| 1997 |
Vam6/Vps39 (123 kDa) and Vam2/Vps41 physically interact and co-exist as components of a large protein complex on vacuolar membranes in S. cerevisiae. Loss of either protein causes accumulation of small vacuole-related structures (~200–400 nm), inefficient processing of vacuolar proteases (proteinase A, B, carboxypeptidase Y, alkaline phosphatase), and missortng of CPY to the cell surface, establishing their role in vacuolar assembly. |
Chemical cross-linking, co-fractionation, GFP-tagging with live imaging, density gradient fractionation |
The Journal of biological chemistry |
High |
9111041
|
| 2009 |
Yeast Vam6/Vps39 functions as a guanine nucleotide exchange factor (GEF) for the Rag GTPase homolog Gtr1, loading it with GTP to activate TORC1 in response to amino acids. GTP-bound Gtr1 interacts strongly with TORC1, and Vam6 thereby connects its established role in vacuolar fusion (HOPS complex) to nutrient-sensitive TORC1 regulation via the EGO complex. |
GTP-binding assays, constitutively active/dominant-negative Gtr1 mutant expression, TORC1 activity assays, co-immunoprecipitation |
Molecular cell |
High |
19748348 19748353
|
| 2007 |
Loss of zebrafish vam6/vps39 (lbk mutant) causes hypopigmentation of melanocytes and RPE, absence of iridophore reflections, defects in liver, intestine, vision, and macrophage function, with accumulation of enlarged intracellular vesicles in affected cells. Positional cloning, allele screening, rescue experiments, and morpholino knockdown confirm vam6/vps39 as causative, establishing its essential role in HOPS-mediated vesicle tethering and fusion in a multicellular organism. |
Positional cloning, rescue experiments, morpholino knockdown, electron microscopy, behavioral/physiological assays |
Development (Cambridge, England) |
High |
18077594
|
| 2010 |
Mammalian Vps39 (mVps39) induces lysosomal clustering when overexpressed, but contrary to expectation for a Rab7 GEF, does not increase Rab7-GTP levels as measured by RILP effector pulldown. A dominant-negative mVps39 mutant fragments lysosomes and promotes growth factor independence without reducing Rab7-GTP, indicating that mVps39 regulates lysosomal morphology and cell survival via a Rab7-GTP-independent mechanism and is not the bona fide Rab7 GEF. |
Effector pulldown assay (RILP-based Rab7 activation), dominant-negative mutant expression, lysosome morphology imaging, cell death assays |
The Journal of biological chemistry |
High |
20363736
|
| 2010 |
VPS39 (also known as TLP/TRAP1-Like-Protein) is essential for early mouse embryonic development; homozygous VPS39-knockout mice die before E6.5, demonstrating a non-redundant in vivo requirement distinct from the paralog TRAP1. |
Knockout mouse generation, embryonic lethal phenotype analysis |
Immunobiology |
Medium |
20961651
|
| 2012 |
In fission yeast (S. pombe), Vam6 functions upstream of Gtr1/Gtr2 (Rag GTPase homologs) and upstream of TORC1 in an amino-acid-sensing pathway. Epistasis analysis places Vam6 as the upstream activator in the Vam6–Gtr1/Gtr2–TORC1 axis that promotes cell growth and inhibits sexual differentiation, confirming evolutionary conservation of this signaling pathway. |
Genetic epistasis analysis, deletion mutants, colocalization imaging, mating/sporulation phenotype assays |
Journal of cell science |
Medium |
22344254
|
| 2014 |
Human CORVET lacks a defined Vps3 subunit; hVps39-2/TRAP1 (a VPS39 isoform) co-localizes with Rab5-positive endosomes and directly binds Rab5-GTP in vitro, identifying it as an effector of Rab5 and the likely Vps3 subunit of the human CORVET complex. |
In vitro Rab5-GTP binding assay, co-localization imaging in HEK293 cells and yeast, yeast complementation |
Cellular logistics |
Medium |
25750764
|
| 2014 |
VPS39 (as a component of the HOPS complex) is required for autophagosome-lysosome fusion in mammalian cells. VPS39 knockdown blocks autophagic flux and causes accumulation of STX17/LC3-positive autophagosomes. HOPS interacts with the autophagosomal SNARE STX17 (co-precipitated via VPS33A/VPS16/VPS39), linking VPS39 to the STX17–SNAP29–VAMP8 SNARE assembly needed for fusion. |
siRNA knockdown, immunoprecipitation/mass spectrometry, autophagic flux assays, fluorescence microscopy |
Molecular biology of the cell |
High |
24554770
|
| 2020 |
SARS-CoV-2 ORF3a directly interacts with VPS39, sequestering it in late endosomes, which prevents the HOPS complex from interacting with the autophagosomal SNARE protein STX17, thus blocking assembly of the STX17–SNAP29–VAMP8 SNARE complex required for autophagosome/lysosome fusion and leading to accumulation of unfused autophagosomes. SARS-CoV ORF3a does not interact with HOPS/VPS39. |
Co-immunoprecipitation, autophagosome-lysosome fusion assays, fluorescence co-localization, siRNA knockdown, SARS-CoV-2 infection |
Developmental cell |
High |
33422265
|
| 2021 |
VPS39 is downregulated in myoblasts and myotubes from individuals with type 2 diabetes. VPS39 knockdown in human myoblasts impairs autophagic flux, dysregulates insulin signaling, alters epigenetic enzyme expression and DNA methylation at myogenic regulator loci, and perturbs differentiation. Vps39+/− mice display reduced muscle glucose uptake and altered expression of genes involved in autophagy, epigenetic programming, and myogenesis. |
siRNA knockdown in human myoblasts, RRBS DNA methylation, RNA-seq, autophagic flux assays, heterozygous mouse model with glucose uptake measurement |
Nature communications |
High |
33893273
|
| 2021 |
SARS-CoV-2 ORF3a interacts with VPS39 and prevents binding of HOPS to RAB7, blocking the assembly of fusion machinery and causing accumulation of unfused autophagosomes, consistent with VPS39 being the critical HOPS subunit bridging RAB7 interaction for autophagosome–lysosome fusion. |
Co-immunoprecipitation, autophagosome-lysosome fusion assays, RAB7-HOPS interaction assays, fluorescence microscopy |
Cell discovery |
Medium |
33947832
|
| 2020 |
Yeast Vps39 has a specific role in phosphatidylethanolamine (PE) transport to the mitochondria. Deletion of VPS39 prevents ethanolamine-stimulated elevation of mitochondrial PE without affecting PE biosynthesis in the ER or PE transport to other organelles. Vps39 abundance and its recruitment to mitochondria and ER is regulated by local PE levels, and this function is independent of the intact HOPS or vCLAMP complexes. |
Lipid extraction and quantification (TLC, mass spectrometry), subcellular fractionation, genetic deletion of complex subunits, ethanolamine-labeling experiments |
Biochimica et biophysica acta. Molecular and cell biology of lipids |
Medium |
32058032
|
| 2020 |
VPS39 controls ciliogenesis in human renal cells by regulating the localization of IFT20 (intraflagellar transport 20) at the base of cilia through autophagy. VPS39 acts as a negative regulator of ciliogenesis, and this function is conserved in vivo in medaka fish renal tubules. |
siRNA knockdown in human renal cells, morpholino knockdown in medaka, autophagy modulation, immunofluorescence of IFT20 localization, cilia length/number quantification |
Human molecular genetics |
Medium |
32077937
|
| 2022 |
SGPL1 (sphingosine-1-phosphate lyase) upregulation stimulates VPS39 recruitment to the mitochondria, enhancing mitochondria-lysosome membrane contact sites (MCS). VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1-deficient cells, placing VPS39 as a key effector in SGPL1-mediated organelle interaction and autophagy sustenance. |
Quantitative proteomics, transcriptomics, biochemical fractionation, imaging of MCS, VPS39 knockdown, MICU1-deficient C. elegans and mammalian cell models |
Molecular metabolism |
Medium |
35452878
|
| 2023 |
ASFV protein CP204L binds VPS39 and blocks its association with the lysosomal HOPS complex, redirecting CP204L-VPS39 complexes to virus factories. Loss of VPS39 reduces early viral protein synthesis and delays ASFV replication, demonstrating that VPS39 is exploited by ASFV for early replication steps and is involved in endolysosomal trafficking during infection. |
Co-immunoprecipitation, proximity ligation, fluorescence colocalization, VPS39 knockout/knockdown, viral replication assays |
Journal of virology |
Medium |
36722971
|
| 2025 |
SARS-CoV-2 ORF3a binds VPS39 and through this interaction: (1) traps the CI-MPR sorting receptor and retromer complex in endosomes/lysosomes, impairing NPC2 cholesterol transporter trafficking; and (2) reduces bis(monoacylglycerol)phosphate (BMP) lipids required for cholesterol export by decreasing lysosome-mitochondrion membrane contact sites (MCS). VPS39 deletion alone decreases MCS and BMPs, identifying VPS39 as a regulator of NPC2 trafficking and BMP biosynthesis. |
Lipidomics, proteomics, retromer deletion epistasis, MCS quantification, NPC2 trafficking assays, cholesterol efflux assays |
bioRxivpreprint |
Medium |
39605369
|
| 2020 |
Crystal structure of the C-terminal putative zinc finger domain of VPS39 was solved, revealing it adopts a non-native anti-parallel β-hairpin fold incorporated into a homotetrameric eight-stranded β-barrel under the recombinant conditions used, stabilized by tag-mediated zinc coordination and an intramolecular disulfide bond rather than the expected zinc finger fold. |
Recombinant protein expression, X-ray crystallography |
Wellcome open research |
Low |
32724865
|