Affinage

STX18

Syntaxin-18 · UniProt Q9P2W9

Round 2 corrected
Length
335 aa
Mass
38.7 kDa
Annotated
2026-04-28
69 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STX18 is an ER-resident Qa-SNARE that orchestrates membrane fusion events essential for ER homeostasis, bidirectional ER–Golgi trafficking, and selective autophagy regulation. It assembles into a multi-subunit complex with BNIP1/p31, Sec22b, ZW10, RINT-1, NAG, and Sly1/SCFD1, in which ZW10–RINT-1–NAG form a peripheral tethering subcomplex that is released upon NSF/α-SNAP–driven SNARE disassembly, mediating Golgi-to-ER retrograde transport and anterograde export of large cargo such as type II collagen (PMID:10788491, PMID:15029241, PMID:19369418, PMID:27851892). STX18 also negatively regulates ATG14-dependent lipophagy by binding ATG14 and disrupting ATG14–ATG8 interactions; coronavirus M protein subverts this axis to induce lipophagy-mediated degradation of the antiviral protein Viperin (PMID:38245527). A homozygous STX18 missense variant was identified as a candidate cause of recessive osteochondrodysplasia, with zebrafish crispants recapitulating cartilage and bone defects (PMID:37718532).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 High

    Identifying STX18 as the first ER-localized t-SNARE established that a dedicated SNARE mediates ER membrane dynamics and ER-to-Golgi transport, resolving the question of which syntaxin operates at the ER.

    Evidence Yeast two-hybrid, subcellular fractionation, immunocytochemistry, and overexpression/dominant-negative assays in mammalian cells

    PMID:10788491

    Open questions at the time
    • Cognate v-SNARE partners not yet identified
    • Mechanism of ER membrane aggregation upon overexpression unclear
    • No structural information on STX18
  2. 2004 High

    Demonstrating that ZW10, RINT-1, and BNIP1/p31 assemble with STX18 into a SNARE complex that is disassembled by NSF/α-SNAP defined the compositional architecture and ATP-dependent cycling of the STX18 fusion machinery, and revealed an unexpected link between ER membrane fusion and apoptosis through BNIP1's BH3 domain.

    Evidence Co-immunoprecipitation, NSF/α-SNAP disassembly assay, domain mutagenesis, RNAi knockdown, apoptosis assays

    PMID:15029241 PMID:15272311

    Open questions at the time
    • Physiological relevance of BNIP1–α-SNAP competition for apoptosis regulation in vivo not tested
    • Stoichiometry of the complex not determined
  3. 2009 High

    Identification of NAG as a peripheral bridging subunit connecting p31 to ZW10–RINT-1 completed the tethering architecture of the STX18 complex and showed its requirement for Golgi-to-ER retrograde transport.

    Evidence Co-immunoprecipitation, GST pulldown, siRNA knockdown with Golgi morphology and glycosylation readouts

    PMID:19369418

    Open questions at the time
    • Mechanism by which NAG is recruited to ER membranes unknown
    • No reconstitution of the full complex in vitro
  4. 2016 Medium

    Three independent studies broadened STX18's functional scope: the SCFD1–STX18 interaction proved essential for anterograde export of type II collagen during chondrogenesis; the STX18 complex was linked to neuronal ER homeostasis and autophagy via RINT-1 conditional knockout; and STX18 was identified as a regulator of MR1 surface translocation for MAIT-cell antigen presentation.

    Evidence Zebrafish mutagenesis and mammalian chondrocyte knockdown (collagen transport, UPR assays); conditional KO mouse neurons (ER stress, autophagy flux); shRNA screen in antigen-presenting cells (flow cytometry, T-cell activation)

    PMID:27031111 PMID:27367497 PMID:27851892

    Open questions at the time
    • Direct versus indirect role of STX18 in MR1 trafficking not resolved
    • Whether neuronal autophagy defects are STX18-intrinsic or secondary to RINT-1 loss unclear
    • Structural basis for STX18-SCFD1 interaction and large-cargo selectivity unknown
  5. 2023 Medium

    A human homozygous STX18 missense variant linked to severe osteochondrodysplasia, recapitulated in zebrafish crispants, established STX18 as a disease gene and confirmed that both anterograde and retrograde vesicular transport depend on its function in skeletal tissues.

    Evidence Homozygosity mapping in a consanguineous family, CRISPR/Cas9 zebrafish model with skeletal staining and transcriptomic/proteomic analysis

    PMID:37718532

    Open questions at the time
    • Single family reported; additional kindreds needed for definitive causality
    • Biochemical impact of p.Arg10Pro on SNARE complex assembly not characterized
    • Whether compensatory upregulation of COP components is adaptive or pathogenic is unclear
  6. 2024 High

    The discovery that STX18 binds ATG14 and suppresses ATG14–ATG8 interaction revealed a non-canonical role as a negative regulator of lipophagy, and showed that coronavirus M protein hijacks this axis to degrade the antiviral effector Viperin.

    Evidence Co-immunoprecipitation, knockdown, lipid droplet imaging, autophagy flux assays, and viral replication assays in mammalian cells

    PMID:38245527

    Open questions at the time
    • Whether STX18-dependent lipophagy regulation occurs in non-infection contexts is unknown
    • Structural basis of the STX18–ATG14 interaction not determined
    • Generality across coronavirus species beyond those tested not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structural model of the STX18 SNARE complex exists, the mechanisms linking its SNARE activity to lipophagy suppression versus canonical membrane fusion remain unresolved, and the full spectrum of STX18-dependent cargo is undefined.
  • No crystal or cryo-EM structure of the STX18 complex
  • Relationship between SNARE-mediated fusion and ATG14-binding functions not mechanistically separated
  • Cargo selectivity determinants for anterograde large-cargo export unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 4
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 4 R-HSA-9612973 Autophagy 2
Partners
ATG14BNIP1KIAA0665NAPARINT1SCFD1ZW10
Complex memberships
NRZ/ZW10–RINT-1–NAG tethering complexSTX18 SNARE complex (STX18–BNIP1/p31–Sec22b–Use1)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Syntaxin 18 (STX18) was identified as a novel ER-localized t-SNARE that binds α-SNAP. Subcellular fractionation and immunocytochemistry showed it is principally located in the endoplasmic reticulum. Overexpression caused ER membrane aggregation, while a truncation mutant lacking the N-terminal 81 amino acids caused dispersion of the ER-Golgi intermediate compartment and cis-Golgi, and inhibited protein export from the ER, establishing a role in ER-to-Golgi transport. Yeast two-hybrid, subcellular fractionation, immunocytochemistry, overexpression/dominant-negative functional assays The Journal of biological chemistry High 10788491
2004 ZW10 (a kinetochore/spindle-checkpoint protein) localizes to the ER during interphase and forms a subcomplex with RINT-1 and p31 within a larger complex that includes syntaxin 18. ZW10, RINT-1, and p31 dissociated from STX18 upon Mg²⁺-ATP treatment in the presence of NSF and α-SNAP, indicating SNARE complex disassembly. Overexpression, microinjection, and knockdown experiments established that ZW10 is required for membrane trafficking between the ER and Golgi. Co-immunoprecipitation, subcellular fractionation, NSF/α-SNAP disassembly assay, overexpression, microinjection, RNAi knockdown The EMBO journal High 15029241
2004 BNIP1 (a BH3-only protein) is a component of the STX18 SNARE complex at the ER. BNIP1 participates in ER network formation but not in ER-to-Golgi trafficking. A conserved leucine in BNIP1's BH3 domain is required both for apoptosis induction and for binding α-SNAP, suggesting that α-SNAP can compete with anti-apoptotic proteins for BNIP1's BH3 domain. Overexpression of α-SNAP delayed staurosporine-induced apoptosis, revealing crosstalk between ER membrane fusion and apoptosis. Co-immunoprecipitation, domain mutagenesis, ER morphology assays, apoptosis assays, α-SNAP overexpression rescue The EMBO journal High 15272311
2009 The neuroblastoma-amplified gene product (NAG) is a peripheral membrane subunit of the STX18 complex, analogous to yeast Dsl3p/Sec39p. NAG bridges p31 (via its N-terminal region) and the ZW10-RINT-1 subcomplex (via its C-terminal region). Under SNARE-disassembly conditions, NAG dissociates from STX18 but remains in the p31-ZW10-RINT-1 subcomplex. NAG knockdown caused redistribution of Golgi recycling proteins and defective protein glycosylation, indicating a role in Golgi-to-ER retrograde transport. Co-immunoprecipitation, GST pulldown, siRNA knockdown, Golgi morphology/glycosylation assays Molecular biology of the cell High 19369418
2016 STX18 knockdown in antigen-presenting cells impaired surface translocation of MR1 (a Class I-like molecule) and reduced MAIT cell recognition of Mycobacterium tuberculosis-infected cells, identifying STX18 as a trafficking molecule regulating MR1-dependent antigen presentation via an endosomal pathway distinct from VAMP4- and Rab6-dependent routes. Lentiviral shRNA screen, flow cytometry for MR1 surface expression, T-cell activation assay PLoS pathogens Medium 27031111
2016 SCFD1 (Sly1) and STX18 form a conserved complex that mediates ER-to-Golgi export of large ECM proteins including type II collagen during chondrogenesis. Loss of either SCFD1 or STX18 in mammalian chondrocytes severely impaired type II collagen transport and activated the unfolded protein response. Zebrafish mutagenesis screen, siRNA knockdown in mammalian chondrocytes, collagen transport assay, UPR reporter assay Developmental biology Medium 27851892
2016 RINT-1, previously known to interact with STX18 as part of an ER tethering complex, is required for ER homeostasis and genomic stability in neurons; its loss triggers ER stress, neural progenitor depletion, and inhibition of autophagy, placing the STX18-RINT-1 complex at the intersection of ER trafficking and neuronal autophagy regulation. Conditional knockout mouse, neuronal phenotyping, ER stress markers, autophagy flux assays Autophagy Medium 27367497
2023 A homozygous p.Arg10Pro substitution in STX18 was identified in a fetus with severe osteochondrodysplasia. CRISPR/Cas9 stx18 crispant zebrafish showed defects in cartilage and bone development. Increased expression of multiple STX18 SNARE complex components and of COPI/COPII proteins in crispants suggested that STX18 deficiency impairs both anterograde and retrograde vesicular transport, broadening the known function of STX18 to skeletal development and establishing it as a candidate gene for a recessive osteochondrodysplasia (SNAREopathy). Human genetics (homozygosity mapping), CRISPR/Cas9 zebrafish model, skeletal staining, transcriptomic/proteomic analysis of SNARE/COP components Journal of bone and mineral research Medium 37718532
2024 STX18 acts as a negative regulator of lipophagy by binding ATG14, disrupting ATG14-ATG8 family member interactions and subverting PI3KC3-C1 complex formation. STX18 knockdown activates ATG14-dependent lipophagy, leading to degradation of lipid droplet-associated anti-viral protein Viperin. Coronavirus M protein binds STX18 and subverts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, thereby facilitating virus production. Co-immunoprecipitation, siRNA/shRNA knockdown, lipid droplet imaging and quantification, autophagy flux assays, viral replication assays, domain interaction mapping Nature communications High 38245527
2008 Downregulation of STX18 by external guide sequence/RNase P-mediated mRNA cleavage in MCF-7 human breast cancer cells led to significant enhancement of cell growth, while STX18 overexpression suppressed growth, establishing a role for STX18 in regulating cell proliferation independently of c-myc transcriptional control. RNase P-mediated mRNA knockdown, cell growth assays, STX18 overexpression, c-myc qRT-PCR and half-life analysis Cancer letters Medium 18722709

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2004 Implication of ZW10 in membrane trafficking between the endoplasmic reticulum and Golgi. The EMBO journal 160 15029241
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
1998 Organelle membrane fusion: a novel function for the syntaxin homolog Ufe1p in ER membrane fusion. Cell 134 9506516
2013 Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16. Nature genetics 120 23708191
1997 A novel SNARE complex implicated in vesicle fusion with the endoplasmic reticulum. The EMBO journal 119 9214619
2000 Syntaxin 18, a SNAP receptor that functions in the endoplasmic reticulum, intermediate compartment, and cis-Golgi vesicle trafficking. The Journal of biological chemistry 111 10788491
2004 Involvement of BNIP1 in apoptosis and endoplasmic reticulum membrane fusion. The EMBO journal 109 15272311
2009 Identification of the neuroblastoma-amplified gene product as a component of the syntaxin 18 complex implicated in Golgi-to-endoplasmic reticulum retrograde transport. Molecular biology of the cell 104 19369418
2021 Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor. Cell & bioscience 93 33766124
2003 Two-hybrid search for proteins that interact with Sad1 and Kms1, two membrane-bound components of the spindle pole body in fission yeast. Molecular genetics and genomics : MGG 89 14655046
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2020 Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress. The EMBO journal 86 32149426
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2003 A SNARE required for retrograde transport to the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America 86 12893879
2017 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III. Cell metabolism 78 28380382
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2018 Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability. Nature communications 73 30194290
2016 Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells. PLoS pathogens 70 27031111
2006 MAIGO2 is involved in exit of seed storage proteins from the endoplasmic reticulum in Arabidopsis thaliana. The Plant cell 68 17194767
2000 Enhancement of the thermostability and hydrolytic activity of xylanase by random gene shuffling. The Biochemical journal 51 10880366
2016 An ER-Localized SNARE Protein Is Exported in Specific COPII Vesicles for Autophagosome Biogenesis. Cell reports 49 26876173
1998 Recycling of the yeast v-SNARE Sec22p involves COPI-proteins and the ER transmembrane proteins Ufe1p and Sec20p. Journal of cell science 48 9580559
2011 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. The Journal of biological chemistry 43 21550981
2024 ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover. Nature communications 41 38245527
2016 The Sec domain protein Scfd1 facilitates trafficking of ECM components during chondrogenesis. Developmental biology 35 27851892
2018 Assembly-hub function of ER-localized SNARE proteins in biogenesis of tombusvirus replication compartment. PLoS pathogens 34 29746582
2021 DNA Methylation Changes Associated With Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population. The Journal of clinical endocrinology and metabolism 29 34214161
2020 Co-opted Cellular Sac1 Lipid Phosphatase and PI(4)P Phosphoinositide Are Key Host Factors during the Biogenesis of the Tombusvirus Replication Compartment. Journal of virology 27 32269127
1998 The Saccharomyces cerevisiae early secretion mutant tip20 is synthetic lethal with mutants in yeast coatomer and the SNARE proteins Sec22p and Ufe1p. Yeast (Chichester, England) 24 9639310
2020 Pilot Study to Establish a Novel Five-Gene Biomarker Panel for Predicting Lymph Node Metastasis in Patients With Early Stage Endometrial Cancer. Frontiers in oncology 21 32039004
2008 Effective stimulation of growth in MCF-7 human breast cancer cells by inhibition of syntaxin18 by external guide sequence and ribonuclease P. Cancer letters 20 18722709
2021 The Dissection of SNAREs Reveals Key Factors for Vesicular Trafficking to the Endosome-like Compartment and Apicoplast via the Secretory System in Toxoplasma gondii. mBio 18 34340555
2007 SM-protein-controlled ER-associated degradation discriminates between different SNAREs. EMBO reports 15 18007658
2016 Serum Autoantibodies in Chronic Prostate Inflammation in Prostate Cancer Patients. PloS one 14 26863016
2016 Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens. Psychoneuroendocrinology 12 27750143
2016 RINT1 functions as a multitasking protein at the crossroads between genomic stability, ER homeostasis, and autophagy. Autophagy 10 27367497
2024 ATG14 and STX18: gatekeepers of lipid droplet degradation and the implications for disease modulation. Autophagy 8 38735055
1997 The sequence of a 54.7 kb fragment of yeast chromosome XV reveals the presence of two tRNAs and 24 new open reading frames. Yeast (Chichester, England) 7 9133743
2024 Coronavirus hijacks STX18-ATG14 axis-regulated lipophagy to evade an anti-viral effect. Autophagy 6 38477940
2019 Association between the 4p16 genomic locus and different types of congenital heart disease: results from adult survivors in the UK Biobank. Scientific reports 6 31712678
2016 Characterization of soluble N-ethylmaleimide-sensitive factor attachment protein receptor gene STX18 variations for possible roles in congenital heart diseases. Gene 6 27816473
2022 Novel classification and risk model based on ferroptosis-related lncRNAs to predict oncologic outcomes for gastric cancer patients. Journal of biochemical and molecular toxicology 5 35315178
2002 Sec20p-interacting proteins (Tip20p, Ufe1p) in the retrograde secretory pathway of the fungal pathogen Candida albicans. Molecular genetics and genomics : MGG 4 12471444
2023 Syntaxin 18 Defects in Human and Zebrafish Unravel Key Roles in Early Cartilage and Bone Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 3 37718532
1996 Molecular analysis of UFE1, a Saccharomyces cerevisiae gene essential for spore formation and vegetative growth. Current genetics 3 8929391
2022 Innovative computational approaches shed light on genetic mechanisms underlying cognitive impairment among children born extremely preterm. Journal of neurodevelopmental disorders 2 35240980
2022 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. Journal of biomolecular structure & dynamics 2 35377265
2021 A novel RNA-mediated mechanism causing down-regulation of insulating promoter interactions in human embryonic stem cells. Scientific reports 2 34853328
2025 Genetic Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility. Circulation. Genomic and precision medicine 1 40859829
2022 Data on cardiac lncRNA STX18-AS1 expression in developing human hearts and function during in vitro hESC-cardiomyocyte differentiation. Data in brief 1 36533287
2025 A Pilot Genome-Wide Association Study of Malignant Transformation of Oral Verrucous Hyperplasia. Oral diseases 0 40698521