VAC14

Protein VAC14 homolog, also known as ArPIKfyve (Associated Regulator of PIKfyve), is a protein that in humans is encoded by the VAC14 gene.[5][6][7]

VAC14
Identifiers
Aliases	VAC14, ArPIKfyve, TAX1BP2, TRX, Vac14, PIKFYVE complex component, VAC14 component of PIKFYVE complex
External IDs	OMIM: 604632 MGI: 2157980 HomoloGene: 6528 GeneCards: VAC14
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q22.1-q22.2 Start 70,687,439 bp[1] End 70,801,160 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 D3-E1|8 57.59 cM Start 110,618,585 bp[2] End 110,720,398 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • signaling receptor activity Cellular component • organelle membrane • Golgi membrane • endosome • early endosome membrane • endosome membrane • PAS complex • endoplasmic reticulum • late endosome membrane • membrane • intracellular membrane-bounded organelle • extrinsic component of vacuolar membrane Biological process • GO:0022415 viral process • signal transduction • phosphatidylinositol biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	55697	234729
Ensembl	ENSG00000103043	ENSMUSG00000010936
UniProt	Q08AM6	Q80WQ2
RefSeq (mRNA)	NM_018052 NM_001351157	NM_146216
RefSeq (protein)	NP_060522 NP_001338086	NP_666328
Location (UCSC)	Chr 16: 70.69 – 70.8 Mb	Chr 8: 110.62 – 110.72 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Functions and interactions

The content of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. The ArPIKfyve protein scaffolds a trimolecular complex to tightly regulate the level of PtdIns(3,5)P2. Other components of this complex are the PtdIns(3,5)P2-synthesizing enzyme PIKFYVE and the Sac1-domain-containing PtdIns(3,5)P2 5-phosphatase Sac3, encoded by the human gene FIG4. VAC14 functions as an activator of PIKFYVE.[5][8] Studies in VAC14 knockout mice indicate that, in addition to increasing the PtdIns(3,5)P2-producing activity of PIKfyve, VAC14 also controls the steady-state levels of another rare phosphoinositide linked to PIKfyve enzyme activity – phosphatidylinositol 5-phosphate.

In addition to the formation of the ternary complex with PIKfyve and Sac3, ArPIKfyve is engaged in a number of other interactions. ArPIKfyve forms a stable complex with the PtdIns(3,5)P2-specific phosphatase Sac3, thereby protecting Sac3 from rapid degradation in the proteasome.[9] ArPIKfyve forms a homooligomer through its carboxyl terminus. However, the number of monomers in the ArPIKfyve homooligomer, ArPIKfyve-Sac3 heterodimer or PIKfyve-ArPIKfyve-Sac3 heterotrimer is unknown.[10] Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase [11] but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.[12]

Lessons from VAC14 mouse models

VAC14 knock-out mice die at, or shortly after birth and exhibit massive neurodegeneration. Fibroblasts from these mice display ~50% lower levels of PtdIns(3,5)P2 and PtdIns(5)P.[13] A spontaneous mouse VAC14-point mutation (with arginine substitution of leucine156) is associated with reduced life span (up to 3 weeks), body size, enlarged brain ventricles, 50% decrease in PtdIns(3,5)P2 levels, diluted pigmentation, tremor and impaired motor function.[14]

VAC14 and human disease

The VAC14 gene is yet to be linked convincingly to human disease.[15]

References

1. GRCh38: Ensembl release 89: ENSG00000103043 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000010936 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Vac14 homolog (S. cerevisiae)".
6. Davy BE, Robinson ML (May 2003). "Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene". Hum. Mol. Genet. 12 (10): 1163–70. doi:10.1093/hmg/ddg122. PMID 12719380.
7. Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A (December 2004). "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity". Mol. Cell. Biol. 24 (23): 10437–47. doi:10.1128/MCB.24.23.10437-10447.2004. PMC 529046. PMID 15542851.
8. Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A (August 2007). "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex". J. Biol. Chem. 282 (33): 23878–91. doi:10.1074/jbc.M611678200. PMID 17556371.
9. Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A (August 2010). "ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder". J. Biol. Chem. 285 (35): 26760–4. doi:10.1074/jbc.C110.154658. PMC 2930674. PMID 20630877.
10. Sbrissa D, Ikonomov OC, Fenner H, Shisheva A (December 2008). "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality". J. Mol. Biol. 384 (4): 766–79. doi:10.1016/j.jmb.2008.10.009. PMC 2756758. PMID 18950639.
11. Lemaire JF, McPherson PS (December 2006). "Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif". FEBS Lett. 580 (30): 6948–54. doi:10.1016/j.febslet.2006.11.061. PMID 17161399. S2CID 40346432.
12. Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A (July 2007). "ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes". Exp. Cell Res. 313 (11): 2404–16. doi:10.1016/j.yexcr.2007.03.024. PMC 2475679. PMID 17475247.
13. Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS (October 2007). "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice". Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17518–23. doi:10.1073/pnas.0702275104. PMC 2077288. PMID 17956977.
14. Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS (December 2008). "VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse" (PDF). EMBO J. 27 (24): 3221–34. doi:10.1038/emboj.2008.248. PMC 2600653. PMID 19037259.
15. "VAC14 - Vac14 homolog (S. cerevisiae)". WikiGenes. Retrieved 2011-07-16.

Further reading

• Mireskandari A, Reid RL, Kashanchi F, et al. (1996). "Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic virus type-I Tax1 binding protein". Biochim. Biophys. Acta. 1306 (1): 9–13. doi:10.1016/0167-4781(96)00012-7. PMID 8611628.