VAC14

Last updated

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; OMA:VAC14 - orthologs
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 Mb Chr 8: 111.35 – 111.45 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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

In 2016, a new condition caused by mutations of the gene was discovered and named childhood-onset striatonigral degeneration (OMIM 617054) [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.

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