VAC14
Identifiers
AliasesVAC14, ArPIKfyve, TAX1BP2, TRX, Vac14, PIKFYVE complex component, VAC14 component of PIKFYVE complex
External IDsOMIM: 604632 MGI: 2157980 HomoloGene: 6528 GeneCards: VAC14
Orthologs
SpeciesHumanMouse
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 MbChr 8: 111.35 – 111.45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Function

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. It is seen that VAC14 is scaffold protein that acts in complex with the lipid kinase PIKfyve which works to phosphorylate phosphatidylinositol-3-phosphate, as well as the counteracting phosphatase FIG4, which removes a phosphate group.[9]

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.[10] 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.[11] Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase [12] but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.[13]

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.[14] 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.[15]

Clinical significance

The VAC14 gene has been linked to human disease.[16] It is thought that the PIKfyve-VAC14-FIG4 complex plays an important role on the maturation of early endosomes to late endosomes/lysosomes. These organelles play critical roles in vesicular trafficking, which move cargo from donor membrane cells to target membranes within the body.[17]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103043 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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". Human Molecular Genetics. 12 (10): 1163–1170. doi:10.1093/hmg/ddg122. PMID 12719380.
  7. Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, et al. (December 2004). "A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity". Molecular and Cellular Biology. 24 (23): 10437–10447. 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". The Journal of Biological Chemistry. 282 (33): 23878–23891. doi:10.1074/jbc.M611678200. PMID 17556371.
  9. Schulze U, Vollenbröker B, Braun DA, Van Le T, Granado D, Kremerskothen J, et al. (June 2014). "The Vac14-interaction network is linked to regulators of the endolysosomal and autophagic pathway". Molecular & Cellular Proteomics. 13 (6): 1397–1411. doi:10.1074/mcp.M113.034108. PMC 4047462. PMID 24578385.
  10. 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". The Journal of Biological Chemistry. 285 (35): 26760–26764. doi:10.1074/jbc.C110.154658. PMC 2930674. PMID 20630877.
  11. 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". Journal of Molecular Biology. 384 (4): 766–779. doi:10.1016/j.jmb.2008.10.009. PMC 2756758. PMID 18950639.
  12. Lemaire JF, McPherson PS (December 2006). "Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif". FEBS Letters. 580 (30): 6948–6954. doi:10.1016/j.febslet.2006.11.061. PMID 17161399. S2CID 40346432.
  13. 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". Experimental Cell Research. 313 (11): 2404–2416. doi:10.1016/j.yexcr.2007.03.024. PMC 2475679. PMID 17475247.
  14. Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, et al. (October 2007). "Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice". Proceedings of the National Academy of Sciences of the United States of America. 104 (44): 17518–17523. Bibcode:2007PNAS..10417518Z. doi:10.1073/pnas.0702275104. PMC 2077288. PMID 17956977.
  15. Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, et al. (December 2008). "VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse". The EMBO Journal. 27 (24): 3221–3234. doi:10.1038/emboj.2008.248. PMC 2600653. PMID 19037259.
  16. Lenk GM, Szymanska K, Debska-Vielhaber G, Rydzanicz M, Walczak A, Bekiesinska-Figatowska M, et al. (July 2016). "Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease". American Journal of Human Genetics. 99 (1): 188–194. doi:10.1016/j.ajhg.2016.05.008. PMC 5005439. PMID 27292112.
  17. Qiu S, Lavallée-Adam M, Côté M (November 2021). "Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID". Journal of Proteome Research. 20 (11): 4959–4973. doi:10.1021/acs.jproteome.1c00408. PMID 34554760. S2CID 237615479.

Further reading


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