Affinage

VTI1B

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

Length
232 aa
Mass
26.7 kDa
Annotated
2026-04-28
19 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VTI1B is a Qb-SNARE protein that functions as a versatile fusogenic component in endosomal, lysosomal, and autophagic membrane trafficking by assembling into distinct four-helix SNARE complexes with partners including syntaxin 6, syntaxin 7, syntaxin 8, syntaxin 11, VAMP8, VAMP3, and VAMP4. VTI1B is required for late endosome–lysosome fusion, autophagosome–lysosome fusion, recycling endosome–autophagosome fusion during xenophagy, and Golgi-to-late-endosome transport of cargo such as TNFα and MT1-MMP; its loss leads to accumulation of multivesicular bodies and autophagic vacuoles, degradation of its stabilizing partner syntaxin 8, and impaired lysosomal degradation (PMID:12861006, PMID:20089838, PMID:27791468, PMID:34476885). PTPN9-mediated dephosphorylation of VTI1B promotes SNARE complex assembly and autophagic flux, while selective incorporation of VTI1B into clathrin-coated vesicles requires the adaptor epsinR (PMID:33112705, PMID:15371541). VTI1B has specialized roles in lytic granule exocytosis in cytotoxic T lymphocytes, TNFα secretion in macrophages, and modulation of TRPV1-dependent inflammatory pain sensitization in sensory neurons, and combined loss of Vti1a and Vti1b causes perinatal lethality with massive peripheral neurodegeneration (PMID:20543108, PMID:15640147, PMID:30335684, PMID:21262811).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing that VTI1B stabilizes syntaxin 8 and is required for efficient late endosome–lysosome fusion resolved the question of which SNARE mediates this trafficking step and revealed in vivo functional redundancy allowing viability of single-knockout mice.

    Evidence Vti1b knockout mouse with western blot for SNARE partners, endocytic degradation assays, and electron microscopy

    PMID:12861006

    Open questions at the time
    • Compensatory SNARE(s) permitting mouse survival not identified
    • Mechanism of syntaxin 8 destabilization not resolved
  2. 2004 High

    Identifying epsinR as the adaptor that selectively sorts VTI1B (but not VTI1A) into clathrin-coated vesicles explained how VTI1B reaches the correct membrane compartment for SNARE complex assembly.

    Evidence siRNA knockdown of epsinR and AP-1 in HeLa cells with CCV isolation and immunofluorescence

    PMID:15371541

    Open questions at the time
    • Direct binding interface between epsinR and VTI1B not mapped
    • Whether other adaptors contribute to VTI1B sorting in non-HeLa cell types unknown
  3. 2005 High

    Demonstrating that VTI1B and syntaxin 6 form a Q-SNARE complex on Golgi membranes that is rate-limiting for TNFα vesicle trafficking established VTI1B's role in regulated secretion beyond constitutive endosomal fusion.

    Evidence Co-immunoprecipitation, Golgi membrane isolation, in vitro vesicle budding, and overexpression studies in macrophages

    PMID:15640147

    Open questions at the time
    • R-SNARE partner for this TNFα trafficking complex not fully defined
    • How LPS upregulates VTI1B/STX6 expression not determined
  4. 2010 High

    Showing that VTI1B and VAMP8 jointly mediate autophagosome–lysosome fusion (for both canonical autophagy and xenophagy) while syntaxin 7/8 are dispensable redefined the SNARE requirements for autophagic flux and bacterial killing.

    Evidence siRNA knockdown with LC3–LAMP1 colocalization, LC3-II degradation assay, and Group A Streptococcus killing assay in human cells

    PMID:20089838

    Open questions at the time
    • Identity of the complete four-helix SNARE complex for autophagosome–lysosome fusion not established
    • Whether other R-SNAREs substitute for VAMP8 in specific tissues unknown
  5. 2010 High

    Establishing that VTI1B and VAMP8 are required for lytic granule exocytosis in CTL extended VTI1B's function to regulated secretory events critical for adaptive immunity.

    Evidence Vti1b and Vamp8 knockout CTL on OT-I TCR-transgenic background with CD107a degranulation and cytotoxicity assays

    PMID:20543108

    Open questions at the time
    • Whether VTI1B acts at granule–plasma membrane fusion or an upstream maturation step not resolved
    • Q-SNARE complex partners for lytic granule exocytosis not defined
  6. 2011 High

    Three contemporaneous studies revealed that VTI1B acts in specialized neuronal and immune contexts: syntaxin 11 regulates VTI1B availability for late endosome fusion in macrophages; VTI1B mediates lytic granule tethering at the immunological synapse in CTL; and combined loss of VTI1A/VTI1B causes lethal neurodegeneration, demonstrating essential neuronal requirements for these SNAREs.

    Evidence Co-IP and siRNA rescue for STX11–VTI1B interaction; TIRF/live imaging with VTI1B knockdown in primary human CTL; Vti1a/Vti1b double-KO mouse with histological and organelle analysis

    PMID:21262811 PMID:21388490 PMID:21562157

    Open questions at the time
    • How disease-causing STX11 mutants mechanistically sequester VTI1B not determined at atomic level
    • Whether neurodegeneration is due to loss of Golgi outposts, endosomal defects, or both is unresolved
    • Whether VTI1B tethering function at the synapse requires a specific tethering factor is unknown
  7. 2016 High

    Identifying the STX6–VTI1B–VAMP3 SNARE complex as the machinery for recycling endosome–autophagosome fusion during xenophagy, recruited by RABGEF1, revealed a new fusion route that feeds membrane from recycling endosomes into the autophagic pathway.

    Evidence Knockdown/knockout of STX6, VTI1B, VAMP3, RABGEF1 with Co-IP and GAS clearance assays in human cells

    PMID:27791468

    Open questions at the time
    • Fourth Q-SNARE in this complex not identified
    • Whether this pathway operates in autophagy beyond xenophagy not tested
  8. 2019 Medium

    Discovering that VTI1B associates with TRPV1 in sensory neurons and that its knockdown attenuates inflammatory thermal hypersensitivity without affecting basal nociception extended VTI1B's functional repertoire to pain signaling modulation.

    Evidence Proximity ligation assay, Co-IP, quantitative interactomics, AAV-mediated knockdown in sensory neurons, and behavioral pain assays in mice

    PMID:30335684

    Open questions at the time
    • Whether VTI1B–TRPV1 interaction is direct or bridged by an intermediate unknown
    • Mechanism by which VTI1B modulates TRPV1 surface delivery or channel function not defined
    • Not replicated in an independent study
  9. 2020 High

    Two studies in 2020 defined upstream regulation of VTI1B: PTPN9 dephosphorylates VTI1B to promote SNARE complex assembly and early autophagosome biogenesis, while the invariant chain (CD74/Ii) binds VTI1B to recruit it to endosomal contact sites and delay endosomal maturation.

    Evidence PTPN9 KO/KD with phosphomimetic/nonphosphorylatable VTI1B mutants and SNARE assembly assays; Co-IP and Ii-truncation mutants with endosomal maturation readouts

    PMID:32907852 PMID:33112705

    Open questions at the time
    • Phosphorylation site(s) on VTI1B and the upstream kinase not identified
    • How Ii-mediated VTI1B recruitment delays maturation at molecular level unclear
    • Whether PTPN9 regulation of VTI1B occurs in all cell types not tested
  10. 2021 Medium

    Demonstrating that the VAMP4/STX6/STX7/VTI1B SNARE complex mediates Golgi-to-late-endosome delivery of MT1-MMP in macrophages showed that VTI1B participates in trafficking that controls extracellular matrix degradation.

    Evidence siRNA depletion and overexpression with surface MT1-MMP quantification and gelatin degradation assay

    PMID:34476885

    Open questions at the time
    • SNARE complex not directly reconstituted in vitro
    • Whether this pathway operates in invasive cancer cells not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the kinase that phosphorylates VTI1B to counterbalance PTPN9-mediated activation; the structural basis for VTI1B's selective incorporation into multiple distinct SNARE complexes; and whether the neurodegeneration phenotype of VTI1A/VTI1B double knockouts reflects a specific trafficking defect (e.g., Golgi outpost loss) or general membrane fusion failure.
  • VTI1B phosphorylation site and kinase unidentified
  • No structural model of VTI1B in any SNARE complex
  • Cell-type-specific roles of VTI1B versus VTI1A not systematically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 7 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 3
Partners
PTPN9STX11STX6STX7STX8VAMP3VAMP4VAMP8
Complex memberships
STX6/STX7/VTI1B/VAMP4 SNARE complexSTX6/VTI1B/VAMP3 SNARE complexSTX7/STX8/VTI1B/VAMP8 SNARE complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Vti1b is specifically required for the stability of its SNARE partner syntaxin 8; deletion of vti1b in mice leads to degradation of syntaxin 8 protein while syntaxin 7 and endobrevin/VAMP-8 levels remain unchanged. Vti1b-deficient mice show delayed lysosomal degradation of endocytosed proteins and accumulation of multivesicular bodies and autophagic vacuoles in hepatocytes. Vti1b knockout mouse model; western blotting for SNARE partners; endocytosis/lysosomal degradation assays; electron microscopy Molecular and cellular biology High 12861006
2004 EpsinR functions as an adaptor for vti1b, selectively incorporating vti1b (but not vti1a) into clathrin-coated vesicles (CCVs); depletion of epsinR or AP-1 by siRNA causes vti1b redistribution from the perinuclear region to the cell periphery and reduces vti1b in CCV preparations by >70%. siRNA knockdown of epsinR and AP-1 in HeLa cells; CCV isolation and cargo content analysis; immunofluorescence microscopy Molecular biology of the cell High 15371541
2005 Vti1b and syntaxin 6 form a novel intracellular Q-SNARE complex on Golgi membranes and on Golgi-derived TNFα vesicles; both proteins are up-regulated in LPS-activated macrophages and are rate-limiting for TNFα trafficking and secretion. Co-immunoprecipitation; Golgi membrane isolation; in vitro vesicle budding; overexpression of full-length and truncated proteins; confocal immunofluorescence The Journal of biological chemistry High 15640147
2010 VAMP8 and Vti1b together mediate fusion of both antimicrobial autophagosomes (xenophagosomes) and canonical autophagosomes with lysosomes; siRNA knockdown of both SNAREs impairs LC3–LAMP1 colocalization and reduces bacterial killing, while knockdown of syntaxin 7 or syntaxin 8 has little effect. siRNA knockdown in human cells; confocal microscopy for LC3/LAMP1 colocalization; bactericidal efficiency assay with Group A Streptococcus; LC3-II degradation assay Molecular biology of the cell High 20089838
2010 Vti1b and VAMP8 are required for lytic granule exocytosis (degranulation) in CTL; Vti1b- and Vamp8-knockout CTL show significantly reduced CD107a surface expression and ~50% reduced cytolytic activity at early timepoints after antigen-specific stimulation. Vti1b and Vamp8 knockout mice (TCR-transgenic OT-I background); flow cytometry for CD107a degranulation marker; cytotoxicity assays Journal of immunology High 20543108
2011 Syntaxin 11 binds Vti1b and regulates its availability to form the Q-SNARE complexes Stx6/Stx7/Vti1b and Stx7/Stx8/Vti1b that mediate late endosome-to-lysosome fusion in macrophages; a disease-causing mutant Stx11 sequesters Vti1b from these complexes, and Stx11 depletion causes enlarged late endosomal compartments and inhibited late endosome-to-lysosome fusion. Co-immunoprecipitation; siRNA knockdown with rescue by siRNA-resistant construct; confocal microscopy; endosomal morphology analysis Traffic High 21388490
2011 Vti1b is required for tethering lytic granules (LG) with CD3-containing endosomes (CD3-endo) in human CTL; Vti1b knockdown reduces LG–CD3-endo tethering, impairs accumulation and docking of LG at the immunological synapse, and reduces target cell killing. TIRF microscopy and fast deconvolution live imaging in primary human CD8+ T cells; siRNA knockdown of Vti1b; confocal microscopy in fixed cells; cytotoxicity assays Journal of immunology High 21562157
2011 Combined loss of vti1a and vti1b in mice causes perinatal lethality with massive peripheral neurodegeneration (>95% neuron loss in dorsal root and geniculate ganglia), missing/misrouted axon tracts, and absence of Golgi outposts in dendrites; fibroblasts lacking both SNAREs survive with only minor trafficking defects, indicating that specialized neuronal membrane trafficking demands are uniquely dependent on these SNAREs. Vti1a/Vti1b double-knockout mouse; histology and immunofluorescence of ganglia and axon tracts; organelle morphology in fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 21262811
2016 During xenophagy of Group A Streptococcus, STX6 forms a SNARE complex with VTI1B and VAMP3 on GAS-containing autophagosome-like vacuoles (GcAVs) to mediate fusion between GcAVs and recycling endosomes; RABGEF1 mediates this RE-GcAV fusion through the STX6-VAMP3-VTI1B complex. Knockdown and knockout of STX6, VTI1B, VAMP3, and RABGEF1 in human cells; co-immunoprecipitation; confocal microscopy for SNARE localization and GcAV-RE colocalization; GAS clearance assays Autophagy High 27791468
2019 Vti1b is in close proximity to and likely interacts (directly or indirectly) with TRPV1 in dorsal root ganglia neurons, as shown by proximity ligation assays and co-immunoprecipitation; virus-mediated knockdown of Vti1b in sensory neurons attenuates thermal hypersensitivity during inflammatory pain without affecting nociceptive pain, and Vti1b is less abundant in the TRPV1 protein complex during inflammatory conditions. Proximity ligation assay; co-immunoprecipitation; mass spectrometry-based quantitative interactomics; AAV-mediated knockdown in sensory neurons; behavioral pain assays in mice Pain Medium 30335684
2020 PTPN9 phosphatase dephosphorylates VTI1B as a substrate; the nonphosphorylatable VTI1B mutant (but not the phosphomimetic mutant) enhances SNARE complex assembly and autophagic flux. PTPN9-mediated dephosphorylation of VTI1B promotes homotypic ATG16L1+ vesicle fusion and early autophagosome biogenesis. PTPN9 knockout/knockdown; colocalization by confocal microscopy; phosphomimetic and nonphosphorylatable VTI1B mutants; autophagic flux assays; SNARE complex assembly assays Autophagy High 33112705
2020 The invariant chain (Ii/CD74) binds to Vti1b, recruits it to contact sites of fusing Ii-positive endosomes, and delays endosomal maturation; knockdown of Vti1b inhibits the Ii-induced maturation delay, and Ii lacking its cytoplasmic tail relocates Vti1b to the plasma membrane. Co-immunoprecipitation; confocal microscopy; siRNA knockdown of Vti1b; Ii-truncation mutant overexpression; endosomal maturation assays Journal of cell science High 32907852
2021 The SNARE complex VAMP4/Stx6/Stx7/Vti1b mediates fusion of Golgi-derived vesicles containing MT1-MMP with late endosomes in macrophages; depletion of any component of the Stx6/Stx7/Vti1b Q-SNARE complex reduces surface MT1-MMP and gelatin degradation, while overexpression increases surface MT1-MMP. Fixed and live imaging; siRNA depletion; overexpression; surface MT1-MMP quantification; gelatin degradation assay Traffic Medium 34476885
2024 Trehalose dimycolate (TDM) from M. tuberculosis binds VTI1B and STX8 via a photoaffinity probe; in the presence of M. tuberculosis, VTI1B and STX8 complex with VAMP2 instead of their canonical partner VAMP8, reducing VAMP8 binding and inhibiting phagosome maturation to promote intracellular bacterial replication. Clickable photoaffinity TDM probe; Co-immunoprecipitation; macrophage infection assays; M. tuberculosis replication 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 177 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 90 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
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
2020 PTPN9-mediated dephosphorylation of VTI1B promotes ATG16L1 precursor fusion and autophagosome formation. Autophagy 12 33112705
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