREpin not resolved","No structural model of the complex"]},{"year":1998,"claim":"Showed STX18/Ufe1 also drives homotypic ER membrane fusion through a Cdc48p-dependent, NSF/Sec17-independent route, distinguishing organelle fusion from vesicle traffic.","evidence":"In vitro ER membrane fusion assay with protein interaction and genetic analysis in yeast","pmids":["9506516"],"confidence":"High","gaps":["How Cdc48p substitutes for NSF mechanistically unclear","Relationship between fusion and traffic roles of the same t-SNARE not dissected"]},{"year":1998,"claim":"Linked STX18/Ufe1 function to COPI-mediated recycling of Sec22 and to the Tip20-containing docking complex, situating it in retrograde coat machinery.","evidence":"Reporter assay, immunofluorescence, and synthetic-lethality analysis with COPI components in yeast","pmids":["9580559","9639310"],"confidence":"Medium","gaps":["Physical architecture of the docking complex not defined","Single-lab genetic evidence"]},{"year":2003,"claim":"Identified Slt1/Use1 as an additional SNARE partner of Ufe1, refining the composition of the retrograde SNAREpin.","evidence":"Complex assembly and functional knockdown in yeast","pmids":["12893879"],"confidence":"Medium","gaps":["Fourth SNARE assignment (Sec20) inferred not proven","Single-lab evidence"]},{"year":2007,"claim":"Revealed that STX18/Ufe1 abundance is set by ERAD and selectively protected by the SM protein Sly1, adding a degradative layer of regulation.","evidence":"Protein stability assays across ERAD-component genetic backgrounds in yeast","pmids":["18007658"],"confidence":"Medium","gaps":["E3 ligase mediating Ufe1 ERAD not identified","Mechanism of Sly1 protection structurally undefined"]},{"year":2011,"claim":"Reconstituted the Dsl1 tethering complex with the ER SNAREs and established R-SNARE preference (Sec22 over Ykt6), defining the tethering-to-fusion handoff for COPI vesicles.","evidence":"In vitro binding, in vivo co-IP, and COPII vesicle fractionation in yeast","pmids":["21550981"],"confidence":"High","gaps":["Regulatory role of Ykt6 displacement by NSF not functionally defined","No structure of the full Dsl1-SNARE assembly"]},{"year":2016,"claim":"Extended STX18 function to mammalian ER export of large ECM cargo, showing it (with SCFD1) is specifically required for type II collagen transport in chondrocytes.","evidence":"Knockdown in mammalian chondrocytes with collagen II transport readout, supported by zebrafish","pmids":["27851892"],"confidence":"Medium","gaps":["Whether STX18 acts directly at the export step or via retrograde recycling unresolved","Single-lab evidence"]},{"year":2016,"claim":"Connected STX18/Ufe1 to autophagy by showing starvation-induced COPII export to autophagosome formation sites and an autophagy defect upon loss, broadening its role beyond ER residency.","evidence":"Live imaging, genetic LOF, and sec23-1 COPII-mutant analysis in yeast","pmids":["26876173"],"confidence":"Medium","gaps":["Identity of non-ER SNARE partners at autophagosomes not defined","Mechanism coupling COPII export to autophagosome biogenesis unclear"]},{"year":2016,"claim":"Implicated STX18 in immune antigen presentation by showing it controls MR1 surface trafficking and MAIT cell recognition of infected cells.","evidence":"shRNA knockdown with surface MR1 quantification and MAIT activation assay in antigen-presenting cells","pmids":["27031111"],"confidence":"Medium","gaps":["Trafficking step at which STX18 acts on MR1 not mapped","Single-lab evidence"]},{"year":2018,"claim":"Demonstrated viral co-option of STX18/Ufe1, with TBSV p33 binding it to build replication compartments, revealing host-membrane machinery hijacking.","evidence":"Co-IP, cell-free replicase assay, imaging, and depletion in yeast","pmids":["29746582"],"confidence":"Medium","gaps":["Whether SNARE activity per se or membrane scaffolding is required not separated","Single-lab evidence"]},{"year":2023,"claim":"Established STX18 as required for vertebrate skeletal development in vivo and linked a human variant to osteochondrodysplasia, providing disease relevance.","evidence":"Human variant identification, CRISPR/Cas9 zebrafish LOF, and SNARE/coat expression analysis","pmids":["37718532"],"confidence":"Medium","gaps":["Causality of p.Arg10Pro not proven by rescue","Mechanism linking transport defect to skeletal phenotype indirect"]},{"year":2024,"claim":"Uncovered a non-canonical role for STX18 as a lipophagy brake via ATG14 binding, and its subversion by coronavirus M protein to degrade antiviral Viperin.","evidence":"Reciprocal co-IP, siRNA knockdown, lipid droplet degradation, Viperin level and virus production assays","pmids":["38245527"],"confidence":"High","gaps":["Structural basis of STX18-ATG14 competition undefined","Whether SNARE/transport activity contributes to lipophagy regulation unknown"]},{"year":null,"claim":"How STX18's canonical SNARE-fusion activity is mechanistically reconciled with its non-canonical autophagy-regulatory and antigen-trafficking functions in mammalian cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of mammalian STX18 complexes","Direct versus indirect contribution to each non-transport role not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,8,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,8,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11]}],"complexes":["ER t-SNARE complex (Ufe1/Sec20/Use1/Sec22)","Dsl1 tethering complex"],"partners":["SEC20","TIP20","SEC22","USE1","SCFD1","CDC48","ATG14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2W9","full_name":"Syntaxin-18","aliases":["Cell growth-inhibiting gene 9 protein"],"length_aa":335,"mass_kda":38.7,"function":"Syntaxin that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9P2W9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/STX18","classification":"Common Essential","n_dependent_lines":1180,"n_total_lines":1208,"dependency_fraction":0.9768211920529801},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000168818","cell_line_id":"CID000758","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"BNIP1","stoichiometry":10.0},{"gene":"PGRMC1","stoichiometry":10.0},{"gene":"SCFD1","stoichiometry":10.0},{"gene":"SEC22B","stoichiometry":10.0},{"gene":"ZW10","stoichiometry":10.0},{"gene":"NSF","stoichiometry":10.0},{"gene":"USE1","stoichiometry":10.0},{"gene":"NBAS","stoichiometry":4.0},{"gene":"SCFD2","stoichiometry":4.0},{"gene":"RINT1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000758","total_profiled":1310},"omim":[{"mim_id":"621221","title":"STX18 ANTISENSE RNA 1, NONCODING; STX18AS1","url":"https://www.omim.org/entry/621221"},{"mim_id":"620631","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 7; EMC7","url":"https://www.omim.org/entry/620631"},{"mim_id":"616245","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 4; EMC4","url":"https://www.omim.org/entry/616245"},{"mim_id":"608025","title":"NBAS SUBUNIT OF NRZ TETHERING COMPLEX; NBAS","url":"https://www.omim.org/entry/608025"},{"mim_id":"607261","title":"EVC CILIARY COMPLEX SUBUNIT 2; EVC2","url":"https://www.omim.org/entry/607261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"cervix","ntpm":112.8}],"url":"https://www.proteinatlas.org/search/STX18"},"hgnc":{"alias_symbol":["Ufe1"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2W9","domains":[{"cath_id":"1.20.58","chopping":"46-168_242-278","consensus_level":"medium","plddt":81.4213,"start":46,"end":278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2W9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2W9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2W9-F1-predicted_aligned_error_v6.png","plddt_mean":72.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STX18","jax_strain_url":"https://www.jax.org/strain/search?query=STX18"},"sequence":{"accession":"Q9P2W9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2W9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2W9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2W9"}},"corpus_meta":[{"pmid":"9506516","id":"PMC_9506516","title":"Organelle membrane fusion: a novel function for the syntaxin homolog Ufe1p in ER membrane fusion.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9506516","citation_count":134,"is_preprint":false},{"pmid":"23708191","id":"PMC_23708191","title":"Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23708191","citation_count":120,"is_preprint":false},{"pmid":"9214619","id":"PMC_9214619","title":"A novel SNARE complex implicated in vesicle fusion with the endoplasmic reticulum.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9214619","citation_count":119,"is_preprint":false},{"pmid":"14655046","id":"PMC_14655046","title":"Two-hybrid search for proteins that interact with Sad1 and Kms1, two membrane-bound components of the spindle pole body in fission yeast.","date":"2003","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/14655046","citation_count":89,"is_preprint":false},{"pmid":"12893879","id":"PMC_12893879","title":"A SNARE required for retrograde transport to the endoplasmic reticulum.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12893879","citation_count":87,"is_preprint":false},{"pmid":"27031111","id":"PMC_27031111","title":"Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27031111","citation_count":73,"is_preprint":false},{"pmid":"10880366","id":"PMC_10880366","title":"Enhancement of the thermostability and hydrolytic activity of xylanase by random gene shuffling.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10880366","citation_count":51,"is_preprint":false},{"pmid":"26876173","id":"PMC_26876173","title":"An ER-Localized SNARE Protein Is Exported in Specific COPII Vesicles for Autophagosome Biogenesis.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26876173","citation_count":50,"is_preprint":false},{"pmid":"38245527","id":"PMC_38245527","title":"ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38245527","citation_count":48,"is_preprint":false},{"pmid":"9580559","id":"PMC_9580559","title":"Recycling of the yeast v-SNARE Sec22p involves COPI-proteins and the ER transmembrane proteins Ufe1p and Sec20p.","date":"1998","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9580559","citation_count":48,"is_preprint":false},{"pmid":"21550981","id":"PMC_21550981","title":"The Dsl1 protein tethering complex is a resident endoplasmic reticulum complex, which interacts with five soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptors (SNAREs): implications for fusion and fusion regulation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21550981","citation_count":43,"is_preprint":false},{"pmid":"29746582","id":"PMC_29746582","title":"Assembly-hub function of ER-localized SNARE proteins in biogenesis of tombusvirus replication compartment.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29746582","citation_count":35,"is_preprint":false},{"pmid":"27851892","id":"PMC_27851892","title":"The Sec domain protein Scfd1 facilitates trafficking of ECM components during chondrogenesis.","date":"2016","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27851892","citation_count":35,"is_preprint":false},{"pmid":"34214161","id":"PMC_34214161","title":"DNA Methylation Changes Associated With Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population.","date":"2021","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34214161","citation_count":30,"is_preprint":false},{"pmid":"32269127","id":"PMC_32269127","title":"Co-opted Cellular Sac1 Lipid Phosphatase and PI(4)P Phosphoinositide Are Key Host Factors during the Biogenesis of the Tombusvirus Replication Compartment.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32269127","citation_count":28,"is_preprint":false},{"pmid":"9639310","id":"PMC_9639310","title":"The Saccharomyces cerevisiae early secretion mutant tip20 is synthetic lethal with mutants in yeast coatomer and the SNARE proteins Sec22p and Ufe1p.","date":"1998","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9639310","citation_count":24,"is_preprint":false},{"pmid":"32039004","id":"PMC_32039004","title":"Pilot Study to Establish a Novel Five-Gene Biomarker Panel for Predicting Lymph Node Metastasis in Patients With Early Stage Endometrial Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32039004","citation_count":21,"is_preprint":false},{"pmid":"18722709","id":"PMC_18722709","title":"Effective stimulation of growth in MCF-7 human breast cancer cells by inhibition of syntaxin18 by external guide sequence and ribonuclease P.","date":"2008","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/18722709","citation_count":20,"is_preprint":false},{"pmid":"34340555","id":"PMC_34340555","title":"The Dissection of SNAREs Reveals Key Factors for Vesicular Trafficking to the Endosome-like Compartment and Apicoplast via the Secretory System in Toxoplasma gondii.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/34340555","citation_count":19,"is_preprint":false},{"pmid":"18007658","id":"PMC_18007658","title":"SM-protein-controlled ER-associated degradation discriminates between different SNAREs.","date":"2007","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/18007658","citation_count":15,"is_preprint":false},{"pmid":"26863016","id":"PMC_26863016","title":"Serum Autoantibodies in Chronic Prostate Inflammation in Prostate Cancer Patients.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26863016","citation_count":14,"is_preprint":false},{"pmid":"27750143","id":"PMC_27750143","title":"Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens.","date":"2016","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27750143","citation_count":12,"is_preprint":false},{"pmid":"38735055","id":"PMC_38735055","title":"ATG14 and STX18: gatekeepers of lipid droplet degradation and the implications for disease modulation.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38735055","citation_count":11,"is_preprint":false},{"pmid":"38477940","id":"PMC_38477940","title":"Coronavirus hijacks STX18-ATG14 axis-regulated lipophagy to evade an anti-viral effect.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38477940","citation_count":10,"is_preprint":false},{"pmid":"27367497","id":"PMC_27367497","title":"RINT1 functions as a multitasking protein at the crossroads between genomic stability, ER homeostasis, and autophagy.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27367497","citation_count":10,"is_preprint":false},{"pmid":"9133743","id":"PMC_9133743","title":"The sequence of a 54.7 kb fragment of yeast chromosome XV reveals the presence of two tRNAs and 24 new open reading frames.","date":"1997","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9133743","citation_count":7,"is_preprint":false},{"pmid":"27816473","id":"PMC_27816473","title":"Characterization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor gene STX18 variations for possible roles in congenital heart diseases.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27816473","citation_count":6,"is_preprint":false},{"pmid":"31712678","id":"PMC_31712678","title":"Association between the 4p16 genomic locus and different types of congenital heart disease: results from adult survivors in the UK Biobank.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31712678","citation_count":6,"is_preprint":false},{"pmid":"35315178","id":"PMC_35315178","title":"Novel classification and risk model based on ferroptosis-related lncRNAs to predict oncologic outcomes for gastric cancer patients.","date":"2022","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35315178","citation_count":5,"is_preprint":false},{"pmid":"12471444","id":"PMC_12471444","title":"Sec20p-interacting proteins (Tip20p, Ufe1p) in the retrograde secretory pathway of the fungal pathogen Candida albicans.","date":"2002","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/12471444","citation_count":4,"is_preprint":false},{"pmid":"8929391","id":"PMC_8929391","title":"Molecular analysis of UFE1, a Saccharomyces cerevisiae gene essential for spore formation and vegetative growth.","date":"1996","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8929391","citation_count":3,"is_preprint":false},{"pmid":"37718532","id":"PMC_37718532","title":"Syntaxin 18 Defects in Human and Zebrafish Unravel Key Roles in Early Cartilage and Bone Development.","date":"2023","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/37718532","citation_count":3,"is_preprint":false},{"pmid":"34853328","id":"PMC_34853328","title":"A novel RNA-mediated mechanism causing down-regulation of insulating promoter interactions in human embryonic stem cells.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34853328","citation_count":2,"is_preprint":false},{"pmid":"35377265","id":"PMC_35377265","title":"In silico analysis of the predicted protein-protein interaction of syntaxin-18, a putative receptor of Peregrinus maidis Ashmead (Hemiptera: Delphacidae) with Maize mosaic virus glycoprotein.","date":"2022","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/35377265","citation_count":2,"is_preprint":false},{"pmid":"35240980","id":"PMC_35240980","title":"Innovative computational approaches shed light on genetic mechanisms underlying cognitive impairment among children born extremely preterm.","date":"2022","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/35240980","citation_count":2,"is_preprint":false},{"pmid":"36533287","id":"PMC_36533287","title":"Data on cardiac lncRNA STX18-AS1 expression in developing human hearts and function during in vitro hESC-cardiomyocyte differentiation.","date":"2022","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/36533287","citation_count":1,"is_preprint":false},{"pmid":"40859829","id":"PMC_40859829","title":"Genetic Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility.","date":"2025","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40859829","citation_count":1,"is_preprint":false},{"pmid":"40698521","id":"PMC_40698521","title":"A Pilot Genome-Wide Association Study of Malignant Transformation of Oral Verrucous Hyperplasia.","date":"2025","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40698521","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20368,"output_tokens":3932,"usd":0.060042,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11609,"output_tokens":3937,"usd":0.078235,"stage2_stop_reason":"end_turn"},"total_usd":0.138277,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"UFE1 (STX18 ortholog in S. cerevisiae) is an essential gene required for both spore germination and vegetative growth, with sequence similarity to SED5 and the coiled-coil region of USO1, suggesting involvement in the secretory pathway.\",\n      \"method\": \"Gene disruption experiments, sequence analysis\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined growth phenotype, single lab, single method\",\n      \"pmids\": [\"8929391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Ufe1p (yeast STX18 ortholog) functions as an ER t-SNARE mediating retrograde transport from the Golgi to the ER. It forms a functional SNARE complex with Sec20p, Tip20p, and the v-SNARE Sec22p. A growth-inhibiting mutation in Ufe1p is compensated by a mutation in Sec20p, and SEC22 acts as an allele-specific multicopy suppressor of a temperature-sensitive ufe1 mutation.\",\n      \"method\": \"Co-precipitation, genetic suppressor analysis, allele-specific multicopy suppressor screen\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-precipitation plus genetic epistasis (suppressor screen), replicated across multiple orthogonal methods in one study, foundational paper with 119 citations\",\n      \"pmids\": [\"9214619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Ufe1p (yeast STX18 ortholog) is required for ER membrane fusion in a process that does not require Sec18p/NSF or Sec17p but instead requires the NSF-related ATPase Cdc48p. Ufe1p acts as a t-SNARE undergoing direct t-t-SNARE and Cdc48p interactions during organelle (ER) membrane fusion, in addition to its role as a t-SNARE for vesicular traffic.\",\n      \"method\": \"In vitro ER membrane fusion assay, protein interaction studies, genetic analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of ER membrane fusion combined with protein interaction studies, 134 citations, foundational mechanistic study\",\n      \"pmids\": [\"9506516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The v-SNARE Sec22p recycles from the Golgi back to the ER via retrograde COPI vesicles, and this recycling requires functional Ufe1p (yeast STX18 ortholog) as well as Sec20p, Sec21p, and Sec27p. Ufe1-1 mutant cells show mislocalization of Sec22p to Golgi structures rather than ER.\",\n      \"method\": \"Immunofluorescence microscopy, subcellular fractionation, alpha-factor-tagged Sec22 reporter assay in yeast mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (reporter assay and immunofluorescence), single lab\",\n      \"pmids\": [\"9580559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Temperature-sensitive tip20 mutants are synthetic lethal with ufe1-1 and ret2-1 (delta-COP), indicating Tip20p and Ufe1p (yeast STX18 ortholog) function together in ER-Golgi retrograde transport, likely as part of the docking complex for Golgi-derived retrograde transport vesicles.\",\n      \"method\": \"Synthetic lethality / genetic epistasis analysis\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, single lab\",\n      \"pmids\": [\"9639310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Candida albicans Ufe1p (ortholog of STX18) functionally complements a thermosensitive ufe1 mutation in S. cerevisiae, demonstrating functional conservation of the ER t-SNARE activity across fungal species. CaUfe1p interacts with CaSec20p and CaTip20p as part of an ER-tSNARE complex.\",\n      \"method\": \"Complementation assay, two-hybrid analysis, co-immunoprecipitation\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation plus two-hybrid and co-IP, single lab\",\n      \"pmids\": [\"12471444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Slt1 (a previously uncharacterized ER-localized SNARE) forms a SNARE complex with Sec22 and the ER syntaxin Ufe1 (yeast STX18 ortholog) and is required for retrograde traffic to the ER. Down-regulation of Slt1 leads to improper secretion of proteins normally resident in the ER. Sec20 likely contributes the fourth SNARE to this SNAREpin.\",\n      \"method\": \"Sequence analysis, localization studies, functional knockdown, complex assembly assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SNARE complex assembly plus functional knockdown showing ER retention defects, single lab\",\n      \"pmids\": [\"12893879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast Ufe1 (STX18 ortholog) is subject to ERAD-like degradation by the ubiquitin-proteasome system, and is protected from this degradation by binding to the SM protein Sly1. This SM-protein-controlled stabilization is specific to Ufe1 and does not apply to the Golgi Qa-SNARE Sed5, despite both being Sly1 partners.\",\n      \"method\": \"Protein stability assays, genetic manipulation of ERAD components, interaction studies\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein stability measurements with multiple genetic backgrounds, single lab\",\n      \"pmids\": [\"18007658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Dsl1 tethering complex (Dsl1, Dsl3/Sec39, Tip20) forms a stable complex with the ER SNAREs Ufe1, Use1, and Sec20 to mediate fusion of COPI vesicles with the ER. Among R-SNAREs, Sec22 is preferred over Ykt6 in the Dsl-SNARE complex. NSF/Sec18 can displace Ykt6 but not Sec22, suggesting a regulatory role for Ykt6. Ufe1 and Sec20 are ER-resident proteins that do not enter COPII vesicles.\",\n      \"method\": \"In vitro binding assays, in vivo co-immunoprecipitation, subcellular fractionation (COPII vesicle analysis)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro and in vivo orthogonal methods, reconstitution of complex interactions with defined subunit preferences, single lab with multiple methods\",\n      \"pmids\": [\"21550981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During starvation in yeast, Ufe1 (STX18 ortholog) is increasingly exported from the ER in specific COPII vesicles (dependent on Sec23) and targeted to autophagosome formation sites containing Atg8 and Atg9. Ufe1 interacts with non-ER SNARE proteins implicated in autophagosome formation. Loss of Ufe1 function impairs autophagy, resulting in fewer and smaller autophagosomes.\",\n      \"method\": \"Fluorescence microscopy (co-localization with autophagy markers), genetic loss-of-function, COPII mutant analysis (sec23-1), starvation sensitivity assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (live imaging, genetic LOF, COPII mutant), single lab\",\n      \"pmids\": [\"26876173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STX18 (human) is required for ER to Golgi transport of type II collagen during chondrogenesis. Loss of STX18 or its partner SCFD1 (SLY1) severely impairs transport of type II collagen in mammalian chondrocytes, establishing a specific ER export pathway for large ECM proteins during chondrogenesis.\",\n      \"method\": \"Loss-of-function (knockdown) in mammalian chondrocytes, co-localization/transport assay for type II collagen\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mammalian cell loss-of-function with specific cargo readout, single lab, supported by zebrafish genetic model\",\n      \"pmids\": [\"27851892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STX18 knockdown in antigen-presenting cells decreases surface translocation of MR1 and impairs MR1-dependent MAIT cell recognition of Mycobacterium tuberculosis-infected cells, indicating STX18 regulates MR1 trafficking and loading of intracellular mycobacterially-derived ligands.\",\n      \"method\": \"Lentiviral shRNA screen, surface MR1 quantification, MAIT cell activation assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral shRNA knockdown with functional cell-based readout, single lab\",\n      \"pmids\": [\"27031111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ER-resident SNARE Ufe1 (STX18 ortholog) is co-opted by Tomato bushy stunt virus (TBSV) into the viral replication compartment. The viral p33 replication protein physically interacts with both Ufe1p and Use1p, and depletion of Ufe1 causes mislocalization of the p33 protein to the ER membrane, reduces viral RNA accumulation, and impairs formation of membrane contact sites, sterol enrichment at replication sites, and recruitment of pro-viral host factors.\",\n      \"method\": \"Co-immunoprecipitation (p33-Ufe1 interaction), cell-free replicase assay, fluorescence microscopy (localization of p33), dominant-negative overexpression, genetic depletion of Ufe1\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, cell-free assay, imaging, dominant-negative), single lab\",\n      \"pmids\": [\"29746582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STX18 is required for cartilage and bone development in vivo. A homozygous p.Arg10Pro substitution in STX18 is associated with severe osteochondrodysplasia in a human fetus. CRISPR/Cas9-mediated Stx18 deficiency in zebrafish causes defects in cartilage and bone development. Stx18 deficiency is accompanied by increased expression of multiple SNARE complex components (Ufe1 complex) and COPI/COPII proteins, suggesting impairment of both anterograde and retrograde vesicular transport.\",\n      \"method\": \"Human genetics (homozygous variant identification), CRISPR/Cas9 zebrafish loss-of-function, expression analysis of SNARE and coat proteins\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR zebrafish model with defined skeletal phenotype plus human genetic variant, single lab\",\n      \"pmids\": [\"37718532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STX18 acts as a negative regulator of lipophagy by binding ATG14, disrupting ATG14 interactions with ATG8-family members and subverting PI3KC3-C1 complex formation. Knockdown of STX18 activates ATG14-dependent lipophagy, leading to degradation of lipid droplet-associated anti-viral protein Viperin (RSAD2). Coronavirus M protein binds STX18 and disrupts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production.\",\n      \"method\": \"Co-immunoprecipitation (STX18-ATG14 interaction), siRNA knockdown, lipid droplet degradation assay, Viperin/RSAD2 protein level measurement, virus production assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with multiple orthogonal readouts (lipophagy, protein degradation, viral production), single lab with multiple methods\",\n      \"pmids\": [\"38245527\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STX18 (Ufe1 in yeast) is an ER-resident Qa/t-SNARE that mediates retrograde vesicular transport from the Golgi to the ER by forming a SNAREpin with Sec20/Use1, Tip20, and the v-SNARE Sec22, is stabilized by the SM protein Sly1/SCFD1, participates in ER membrane fusion via interaction with the AAA-ATPase Cdc48p/p97, is required for ER-to-Golgi export of large ECM proteins (e.g., collagen II) during chondrogenesis, regulates MR1 antigen-presenting molecule trafficking, can be exported in COPII vesicles to autophagosome formation sites during starvation, and acts as a negative regulator of lipophagy by binding ATG14 to suppress PI3KC3-C1 complex formation and ATG14-ATG8 interactions—a mechanism exploited by coronavirus M protein to degrade the anti-viral protein Viperin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STX18 (yeast Ufe1) is an ER-resident Qa/t-SNARE that drives retrograde vesicular transport from the Golgi to the endoplasmic reticulum [#1]. It assembles a functional SNARE complex with Sec20, Tip20, and the v-SNARE Sec22, an arrangement confirmed by reciprocal co-precipitation and allele-specific genetic suppression and conserved across fungal species [#1, #5]; this t-SNARE machinery operates as the docking apparatus for Golgi-derived COPI retrograde vesicles together with the Dsl1 tethering complex, while STX18 itself remains an ER-resident protein that does not enter COPII vesicles under normal conditions [#4, #8]. Beyond vesicular fusion, STX18 mediates homotypic ER membrane fusion through direct t-t-SNARE and AAA-ATPase Cdc48p/p97 interactions, a fusion route independent of NSF/Sec18 [#2], and its stability is controlled by the SM protein Sly1/SCFD1, which protects it from ERAD-mediated proteasomal degradation [#7]. In mammals STX18 supports ER-to-Golgi export of large extracellular-matrix cargo such as type II collagen during chondrogenesis and is required for cartilage and bone development, with a homozygous p.Arg10Pro substitution associated with severe osteochondrodysplasia [#10, #13]. STX18 additionally functions outside its canonical transport role: it can be exported in COPII vesicles to autophagosome formation sites during starvation [#9], regulates surface trafficking of the MR1 antigen-presenting molecule [#11], and acts as a negative regulator of lipophagy by binding ATG14 to block PI3KC3-C1 complex assembly and ATG14-ATG8 interactions—a brake that coronavirus M protein subverts to degrade the antiviral protein Viperin [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the STX18 ortholog UFE1 is an essential gene whose sequence ties it to the secretory pathway, motivating its mechanistic characterization.\",\n      \"evidence\": \"Gene disruption and sequence analysis in S. cerevisiae\",\n      \"pmids\": [\"8929391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"Secretory-pathway role inferred only from sequence similarity\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined STX18/Ufe1 as the ER t-SNARE for Golgi-to-ER retrograde transport and identified its core SNARE partners, resolving the directionality and machinery of the pathway.\",\n      \"evidence\": \"Co-precipitation plus allele-specific multicopy suppressor screen in yeast (Sec20p, Tip20p, Sec22p)\",\n      \"pmids\": [\"9214619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the SNAREpin not resolved\", \"No structural model of the complex\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed STX18/Ufe1 also drives homotypic ER membrane fusion through a Cdc48p-dependent, NSF/Sec17-independent route, distinguishing organelle fusion from vesicle traffic.\",\n      \"evidence\": \"In vitro ER membrane fusion assay with protein interaction and genetic analysis in yeast\",\n      \"pmids\": [\"9506516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cdc48p substitutes for NSF mechanistically unclear\", \"Relationship between fusion and traffic roles of the same t-SNARE not dissected\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked STX18/Ufe1 function to COPI-mediated recycling of Sec22 and to the Tip20-containing docking complex, situating it in retrograde coat machinery.\",\n      \"evidence\": \"Reporter assay, immunofluorescence, and synthetic-lethality analysis with COPI components in yeast\",\n      \"pmids\": [\"9580559\", \"9639310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical architecture of the docking complex not defined\", \"Single-lab genetic evidence\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified Slt1/Use1 as an additional SNARE partner of Ufe1, refining the composition of the retrograde SNAREpin.\",\n      \"evidence\": \"Complex assembly and functional knockdown in yeast\",\n      \"pmids\": [\"12893879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fourth SNARE assignment (Sec20) inferred not proven\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed that STX18/Ufe1 abundance is set by ERAD and selectively protected by the SM protein Sly1, adding a degradative layer of regulation.\",\n      \"evidence\": \"Protein stability assays across ERAD-component genetic backgrounds in yeast\",\n      \"pmids\": [\"18007658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating Ufe1 ERAD not identified\", \"Mechanism of Sly1 protection structurally undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstituted the Dsl1 tethering complex with the ER SNAREs and established R-SNARE preference (Sec22 over Ykt6), defining the tethering-to-fusion handoff for COPI vesicles.\",\n      \"evidence\": \"In vitro binding, in vivo co-IP, and COPII vesicle fractionation in yeast\",\n      \"pmids\": [\"21550981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory role of Ykt6 displacement by NSF not functionally defined\", \"No structure of the full Dsl1-SNARE assembly\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended STX18 function to mammalian ER export of large ECM cargo, showing it (with SCFD1) is specifically required for type II collagen transport in chondrocytes.\",\n      \"evidence\": \"Knockdown in mammalian chondrocytes with collagen II transport readout, supported by zebrafish\",\n      \"pmids\": [\"27851892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STX18 acts directly at the export step or via retrograde recycling unresolved\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected STX18/Ufe1 to autophagy by showing starvation-induced COPII export to autophagosome formation sites and an autophagy defect upon loss, broadening its role beyond ER residency.\",\n      \"evidence\": \"Live imaging, genetic LOF, and sec23-1 COPII-mutant analysis in yeast\",\n      \"pmids\": [\"26876173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of non-ER SNARE partners at autophagosomes not defined\", \"Mechanism coupling COPII export to autophagosome biogenesis unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated STX18 in immune antigen presentation by showing it controls MR1 surface trafficking and MAIT cell recognition of infected cells.\",\n      \"evidence\": \"shRNA knockdown with surface MR1 quantification and MAIT activation assay in antigen-presenting cells\",\n      \"pmids\": [\"27031111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking step at which STX18 acts on MR1 not mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated viral co-option of STX18/Ufe1, with TBSV p33 binding it to build replication compartments, revealing host-membrane machinery hijacking.\",\n      \"evidence\": \"Co-IP, cell-free replicase assay, imaging, and depletion in yeast\",\n      \"pmids\": [\"29746582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNARE activity per se or membrane scaffolding is required not separated\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established STX18 as required for vertebrate skeletal development in vivo and linked a human variant to osteochondrodysplasia, providing disease relevance.\",\n      \"evidence\": \"Human variant identification, CRISPR/Cas9 zebrafish LOF, and SNARE/coat expression analysis\",\n      \"pmids\": [\"37718532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of p.Arg10Pro not proven by rescue\", \"Mechanism linking transport defect to skeletal phenotype indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a non-canonical role for STX18 as a lipophagy brake via ATG14 binding, and its subversion by coronavirus M protein to degrade antiviral Viperin.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA knockdown, lipid droplet degradation, Viperin level and virus production assays\",\n      \"pmids\": [\"38245527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STX18-ATG14 competition undefined\", \"Whether SNARE/transport activity contributes to lipophagy regulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STX18's canonical SNARE-fusion activity is mechanistically reconciled with its non-canonical autophagy-regulatory and antigen-trafficking functions in mammalian cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of mammalian STX18 complexes\", \"Direct versus indirect contribution to each non-transport role not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 8, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 8, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"ER t-SNARE complex (Ufe1/Sec20/Use1/Sec22)\", \"Dsl1 tethering complex\"],\n    \"partners\": [\"SEC20\", \"TIP20\", \"SEC22\", \"USE1\", \"SCFD1\", \"CDC48\", \"ATG14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}