Affinage

VTI1B

Vesicle transport through interaction with t-SNAREs homolog 1B · UniProt Q9UEU0

Length
232 aa
Mass
26.7 kDa
Annotated
2026-06-11
19 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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].

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    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

    PMID:12861006

    Open questions at the time
    • Does not resolve how VTI1B selectively protects syntaxin 8 from degradation
    • No structural basis for complex assembly
  2. 2004 High

    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

    PMID:15371541

    Open questions at the time
    • Recognition motif on VTI1B used by epsinR not mapped
    • Whether sorting is required for specific fusion events not tested
  3. 2005 High

    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

    PMID:15640147

    Open questions at the time
    • R-SNARE partner for this Golgi complex not defined here
    • Direct fusion activity not reconstituted
  4. 2010 High

    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

    PMID:20089838

    Open questions at the time
    • Q-SNARE partners completing this autophagic complex not fully enumerated
    • Mechanism distinguishing it from the endosomal complex unclear
  5. 2010 High

    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

    PMID:20543108

    Open questions at the time
    • Molecular fusion step at the synapse not yet resolved
    • Partner SNAREs in CTL granule fusion not identified here
  6. 2011 High

    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

    PMID:21562157

    Open questions at the time
    • Whether tethering is SNARE-complex-dependent not dissected
    • Identity of the tethering counterpart on CD3-endosomes unknown
  7. 2011 High

    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

    PMID:21388490

    Open questions at the time
    • Stoichiometry and structural basis of STX11-VTI1B sequestration not defined
    • How STX11 selects between VTI1B complexes unclear
  8. 2011 High

    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

    PMID:21262811

    Open questions at the time
    • Which specific neuronal fusion events require the pair not resolved
    • Molecular basis of redundancy not characterized
  9. 2016 High

    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

    PMID:27791468

    Open questions at the time
    • How RABGEF1 activates this complex mechanistically not detailed
    • Relationship to the VAMP8 autophagic complex not reconciled
  10. 2019 Medium

    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

    PMID:30335684

    Open questions at the time
    • Whether the VTI1B-TRPV1 interaction is direct or indirect is unresolved
    • Mechanism by which VTI1B sensitizes TRPV1 not defined
  11. 2020 High

    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

    PMID:33112705

    Open questions at the time
    • The kinase that phosphorylates VTI1B not identified
    • Phosphosite-level structural effect on assembly not mapped
  12. 2020 Medium

    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

    PMID:32907852

    Open questions at the time
    • Directness of VTI1B-Ii binding not established
    • Mechanism by which VTI1B delays maturation unknown
  13. 2021 Medium

    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

    PMID:34476885

    Open questions at the time
    • Trans-SNARE pairing geometry not structurally verified
    • Whether this complex overlaps with the TNF-alpha trafficking machinery unclear
  14. 2022 Medium

    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

    PMID:36111340

    Open questions at the time
    • Redundancy not directly tested by double deletion in B cells
    • Localization function in B cells remains undefined
  15. 2024 Medium

    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)

    PMID:bio_10.1101_2024.12.16.627577

    Open questions at the time
    • Preprint, single lab, awaiting peer review
    • Direct binding site of TDM on VTI1B not mapped
    • Whether VAMP2 substitution is the causal step not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VTI1B selectively partitions among its many distinct SNARE complexes across compartments, and what determines partner choice in vivo, remains unresolved.
  • No structural model of complex selectivity
  • Upstream regulators of partner switching incompletely defined
  • Kinase counterpart to PTPN9 unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 3 GO:0005794 Golgi apparatus 3 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
PTPN9STX11STX6STX7STX8TRPV1VAMP3VAMP8
Complex memberships
STX6/STX7/VAMP4 MT1-MMP trafficking SNARE complexSTX6/VAMP3 recycling endosome-autophagosome SNARE complexSTX6/VTI1B Golgi Q-SNARE complexSTX7/STX8/VAMP8 late endosome SNARE complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Knockout mouse generation, western blotting for SNARE partner protein levels, lysosomal degradation assays in hepatocytes Molecular and cellular biology High 12861006
2005 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. Immunoprecipitation, subcellular fractionation (Golgi isolation), in vitro vesicle budding assay, overexpression of full-length and truncated constructs, co-localization by immunofluorescence The Journal of biological chemistry High 15640147
2004 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%. siRNA knockdown of epsinR and AP-1 in HeLa cells, clathrin-coated vesicle isolation, quantitative western blotting, immunofluorescence microscopy Molecular biology of the cell High 15371541
2010 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. siRNA knockdown, confocal microscopy, bactericidal efficiency assays, LC3/LAMP1 colocalization analysis Molecular biology of the cell High 20089838
2010 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. Knockout mouse model (TCR-transgenic OT-I background), flow cytometry for CD107a degranulation marker, cytotoxicity assays Journal of immunology High 20543108
2011 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. Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy, rescue experiments with siRNA-resistant constructs Traffic High 21388490
2011 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. TIRF microscopy, fast deconvolution live microscopy, confocal microscopy, siRNA knockdown, cytotoxicity assays Journal of immunology High 21562157
2011 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. Double knockout mouse generation, histological analysis, immunofluorescence, embryo analysis PNAS High 21262811
2016 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. siRNA knockdown, CRISPR/Cas9 knockout, co-immunoprecipitation, immunofluorescence microscopy, bactericidal assays Autophagy High 27791468
2019 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. Proximity ligation assay, co-immunoprecipitation, mass spectrometry-based quantitative interactomics, viral knockdown in vivo, behavioral pain assays Pain Medium 30335684
2020 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. PTPN9 knockdown/depletion, colocalization assays, phosphomimetic and nonphosphorylatable VTI1B mutant overexpression, autophagic flux assays, SNARE complex assembly assays Autophagy High 33112705
2020 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. Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, Ii knockout cell line, live-cell imaging Journal of cell science Medium 32907852
2021 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. Fixed and live imaging, siRNA depletion, overexpression, gelatin degradation assays, co-immunoprecipitation Traffic Medium 34476885
2022 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. GFP-fusion protein live imaging, primary B cells from Vti1b knockout mice, flow cytometry, immunofluorescence, antigen presentation assays Frontiers in cell and developmental biology Medium 36111340
2024 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. Photoaffinity/clickable TDM probe pulldown, co-immunoprecipitation, macrophage infection assays bioRxivpreprint Medium bio_10.1101_2024.12.16.627577

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Molecular biology of the cell 178 20089838
2005 Syntaxin 6 and Vti1b form a novel SNARE complex, which is up-regulated in activated macrophages to facilitate exocytosis of tumor necrosis Factor-alpha. The Journal of biological chemistry 129 15640147
2003 Deletion of the SNARE vti1b in mice results in the loss of a single SNARE partner, syntaxin 8. Molecular and cellular biology 91 12861006
2004 EpsinR is an adaptor for the SNARE protein Vti1b. Molecular biology of the cell 79 15371541
2011 Lack of the endosomal SNAREs vti1a and vti1b led to significant impairments in neuronal development. Proceedings of the National Academy of Sciences of the United States of America 55 21262811
2011 Syntaxin 11 binds Vti1b and regulates late endosome to lysosome fusion in macrophages. Traffic (Copenhagen, Denmark) 54 21388490
2011 Docking of lytic granules at the immunological synapse in human CTL requires Vti1b-dependent pairing with CD3 endosomes. Journal of immunology (Baltimore, Md. : 1950) 51 21562157
2010 The exocytosis of lytic granules is impaired in Vti1b- or Vamp8-deficient CTL leading to a reduced cytotoxic activity following antigen-specific activation. Journal of immunology (Baltimore, Md. : 1950) 45 20543108
2016 The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes. Autophagy 39 27791468
2019 Vti1b promotes TRPV1 sensitization during inflammatory pain. Pain 20 30335684
2020 PTPN9-mediated dephosphorylation of VTI1B promotes ATG16L1 precursor fusion and autophagosome formation. Autophagy 13 33112705
2021 The trans-SNARE complex VAMP4/Stx6/Stx7/Vti1b is a key regulator of Golgi to late endosome MT1-MMP transport in macrophages. Traffic (Copenhagen, Denmark) 12 34476885
2022 Primary neurons lacking the SNAREs vti1a and vti1b show altered neuronal development. Neural development 11 36419086
2020 Invariant chain regulates endosomal fusion and maturation through an interaction with the SNARE Vti1b. Journal of cell science 11 32907852
2022 The SNARE protein Vti1b is recruited to the sites of BCR activation but is redundant for antigen internalisation, processing and presentation. Frontiers in cell and developmental biology 5 36111340
2024 The double deficiency of the SNARE proteins vti1a and vti1b affects neurite outgrowth and signaling in N1E-115 neuroblastoma cells. European journal of cell biology 2 39406055
2025 Mir-16 Decreases the Expression of VTI1B and SMPD1, Genes Involved in Membrane-Protein Trafficking in Melanoma. Cancers 1 40647495
2026 Alterations in bone malformation in the absence of the endosomal SNAREs Vti1a and Vti1b. PloS one 0 41838692
2026 Reduction in Synaptic Vesicle Protein Abundance but Increased Amounts of Nsg2 and Lpcat1 in Cerebral Cortices Without the Endosomal SNARE Proteins Vti1a and Vti1b. Proteomics 0 41859820

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