{"gene":"VTI1B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2003,"finding":"VTI1B is a component of a SNARE complex with syntaxin 8, syntaxin 7, and endobrevin/VAMP-8 required for late endosome fusion; deletion of vti1b in mice specifically destabilizes syntaxin 8 (via protein degradation) while levels of syntaxin 7 and endobrevin remain unchanged, indicating VTI1B is required for stability of a single SNARE partner.","method":"Knockout mouse generation, western blotting for SNARE partner protein levels, lysosomal degradation assays in hepatocytes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with multiple orthogonal biochemical readouts, replicated across SNARE partners, published in peer-reviewed journal","pmids":["12861006"],"is_preprint":false},{"year":2005,"finding":"VTI1B forms a novel Q-SNARE complex with syntaxin 6 on Golgi-derived membranes in macrophages and has a rate-limiting role in TNF-alpha trafficking and secretion; both proteins localize to Golgi membranes and TNFalpha-containing vesicles.","method":"Immunoprecipitation, subcellular fractionation (Golgi isolation), in vitro vesicle budding assay, overexpression of full-length and truncated constructs, co-localization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, subcellular fractionation, functional overexpression studies with truncation mutants, single lab but multiple orthogonal methods","pmids":["15640147"],"is_preprint":false},{"year":2004,"finding":"EpsinR acts as an adaptor specifically for VTI1B (but not VTI1A) into clathrin-coated vesicles; knockdown of epsinR causes VTI1B redistribution from perinuclear region to cell periphery and reduces VTI1B in clathrin-coated vesicles by >70%.","method":"siRNA knockdown of epsinR and AP-1 in HeLa cells, clathrin-coated vesicle isolation, quantitative western blotting, immunofluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CCV isolation as functional assay, siRNA knockdown with multiple cargo controls, single lab with orthogonal methods","pmids":["15371541"],"is_preprint":false},{"year":2010,"finding":"VTI1B (together with VAMP8) mediates fusion of both antimicrobial autophagosomes (xenophagosomes) and canonical autophagosomes with lysosomes; siRNA knockdown of Vti1b and VAMP8 disrupts LC3/LAMP1 colocalization and impairs bactericidal efficiency against Group A Streptococcus, while knockdown of syntaxin 7 and syntaxin 8 has little effect.","method":"siRNA knockdown, confocal microscopy, bactericidal efficiency assays, LC3/LAMP1 colocalization analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with epistatic comparison to other SNAREs, multiple functional readouts (colocalization and bactericidal assay), single lab","pmids":["20089838"],"is_preprint":false},{"year":2010,"finding":"VTI1B is required for lytic granule exocytosis (degranulation) in CTL; Vti1b knockout mice show significantly reduced CTL degranulation (CD107a surface expression) and approximately 50% reduced cytolytic activity at early timepoints after antigen-specific stimulation.","method":"Knockout mouse model (TCR-transgenic OT-I background), flow cytometry for CD107a degranulation marker, cytotoxicity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with antigen-specific functional readout (degranulation marker + cytotoxicity), multiple timepoints, single lab","pmids":["20543108"],"is_preprint":false},{"year":2011,"finding":"Syntaxin 11 binds directly to VTI1B and regulates the availability of VTI1B to form the Q-SNARE complexes Stx6/Stx7/Vti1b and Stx7/Stx8/Vti1b; a disease-associated mutant form of Stx11 sequesters VTI1B from forming the complex that mediates late endosome to lysosome fusion.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy, rescue experiments with siRNA-resistant constructs","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of interaction, siRNA knockdown with rescue, functional readouts (endosomal morphology, fusion), single lab with multiple orthogonal methods","pmids":["21388490"],"is_preprint":false},{"year":2011,"finding":"VTI1B mediates tethering of lytic granules (LG) with CD3-containing endosomes (CD3-endo) in human CTL; downregulation of Vti1b reduces LG-CD3-endo tethering, impairs LG accumulation and docking at the immunological synapse, and reduces target cell killing.","method":"TIRF microscopy, fast deconvolution live microscopy, confocal microscopy, siRNA knockdown, cytotoxicity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with multiple microscopy modalities, siRNA knockdown with functional readout, single lab","pmids":["21562157"],"is_preprint":false},{"year":2011,"finding":"Combined loss of vti1a and vti1b (but not either alone) results in perinatal lethality with missing/misrouted major axon tracts and progressive neurodegeneration in peripheral ganglia (>95% neuronal loss in dorsal root and geniculate ganglia by E18.5), demonstrating functional redundancy between vti1a and vti1b in neuronal endosomal traffic.","method":"Double knockout mouse generation, histological analysis, immunofluorescence, embryo analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double KO mouse with single KO controls establishing redundancy, multiple neuronal phenotype readouts","pmids":["21262811"],"is_preprint":false},{"year":2016,"finding":"VTI1B forms a SNARE complex with STX6 and VAMP3 that mediates fusion between recycling endosomes and GAS-containing autophagosome-like vacuoles (GcAVs) during xenophagy; RABGEF1 mediates this RE-GcAV fusion through the STX6-VAMP3-VTI1B complex.","method":"siRNA knockdown, CRISPR/Cas9 knockout, co-immunoprecipitation, immunofluorescence microscopy, bactericidal assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KO/KD with functional bactericidal readout, epistasis with RABGEF1, single lab with multiple orthogonal methods","pmids":["27791468"],"is_preprint":false},{"year":2019,"finding":"VTI1B physically associates with TRPV1 (by proximity ligation assay and co-immunoprecipitation) and promotes TRPV1 sensitization during inflammation; virus-mediated knockdown of Vti1b in sensory neurons attenuates thermal hypersensitivity during inflammatory pain without affecting basal nociception.","method":"Proximity ligation assay, co-immunoprecipitation, mass spectrometry-based quantitative interactomics, viral knockdown in vivo, behavioral pain assays","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with functional pain readout and co-IP/PLA interaction data, but the nature of direct vs. indirect binding is not fully resolved (abstract states 'directly or indirectly')","pmids":["30335684"],"is_preprint":false},{"year":2020,"finding":"PTPN9 phosphatase dephosphorylates VTI1B as a substrate; dephosphorylation of VTI1B promotes SNARE complex assembly and homotypic fusion of ATG16L1+ vesicles required for autophagosome biogenesis. The nonphosphorylatable VTI1B mutant enhances autophagic flux whereas the phosphomimetic mutant does not.","method":"PTPN9 knockdown/depletion, colocalization assays, phosphomimetic and nonphosphorylatable VTI1B mutant overexpression, autophagic flux assays, SNARE complex assembly assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identification of PTM substrate-writer pair with mutagenesis (phosphomimetic vs. nonphosphorylatable) and functional autophagic flux readout, single lab with multiple orthogonal approaches","pmids":["33112705"],"is_preprint":false},{"year":2020,"finding":"VTI1B binds to the invariant chain (Ii/CD74) and localizes at contact sites of fusing Ii-positive endosomes; VTI1B is required for Ii-induced endosomal maturation delay, as silencing of Vti1b inhibits this delay. Truncated Ii lacking the cytoplasmic tail relocates VTI1B to the plasma membrane, indicating cytoplasmic tail-dependent interaction.","method":"Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, Ii knockout cell line, live-cell imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, siRNA knockdown with functional readout (endosomal maturation), Ii-KO and domain mapping, single lab","pmids":["32907852"],"is_preprint":false},{"year":2021,"finding":"VTI1B forms a trans-SNARE complex with Stx6, Stx7, and VAMP4 that mediates Golgi to late endosome trafficking of MT1-MMP in macrophages; depletion of any SNARE in this complex reduces surface MT1-MMP and gelatin degradation, while overexpression increases surface MT1-MMP.","method":"Fixed and live imaging, siRNA depletion, overexpression, gelatin degradation assays, co-immunoprecipitation","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain- and loss-of-function with multiple SNAREs tested, imaging plus biochemical readout, single lab","pmids":["34476885"],"is_preprint":false},{"year":2022,"finding":"VTI1B localizes to the Golgi complex, Rab7+ lysosomal vesicles, and polarizes to the immunological synapse colocalizing with lysosomes at actin foci upon BCR activation with surface-bound antigen in B cells; however, loss of Vti1b in primary B cells does not impair BCR signaling, immunological synapse formation, or antigen processing and presentation, suggesting functional redundancy with Vti1a.","method":"GFP-fusion protein live imaging, primary B cells from Vti1b knockout mice, flow cytometry, immunofluorescence, antigen presentation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse primary B cells with multiple functional readouts; negative functional result (no defect) explicitly reported alongside localization data","pmids":["36111340"],"is_preprint":false},{"year":2024,"finding":"Trehalose dimycolate (TDM) from M. tuberculosis binds VTI1B; in the presence of M. tuberculosis, VTI1B and STX8 form a non-canonical complex with VAMP2 instead of VAMP8, reducing VAMP8 binding and inhibiting phagosome maturation to promote intracellular M. tuberculosis growth.","method":"Photoaffinity/clickable TDM probe pulldown, co-immunoprecipitation, macrophage infection assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — chemical probe pulldown plus Co-IP showing altered SNARE complex, functional phagosome maturation readout, but preprint and single lab","pmids":["bio_10.1101_2024.12.16.627577"],"is_preprint":true}],"current_model":"VTI1B is a Qb-SNARE protein that participates in multiple membrane fusion events by forming distinct SNARE complexes: it partners with STX7, STX8, and VAMP8 for late endosome/lysosome fusion; with STX6 (and STX7) for Golgi-to-endosome trafficking of cytokines (TNFα) and MT1-MMP; with STX6 and VAMP3 for autophagosome-recycling endosome fusion during xenophagy; and with VAMP8 for autophagosome-lysosome fusion in canonical and antimicrobial autophagy. Its incorporation into clathrin-coated vesicles requires the adaptor epsinR, its stability in the STX7/STX8/VAMP8 complex is maintained by STX8 (which it stabilizes), and its activity is regulated by PTPN9-mediated dephosphorylation that promotes SNARE complex assembly for ATG16L1+ vesicle fusion. In immune cells, VTI1B mediates lytic granule exocytosis in CTL via tethering lytic granules to CD3-endosomes, and it interacts with TRPV1 in sensory neurons to promote inflammatory pain sensitization; STX11 regulates VTI1B availability by sequestering it from productive SNARE complexes."},"narrative":{"mechanistic_narrative":"VTI1B is a Qb-SNARE that drives membrane fusion across the endolysosomal, secretory, and autophagic systems by assembling into functionally distinct SNARE complexes [PMID:12861006, PMID:15640147]. In its canonical role it partners with syntaxin 7, syntaxin 8, and VAMP8/endobrevin to mediate late endosome/lysosome fusion, and within this complex it is specifically required to stabilize syntaxin 8, whose levels collapse via degradation when VTI1B is lost [PMID:12861006]. VTI1B also forms a Golgi-localized Q-SNARE complex with syntaxin 6 that is rate-limiting for TNF-alpha trafficking and secretion in macrophages [PMID:15640147], and with syntaxin 6/syntaxin 7/VAMP4 it routes MT1-MMP from the Golgi to late endosomes to support surface metalloprotease delivery and matrix degradation [PMID:34476885]. In autophagy it cooperates with VAMP8 to fuse both canonical and antimicrobial autophagosomes with lysosomes [PMID:20089838] and with syntaxin 6/VAMP3 to fuse recycling endosomes with bacteria-containing autophagic vacuoles during xenophagy [PMID:27791468]. Its activity is gated by post-translational and partner-level controls: PTPN9-mediated dephosphorylation promotes SNARE assembly and homotypic fusion of ATG16L1+ vesicles for autophagosome biogenesis [PMID:33112705], while syntaxin 11 binds VTI1B and sequesters it from productive complexes [PMID:21388490]. In cytotoxic T lymphocytes VTI1B is required for lytic granule exocytosis, tethering lytic granules to CD3-containing endosomes to enable docking at the immunological synapse and target killing [PMID:20543108, PMID:21562157]. Combined deletion of Vti1b and the paralog Vti1a causes perinatal lethality with axon misrouting and neurodegeneration, establishing functional redundancy between the two in neuronal traffic [PMID:21262811]. Pathogens subvert VTI1B: trehalose dimycolate from M. tuberculosis binds VTI1B and reroutes it into a non-canonical VAMP2-containing complex that blocks phagosome maturation [PMID:bio_10.1101_2024.12.16.627577].","teleology":[{"year":2003,"claim":"Established VTI1B as a core Qb-SNARE of the late endosome fusion machinery and revealed that it acts as a stability factor for a specific partner rather than a passive subunit.","evidence":"Vti1b knockout mouse with western blotting of SNARE partner levels and lysosomal degradation assays in hepatocytes","pmids":["12861006"],"confidence":"High","gaps":["Does not resolve how VTI1B selectively protects syntaxin 8 from degradation","No structural basis for complex assembly"]},{"year":2004,"claim":"Answered how VTI1B is sorted into transport carriers by identifying epsinR as a dedicated adaptor distinguishing VTI1B from its paralog VTI1A.","evidence":"siRNA knockdown of epsinR/AP-1 in HeLa cells with clathrin-coated vesicle isolation and quantitative western blotting","pmids":["15371541"],"confidence":"High","gaps":["Recognition motif on VTI1B used by epsinR not mapped","Whether sorting is required for specific fusion events not tested"]},{"year":2005,"claim":"Showed VTI1B builds a distinct Golgi Q-SNARE complex with syntaxin 6 dedicated to secretory cargo, broadening its role beyond endolysosomal fusion.","evidence":"Reciprocal co-IP, Golgi fractionation, in vitro vesicle budding, and truncation-construct overexpression in macrophages","pmids":["15640147"],"confidence":"High","gaps":["R-SNARE partner for this Golgi complex not defined here","Direct fusion activity not reconstituted"]},{"year":2010,"claim":"Defined VTI1B's autophagic function, showing it (with VAMP8) drives autophagosome-lysosome fusion in canonical and antimicrobial autophagy independent of syntaxin 7/8.","evidence":"siRNA knockdown with epistatic SNARE comparison, LC3/LAMP1 colocalization, and bactericidal assays against Group A Streptococcus","pmids":["20089838"],"confidence":"High","gaps":["Q-SNARE partners completing this autophagic complex not fully enumerated","Mechanism distinguishing it from the endosomal complex unclear"]},{"year":2010,"claim":"Extended VTI1B function to immune effector secretion by demonstrating it is required for lytic granule exocytosis in cytotoxic T lymphocytes.","evidence":"Vti1b knockout OT-I mice with CD107a degranulation flow cytometry and cytotoxicity assays","pmids":["20543108"],"confidence":"High","gaps":["Molecular fusion step at the synapse not yet resolved","Partner SNAREs in CTL granule fusion not identified here"]},{"year":2011,"claim":"Resolved the synapse-proximal step by showing VTI1B tethers lytic granules to CD3-endosomes to enable docking and killing.","evidence":"TIRF and deconvolution live imaging, siRNA knockdown, and cytotoxicity assays in human CTL","pmids":["21562157"],"confidence":"High","gaps":["Whether tethering is SNARE-complex-dependent not dissected","Identity of the tethering counterpart on CD3-endosomes unknown"]},{"year":2011,"claim":"Identified syntaxin 11 as a regulator that controls VTI1B availability, linking VTI1B function to disease via a sequestering mutant.","evidence":"Co-IP, siRNA knockdown with siRNA-resistant rescue, and endosomal fusion/morphology readouts","pmids":["21388490"],"confidence":"High","gaps":["Stoichiometry and structural basis of STX11-VTI1B sequestration not defined","How STX11 selects between VTI1B complexes unclear"]},{"year":2011,"claim":"Demonstrated genetic redundancy with the paralog VTI1A, defining the in vivo essentiality of the VTI1 pair in neuronal endosomal traffic.","evidence":"Vti1a/Vti1b double knockout mice with single-KO controls, histology, and embryo analysis","pmids":["21262811"],"confidence":"High","gaps":["Which specific neuronal fusion events require the pair not resolved","Molecular basis of redundancy not characterized"]},{"year":2016,"claim":"Expanded the xenophagy mechanism by defining a STX6-VAMP3-VTI1B complex, downstream of RABGEF1, that fuses recycling endosomes with bacteria-containing vacuoles.","evidence":"siRNA/CRISPR knockout, co-IP, immunofluorescence, and bactericidal assays","pmids":["27791468"],"confidence":"High","gaps":["How RABGEF1 activates this complex mechanistically not detailed","Relationship to the VAMP8 autophagic complex not reconciled"]},{"year":2019,"claim":"Linked VTI1B to sensory signaling by showing it associates with TRPV1 and promotes inflammatory pain sensitization.","evidence":"Proximity ligation assay, co-IP, quantitative interactomics, and viral knockdown with behavioral pain assays","pmids":["30335684"],"confidence":"Medium","gaps":["Whether the VTI1B-TRPV1 interaction is direct or indirect is unresolved","Mechanism by which VTI1B sensitizes TRPV1 not defined"]},{"year":2020,"claim":"Uncovered a regulatory PTM circuit in which PTPN9-mediated dephosphorylation of VTI1B licenses SNARE assembly for ATG16L1+ vesicle fusion during autophagosome biogenesis.","evidence":"PTPN9 depletion, phosphomimetic/nonphosphorylatable VTI1B mutants, SNARE assembly and autophagic flux assays","pmids":["33112705"],"confidence":"High","gaps":["The kinase that phosphorylates VTI1B not identified","Phosphosite-level structural effect on assembly not mapped"]},{"year":2020,"claim":"Showed VTI1B interacts with the MHC class II invariant chain and is required for Ii-induced endosomal maturation delay, implicating it in antigen-pathway endosome dynamics.","evidence":"Co-IP, colocalization, siRNA knockdown, Ii-KO cells, and cytoplasmic-tail domain mapping","pmids":["32907852"],"confidence":"Medium","gaps":["Directness of VTI1B-Ii binding not established","Mechanism by which VTI1B delays maturation unknown"]},{"year":2021,"claim":"Defined a STX6-STX7-VAMP4-VTI1B trans-SNARE complex routing MT1-MMP from Golgi to late endosomes, connecting VTI1B to surface metalloprotease delivery and matrix degradation.","evidence":"Live/fixed imaging, siRNA depletion, overexpression, gelatin degradation, and co-IP in macrophages","pmids":["34476885"],"confidence":"Medium","gaps":["Trans-SNARE pairing geometry not structurally verified","Whether this complex overlaps with the TNF-alpha trafficking machinery unclear"]},{"year":2022,"claim":"Refined VTI1B's immune-cell role by showing it polarizes to the B cell immunological synapse yet is dispensable for BCR signaling and antigen presentation, attributing this to redundancy with VTI1A.","evidence":"GFP-fusion live imaging and Vti1b-KO primary B cells with signaling and antigen presentation assays","pmids":["36111340"],"confidence":"Medium","gaps":["Redundancy not directly tested by double deletion in B cells","Localization function in B cells remains undefined"]},{"year":2024,"claim":"Revealed a pathogen subversion mechanism in which M. tuberculosis trehalose dimycolate binds VTI1B and reroutes it into a non-canonical VAMP2 complex to block phagosome maturation.","evidence":"Clickable TDM probe pulldown, co-IP showing altered SNARE composition, and macrophage infection assays (preprint)","pmids":["bio_10.1101_2024.12.16.627577"],"confidence":"Medium","gaps":["Preprint, single lab, awaiting peer review","Direct binding site of TDM on VTI1B not mapped","Whether VAMP2 substitution is the causal step not isolated"]},{"year":null,"claim":"How VTI1B selectively partitions among its many distinct SNARE complexes across compartments, and what determines partner choice in vivo, remains unresolved.","evidence":"No single study reconciles the compartment-specific complex repertoire mechanistically","pmids":[],"confidence":"Medium","gaps":["No structural model of complex selectivity","Upstream regulators of partner switching incompletely defined","Kinase counterpart to PTPN9 unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3,8,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,12,13]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,8,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,14]}],"complexes":["STX7/STX8/VAMP8 late endosome SNARE complex","STX6/VTI1B Golgi Q-SNARE complex","STX6/STX7/VAMP4 MT1-MMP trafficking SNARE complex","STX6/VAMP3 recycling endosome-autophagosome SNARE complex"],"partners":["STX8","STX7","VAMP8","STX6","VAMP3","STX11","PTPN9","TRPV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UEU0","full_name":"Vesicle transport through interaction with t-SNAREs homolog 1B","aliases":["Vesicle transport v-SNARE protein Vti1-like 1","Vti1-rp1"],"length_aa":232,"mass_kda":26.7,"function":"V-SNARE that mediates vesicle transport pathways through interactions with t-SNAREs on the target membrane. These interactions are proposed to mediate aspects of the specificity of vesicle trafficking and to promote fusion of the lipid bilayers. May be concerned with increased secretion of cytokines associated with cellular senescence","subcellular_location":"Early endosome membrane; Late endosome membrane; Lysosome membrane; Cytoplasmic granule; Recycling endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UEU0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VTI1B","classification":"Common Essential","n_dependent_lines":311,"n_total_lines":1208,"dependency_fraction":0.2574503311258278},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100568","cell_line_id":"CID000757","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"STX8","stoichiometry":10.0},{"gene":"VTI1A","stoichiometry":10.0},{"gene":"VAMP3;VAMP2","stoichiometry":10.0},{"gene":"NSF","stoichiometry":10.0},{"gene":"STX12","stoichiometry":4.0},{"gene":"SCFD1","stoichiometry":4.0},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"NAPA","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2},{"gene":"VAMP3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000757","total_profiled":1310},"omim":[{"mim_id":"607265","title":"CLATHRIN INTERACTOR 1; CLINT1","url":"https://www.omim.org/entry/607265"},{"mim_id":"603207","title":"VESICLE TRANSPORT THROUGH INTERACTION WITH T-SNARES 1B; VTI1B","url":"https://www.omim.org/entry/603207"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VTI1B"},"hgnc":{"alias_symbol":["VTI2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UEU0","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEU0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEU0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEU0-F1-predicted_aligned_error_v6.png","plddt_mean":83.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VTI1B","jax_strain_url":"https://www.jax.org/strain/search?query=VTI1B"},"sequence":{"accession":"Q9UEU0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UEU0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UEU0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEU0"}},"corpus_meta":[{"pmid":"20089838","id":"PMC_20089838","title":"Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20089838","citation_count":178,"is_preprint":false},{"pmid":"15640147","id":"PMC_15640147","title":"Syntaxin 6 and Vti1b form a novel SNARE complex, which is up-regulated in activated macrophages to facilitate exocytosis of tumor necrosis Factor-alpha.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15640147","citation_count":129,"is_preprint":false},{"pmid":"12861006","id":"PMC_12861006","title":"Deletion of the SNARE vti1b in mice results in the loss of a single SNARE partner, syntaxin 8.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12861006","citation_count":91,"is_preprint":false},{"pmid":"15371541","id":"PMC_15371541","title":"EpsinR is an adaptor for the SNARE protein Vti1b.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15371541","citation_count":79,"is_preprint":false},{"pmid":"21262811","id":"PMC_21262811","title":"Lack of the endosomal SNAREs vti1a and vti1b led to significant impairments in neuronal development.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21262811","citation_count":55,"is_preprint":false},{"pmid":"21388490","id":"PMC_21388490","title":"Syntaxin 11 binds Vti1b and regulates late endosome to lysosome fusion in macrophages.","date":"2011","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/21388490","citation_count":54,"is_preprint":false},{"pmid":"21562157","id":"PMC_21562157","title":"Docking of lytic granules at the immunological synapse in human CTL requires Vti1b-dependent pairing with CD3 endosomes.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21562157","citation_count":51,"is_preprint":false},{"pmid":"20543108","id":"PMC_20543108","title":"The exocytosis of lytic granules is impaired in Vti1b- or Vamp8-deficient CTL leading to a reduced cytotoxic activity following antigen-specific activation.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20543108","citation_count":45,"is_preprint":false},{"pmid":"27791468","id":"PMC_27791468","title":"The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27791468","citation_count":39,"is_preprint":false},{"pmid":"30335684","id":"PMC_30335684","title":"Vti1b promotes TRPV1 sensitization during inflammatory pain.","date":"2019","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/30335684","citation_count":20,"is_preprint":false},{"pmid":"33112705","id":"PMC_33112705","title":"PTPN9-mediated dephosphorylation of VTI1B promotes ATG16L1 precursor fusion and autophagosome formation.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33112705","citation_count":13,"is_preprint":false},{"pmid":"34476885","id":"PMC_34476885","title":"The trans-SNARE complex VAMP4/Stx6/Stx7/Vti1b is a key regulator of Golgi to late endosome MT1-MMP transport in macrophages.","date":"2021","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/34476885","citation_count":12,"is_preprint":false},{"pmid":"36419086","id":"PMC_36419086","title":"Primary neurons lacking the SNAREs vti1a and vti1b show altered neuronal development.","date":"2022","source":"Neural development","url":"https://pubmed.ncbi.nlm.nih.gov/36419086","citation_count":11,"is_preprint":false},{"pmid":"32907852","id":"PMC_32907852","title":"Invariant chain regulates endosomal fusion and maturation through an interaction with the SNARE Vti1b.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32907852","citation_count":11,"is_preprint":false},{"pmid":"36111340","id":"PMC_36111340","title":"The SNARE protein Vti1b is recruited to the sites of BCR activation but is redundant for antigen internalisation, processing and presentation.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36111340","citation_count":5,"is_preprint":false},{"pmid":"39406055","id":"PMC_39406055","title":"The double deficiency of the SNARE proteins vti1a and vti1b affects neurite outgrowth and signaling in N1E-115 neuroblastoma cells.","date":"2024","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39406055","citation_count":2,"is_preprint":false},{"pmid":"40647495","id":"PMC_40647495","title":"Mir-16 Decreases the Expression of VTI1B and SMPD1, Genes Involved in Membrane-Protein Trafficking in Melanoma.","date":"2025","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/40647495","citation_count":1,"is_preprint":false},{"pmid":"41859820","id":"PMC_41859820","title":"Reduction in Synaptic Vesicle Protein Abundance but Increased Amounts of Nsg2 and Lpcat1 in Cerebral Cortices Without the Endosomal SNARE Proteins Vti1a and Vti1b.","date":"2026","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/41859820","citation_count":0,"is_preprint":false},{"pmid":"41838692","id":"PMC_41838692","title":"Alterations in bone malformation in the absence of the endosomal SNAREs Vti1a and Vti1b.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41838692","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.16.627577","title":"Trehalose dimycolate inhibits phagosome maturation and promotes intracellular  <i>M. tuberculosis</i>  growth via noncanonical SNARE interaction","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.627577","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13356,"output_tokens":4037,"usd":0.050312,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11746,"output_tokens":4927,"usd":0.090953,"stage2_stop_reason":"end_turn"},"total_usd":0.141265,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"VTI1B is a component of a SNARE complex with syntaxin 8, syntaxin 7, and endobrevin/VAMP-8 required for late endosome fusion; deletion of vti1b in mice specifically destabilizes syntaxin 8 (via protein degradation) while levels of syntaxin 7 and endobrevin remain unchanged, indicating VTI1B is required for stability of a single SNARE partner.\",\n      \"method\": \"Knockout mouse generation, western blotting for SNARE partner protein levels, lysosomal degradation assays in hepatocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with multiple orthogonal biochemical readouts, replicated across SNARE partners, published in peer-reviewed journal\",\n      \"pmids\": [\"12861006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VTI1B forms a novel Q-SNARE complex with syntaxin 6 on Golgi-derived membranes in macrophages and has a rate-limiting role in TNF-alpha trafficking and secretion; both proteins localize to Golgi membranes and TNFalpha-containing vesicles.\",\n      \"method\": \"Immunoprecipitation, subcellular fractionation (Golgi isolation), in vitro vesicle budding assay, overexpression of full-length and truncated constructs, co-localization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, subcellular fractionation, functional overexpression studies with truncation mutants, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15640147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EpsinR acts as an adaptor specifically for VTI1B (but not VTI1A) into clathrin-coated vesicles; knockdown of epsinR causes VTI1B redistribution from perinuclear region to cell periphery and reduces VTI1B in clathrin-coated vesicles by >70%.\",\n      \"method\": \"siRNA knockdown of epsinR and AP-1 in HeLa cells, clathrin-coated vesicle isolation, quantitative western blotting, immunofluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CCV isolation as functional assay, siRNA knockdown with multiple cargo controls, single lab with orthogonal methods\",\n      \"pmids\": [\"15371541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VTI1B (together with VAMP8) mediates fusion of both antimicrobial autophagosomes (xenophagosomes) and canonical autophagosomes with lysosomes; siRNA knockdown of Vti1b and VAMP8 disrupts LC3/LAMP1 colocalization and impairs bactericidal efficiency against Group A Streptococcus, while knockdown of syntaxin 7 and syntaxin 8 has little effect.\",\n      \"method\": \"siRNA knockdown, confocal microscopy, bactericidal efficiency assays, LC3/LAMP1 colocalization analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with epistatic comparison to other SNAREs, multiple functional readouts (colocalization and bactericidal assay), single lab\",\n      \"pmids\": [\"20089838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VTI1B is required for lytic granule exocytosis (degranulation) in CTL; Vti1b knockout mice show significantly reduced CTL degranulation (CD107a surface expression) and approximately 50% reduced cytolytic activity at early timepoints after antigen-specific stimulation.\",\n      \"method\": \"Knockout mouse model (TCR-transgenic OT-I background), flow cytometry for CD107a degranulation marker, cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with antigen-specific functional readout (degranulation marker + cytotoxicity), multiple timepoints, single lab\",\n      \"pmids\": [\"20543108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Syntaxin 11 binds directly to VTI1B and regulates the availability of VTI1B to form the Q-SNARE complexes Stx6/Stx7/Vti1b and Stx7/Stx8/Vti1b; a disease-associated mutant form of Stx11 sequesters VTI1B from forming the complex that mediates late endosome to lysosome fusion.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy, rescue experiments with siRNA-resistant constructs\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of interaction, siRNA knockdown with rescue, functional readouts (endosomal morphology, fusion), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21388490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"VTI1B mediates tethering of lytic granules (LG) with CD3-containing endosomes (CD3-endo) in human CTL; downregulation of Vti1b reduces LG-CD3-endo tethering, impairs LG accumulation and docking at the immunological synapse, and reduces target cell killing.\",\n      \"method\": \"TIRF microscopy, fast deconvolution live microscopy, confocal microscopy, siRNA knockdown, cytotoxicity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with multiple microscopy modalities, siRNA knockdown with functional readout, single lab\",\n      \"pmids\": [\"21562157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Combined loss of vti1a and vti1b (but not either alone) results in perinatal lethality with missing/misrouted major axon tracts and progressive neurodegeneration in peripheral ganglia (>95% neuronal loss in dorsal root and geniculate ganglia by E18.5), demonstrating functional redundancy between vti1a and vti1b in neuronal endosomal traffic.\",\n      \"method\": \"Double knockout mouse generation, histological analysis, immunofluorescence, embryo analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double KO mouse with single KO controls establishing redundancy, multiple neuronal phenotype readouts\",\n      \"pmids\": [\"21262811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VTI1B forms a SNARE complex with STX6 and VAMP3 that mediates fusion between recycling endosomes and GAS-containing autophagosome-like vacuoles (GcAVs) during xenophagy; RABGEF1 mediates this RE-GcAV fusion through the STX6-VAMP3-VTI1B complex.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, co-immunoprecipitation, immunofluorescence microscopy, bactericidal assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KO/KD with functional bactericidal readout, epistasis with RABGEF1, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27791468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VTI1B physically associates with TRPV1 (by proximity ligation assay and co-immunoprecipitation) and promotes TRPV1 sensitization during inflammation; virus-mediated knockdown of Vti1b in sensory neurons attenuates thermal hypersensitivity during inflammatory pain without affecting basal nociception.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, mass spectrometry-based quantitative interactomics, viral knockdown in vivo, behavioral pain assays\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with functional pain readout and co-IP/PLA interaction data, but the nature of direct vs. indirect binding is not fully resolved (abstract states 'directly or indirectly')\",\n      \"pmids\": [\"30335684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN9 phosphatase dephosphorylates VTI1B as a substrate; dephosphorylation of VTI1B promotes SNARE complex assembly and homotypic fusion of ATG16L1+ vesicles required for autophagosome biogenesis. The nonphosphorylatable VTI1B mutant enhances autophagic flux whereas the phosphomimetic mutant does not.\",\n      \"method\": \"PTPN9 knockdown/depletion, colocalization assays, phosphomimetic and nonphosphorylatable VTI1B mutant overexpression, autophagic flux assays, SNARE complex assembly assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identification of PTM substrate-writer pair with mutagenesis (phosphomimetic vs. nonphosphorylatable) and functional autophagic flux readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"33112705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VTI1B binds to the invariant chain (Ii/CD74) and localizes at contact sites of fusing Ii-positive endosomes; VTI1B is required for Ii-induced endosomal maturation delay, as silencing of Vti1b inhibits this delay. Truncated Ii lacking the cytoplasmic tail relocates VTI1B to the plasma membrane, indicating cytoplasmic tail-dependent interaction.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, Ii knockout cell line, live-cell imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, siRNA knockdown with functional readout (endosomal maturation), Ii-KO and domain mapping, single lab\",\n      \"pmids\": [\"32907852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VTI1B forms a trans-SNARE complex with Stx6, Stx7, and VAMP4 that mediates Golgi to late endosome trafficking of MT1-MMP in macrophages; depletion of any SNARE in this complex reduces surface MT1-MMP and gelatin degradation, while overexpression increases surface MT1-MMP.\",\n      \"method\": \"Fixed and live imaging, siRNA depletion, overexpression, gelatin degradation assays, co-immunoprecipitation\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain- and loss-of-function with multiple SNAREs tested, imaging plus biochemical readout, single lab\",\n      \"pmids\": [\"34476885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VTI1B localizes to the Golgi complex, Rab7+ lysosomal vesicles, and polarizes to the immunological synapse colocalizing with lysosomes at actin foci upon BCR activation with surface-bound antigen in B cells; however, loss of Vti1b in primary B cells does not impair BCR signaling, immunological synapse formation, or antigen processing and presentation, suggesting functional redundancy with Vti1a.\",\n      \"method\": \"GFP-fusion protein live imaging, primary B cells from Vti1b knockout mice, flow cytometry, immunofluorescence, antigen presentation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse primary B cells with multiple functional readouts; negative functional result (no defect) explicitly reported alongside localization data\",\n      \"pmids\": [\"36111340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Trehalose dimycolate (TDM) from M. tuberculosis binds VTI1B; in the presence of M. tuberculosis, VTI1B and STX8 form a non-canonical complex with VAMP2 instead of VAMP8, reducing VAMP8 binding and inhibiting phagosome maturation to promote intracellular M. tuberculosis growth.\",\n      \"method\": \"Photoaffinity/clickable TDM probe pulldown, co-immunoprecipitation, macrophage infection assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — chemical probe pulldown plus Co-IP showing altered SNARE complex, functional phagosome maturation readout, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.627577\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VTI1B is a Qb-SNARE protein that participates in multiple membrane fusion events by forming distinct SNARE complexes: it partners with STX7, STX8, and VAMP8 for late endosome/lysosome fusion; with STX6 (and STX7) for Golgi-to-endosome trafficking of cytokines (TNFα) and MT1-MMP; with STX6 and VAMP3 for autophagosome-recycling endosome fusion during xenophagy; and with VAMP8 for autophagosome-lysosome fusion in canonical and antimicrobial autophagy. Its incorporation into clathrin-coated vesicles requires the adaptor epsinR, its stability in the STX7/STX8/VAMP8 complex is maintained by STX8 (which it stabilizes), and its activity is regulated by PTPN9-mediated dephosphorylation that promotes SNARE complex assembly for ATG16L1+ vesicle fusion. In immune cells, VTI1B mediates lytic granule exocytosis in CTL via tethering lytic granules to CD3-endosomes, and it interacts with TRPV1 in sensory neurons to promote inflammatory pain sensitization; STX11 regulates VTI1B availability by sequestering it from productive SNARE complexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VTI1B is a Qb-SNARE that drives membrane fusion across the endolysosomal, secretory, and autophagic systems by assembling into functionally distinct SNARE complexes [#0, #1]. In its canonical role it partners with syntaxin 7, syntaxin 8, and VAMP8/endobrevin to mediate late endosome/lysosome fusion, and within this complex it is specifically required to stabilize syntaxin 8, whose levels collapse via degradation when VTI1B is lost [#0]. VTI1B also forms a Golgi-localized Q-SNARE complex with syntaxin 6 that is rate-limiting for TNF-alpha trafficking and secretion in macrophages [#1], and with syntaxin 6/syntaxin 7/VAMP4 it routes MT1-MMP from the Golgi to late endosomes to support surface metalloprotease delivery and matrix degradation [#12]. In autophagy it cooperates with VAMP8 to fuse both canonical and antimicrobial autophagosomes with lysosomes [#3] and with syntaxin 6/VAMP3 to fuse recycling endosomes with bacteria-containing autophagic vacuoles during xenophagy [#8]. Its activity is gated by post-translational and partner-level controls: PTPN9-mediated dephosphorylation promotes SNARE assembly and homotypic fusion of ATG16L1+ vesicles for autophagosome biogenesis [#10], while syntaxin 11 binds VTI1B and sequesters it from productive complexes [#5]. In cytotoxic T lymphocytes VTI1B is required for lytic granule exocytosis, tethering lytic granules to CD3-containing endosomes to enable docking at the immunological synapse and target killing [#4, #6]. Combined deletion of Vti1b and the paralog Vti1a causes perinatal lethality with axon misrouting and neurodegeneration, establishing functional redundancy between the two in neuronal traffic [#7]. Pathogens subvert VTI1B: trehalose dimycolate from M. tuberculosis binds VTI1B and reroutes it into a non-canonical VAMP2-containing complex that blocks phagosome maturation [#14].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established VTI1B as a core Qb-SNARE of the late endosome fusion machinery and revealed that it acts as a stability factor for a specific partner rather than a passive subunit.\",\n      \"evidence\": \"Vti1b knockout mouse with western blotting of SNARE partner levels and lysosomal degradation assays in hepatocytes\",\n      \"pmids\": [\"12861006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how VTI1B selectively protects syntaxin 8 from degradation\", \"No structural basis for complex assembly\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Answered how VTI1B is sorted into transport carriers by identifying epsinR as a dedicated adaptor distinguishing VTI1B from its paralog VTI1A.\",\n      \"evidence\": \"siRNA knockdown of epsinR/AP-1 in HeLa cells with clathrin-coated vesicle isolation and quantitative western blotting\",\n      \"pmids\": [\"15371541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition motif on VTI1B used by epsinR not mapped\", \"Whether sorting is required for specific fusion events not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed VTI1B builds a distinct Golgi Q-SNARE complex with syntaxin 6 dedicated to secretory cargo, broadening its role beyond endolysosomal fusion.\",\n      \"evidence\": \"Reciprocal co-IP, Golgi fractionation, in vitro vesicle budding, and truncation-construct overexpression in macrophages\",\n      \"pmids\": [\"15640147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"R-SNARE partner for this Golgi complex not defined here\", \"Direct fusion activity not reconstituted\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined VTI1B's autophagic function, showing it (with VAMP8) drives autophagosome-lysosome fusion in canonical and antimicrobial autophagy independent of syntaxin 7/8.\",\n      \"evidence\": \"siRNA knockdown with epistatic SNARE comparison, LC3/LAMP1 colocalization, and bactericidal assays against Group A Streptococcus\",\n      \"pmids\": [\"20089838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Q-SNARE partners completing this autophagic complex not fully enumerated\", \"Mechanism distinguishing it from the endosomal complex unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended VTI1B function to immune effector secretion by demonstrating it is required for lytic granule exocytosis in cytotoxic T lymphocytes.\",\n      \"evidence\": \"Vti1b knockout OT-I mice with CD107a degranulation flow cytometry and cytotoxicity assays\",\n      \"pmids\": [\"20543108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular fusion step at the synapse not yet resolved\", \"Partner SNAREs in CTL granule fusion not identified here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the synapse-proximal step by showing VTI1B tethers lytic granules to CD3-endosomes to enable docking and killing.\",\n      \"evidence\": \"TIRF and deconvolution live imaging, siRNA knockdown, and cytotoxicity assays in human CTL\",\n      \"pmids\": [\"21562157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tethering is SNARE-complex-dependent not dissected\", \"Identity of the tethering counterpart on CD3-endosomes unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified syntaxin 11 as a regulator that controls VTI1B availability, linking VTI1B function to disease via a sequestering mutant.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with siRNA-resistant rescue, and endosomal fusion/morphology readouts\",\n      \"pmids\": [\"21388490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of STX11-VTI1B sequestration not defined\", \"How STX11 selects between VTI1B complexes unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated genetic redundancy with the paralog VTI1A, defining the in vivo essentiality of the VTI1 pair in neuronal endosomal traffic.\",\n      \"evidence\": \"Vti1a/Vti1b double knockout mice with single-KO controls, histology, and embryo analysis\",\n      \"pmids\": [\"21262811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific neuronal fusion events require the pair not resolved\", \"Molecular basis of redundancy not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded the xenophagy mechanism by defining a STX6-VAMP3-VTI1B complex, downstream of RABGEF1, that fuses recycling endosomes with bacteria-containing vacuoles.\",\n      \"evidence\": \"siRNA/CRISPR knockout, co-IP, immunofluorescence, and bactericidal assays\",\n      \"pmids\": [\"27791468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RABGEF1 activates this complex mechanistically not detailed\", \"Relationship to the VAMP8 autophagic complex not reconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked VTI1B to sensory signaling by showing it associates with TRPV1 and promotes inflammatory pain sensitization.\",\n      \"evidence\": \"Proximity ligation assay, co-IP, quantitative interactomics, and viral knockdown with behavioral pain assays\",\n      \"pmids\": [\"30335684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the VTI1B-TRPV1 interaction is direct or indirect is unresolved\", \"Mechanism by which VTI1B sensitizes TRPV1 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a regulatory PTM circuit in which PTPN9-mediated dephosphorylation of VTI1B licenses SNARE assembly for ATG16L1+ vesicle fusion during autophagosome biogenesis.\",\n      \"evidence\": \"PTPN9 depletion, phosphomimetic/nonphosphorylatable VTI1B mutants, SNARE assembly and autophagic flux assays\",\n      \"pmids\": [\"33112705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase that phosphorylates VTI1B not identified\", \"Phosphosite-level structural effect on assembly not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed VTI1B interacts with the MHC class II invariant chain and is required for Ii-induced endosomal maturation delay, implicating it in antigen-pathway endosome dynamics.\",\n      \"evidence\": \"Co-IP, colocalization, siRNA knockdown, Ii-KO cells, and cytoplasmic-tail domain mapping\",\n      \"pmids\": [\"32907852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of VTI1B-Ii binding not established\", \"Mechanism by which VTI1B delays maturation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a STX6-STX7-VAMP4-VTI1B trans-SNARE complex routing MT1-MMP from Golgi to late endosomes, connecting VTI1B to surface metalloprotease delivery and matrix degradation.\",\n      \"evidence\": \"Live/fixed imaging, siRNA depletion, overexpression, gelatin degradation, and co-IP in macrophages\",\n      \"pmids\": [\"34476885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-SNARE pairing geometry not structurally verified\", \"Whether this complex overlaps with the TNF-alpha trafficking machinery unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined VTI1B's immune-cell role by showing it polarizes to the B cell immunological synapse yet is dispensable for BCR signaling and antigen presentation, attributing this to redundancy with VTI1A.\",\n      \"evidence\": \"GFP-fusion live imaging and Vti1b-KO primary B cells with signaling and antigen presentation assays\",\n      \"pmids\": [\"36111340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy not directly tested by double deletion in B cells\", \"Localization function in B cells remains undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a pathogen subversion mechanism in which M. tuberculosis trehalose dimycolate binds VTI1B and reroutes it into a non-canonical VAMP2 complex to block phagosome maturation.\",\n      \"evidence\": \"Clickable TDM probe pulldown, co-IP showing altered SNARE composition, and macrophage infection assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.627577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, awaiting peer review\", \"Direct binding site of TDM on VTI1B not mapped\", \"Whether VAMP2 substitution is the causal step not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VTI1B selectively partitions among its many distinct SNARE complexes across compartments, and what determines partner choice in vivo, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the compartment-specific complex repertoire mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of complex selectivity\", \"Upstream regulators of partner switching incompletely defined\", \"Kinase counterpart to PTPN9 unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3, 8, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 12, 13]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 8, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 14]}\n    ],\n    \"complexes\": [\n      \"STX7/STX8/VAMP8 late endosome SNARE complex\",\n      \"STX6/VTI1B Golgi Q-SNARE complex\",\n      \"STX6/STX7/VAMP4 MT1-MMP trafficking SNARE complex\",\n      \"STX6/VAMP3 recycling endosome-autophagosome SNARE complex\"\n    ],\n    \"partners\": [\n      \"STX8\",\n      \"STX7\",\n      \"VAMP8\",\n      \"STX6\",\n      \"VAMP3\",\n      \"STX11\",\n      \"PTPN9\",\n      \"TRPV1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}