Wikipedia

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
AliasesVAC14, ArPIKfyve, TAX1BP2, TRX, Vac14, PIKFYVE complex component, VAC14 component of PIKFYVE complex
External IDsOMIM: 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 MbChr 8: 111.35 – 111.45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000103043 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b "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 12719380.1163-1170&rft.date=2003-05&rft_id=info:doi/10.1093/hmg/ddg122&rft_id=info:pmid/12719380&rft.aulast=Davy&rft.aufirst=BE&rft.au=Robinson, ML&rft_id=https://doi.org/10.1093%2Fhmg%2Fddg122&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 15542851.10437-10447&rft.date=2004-12&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC529046#id-name=PMC&rft_id=info:pmid/15542851&rft_id=info:doi/10.1128/MCB.24.23.10437-10447.2004&rft.aulast=Sbrissa&rft.aufirst=D&rft.au=Ikonomov, OC&rft.au=Strakova, J&rft.au=Dondapati, R&rft.au=Mlak, K&rft.au=Deeb, R&rft.au=Silver, R&rft.au=Shisheva, A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC529046&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 17556371.23878-23891&rft.date=2007-08&rft_id=info:doi/10.1074/jbc.M611678200&rft_id=info:pmid/17556371&rft.aulast=Sbrissa&rft.aufirst=D&rft.au=Ikonomov, OC&rft.au=Fu, Z&rft.au=Ijuin, T&rft.au=Gruenberg, J&rft.au=Takenawa, T&rft.au=Shisheva, A&rft_id=https://doi.org/10.1074%2Fjbc.M611678200&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 24578385.1397-1411&rft.date=2014-06&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047462#id-name=PMC&rft_id=info:pmid/24578385&rft_id=info:doi/10.1074/mcp.M113.034108&rft.aulast=Schulze&rft.aufirst=U&rft.au=Vollenbröker, B&rft.au=Braun, DA&rft.au=Van Le, T&rft.au=Granado, D&rft.au=Kremerskothen, J&rft.au=Fränzel, B&rft.au=Klosowski, R&rft.au=Barth, J&rft.au=Fufezan, C&rft.au=Wolters, DA&rft.au=Pavenstädt, H&rft.au=Weide, T&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047462&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 20630877.26760-26764&rft.date=2010-08&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930674#id-name=PMC&rft_id=info:pmid/20630877&rft_id=info:doi/10.1074/jbc.C110.154658&rft.aulast=Ikonomov&rft.aufirst=OC&rft.au=Sbrissa, D&rft.au=Fligger, J&rft.au=Delvecchio, K&rft.au=Shisheva, A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930674&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 18950639.766-779&rft.date=2008-12&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756758#id-name=PMC&rft_id=info:pmid/18950639&rft_id=info:doi/10.1016/j.jmb.2008.10.009&rft.aulast=Sbrissa&rft.aufirst=D&rft.au=Ikonomov, OC&rft.au=Fenner, H&rft.au=Shisheva, A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756758&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 40346432.6948-6954&rft.date=2006-12&rft_id=https://api.semanticscholar.org/CorpusID:40346432#id-name=S2CID&rft_id=info:pmid/17161399&rft_id=info:doi/10.1016/j.febslet.2006.11.061&rft.aulast=Lemaire&rft.aufirst=JF&rft.au=McPherson, PS&rft_id=https://escholarship.mcgill.ca/concern/theses/6t053m55c&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 17475247.2404-2416&rft.date=2007-07&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475679#id-name=PMC&rft_id=info:pmid/17475247&rft_id=info:doi/10.1016/j.yexcr.2007.03.024&rft.aulast=Ikonomov&rft.aufirst=OC&rft.au=Sbrissa, D&rft.au=Dondapati, R&rft.au=Shisheva, A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475679&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 17956977.17518-17523&rft.date=2007-10&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077288#id-name=PMC&rft_id=info:pmid/17956977&rft_id=info:doi/10.1073/pnas.0702275104&rft_id=info:bibcode/2007PNAS..10417518Z&rft.aulast=Zhang&rft.aufirst=Y&rft.au=Zolov, SN&rft.au=Chow, CY&rft.au=Slutsky, SG&rft.au=Richardson, SC&rft.au=Piper, RC&rft.au=Yang, B&rft.au=Nau, JJ&rft.au=Westrick, RJ&rft.au=Morrison, SJ&rft.au=Meisler, MH&rft.au=Weisman, LS&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077288&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 19037259.3221-3234&rft.date=2008-12&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600653#id-name=PMC&rft_id=info:pmid/19037259&rft_id=info:doi/10.1038/emboj.2008.248&rft.aulast=Jin&rft.aufirst=N&rft.au=Chow, CY&rft.au=Liu, L&rft.au=Zolov, SN&rft.au=Bronson, R&rft.au=Davisson, M&rft.au=Petersen, JL&rft.au=Zhang, Y&rft.au=Park, S&rft.au=Duex, JE&rft.au=Goldowitz, D&rft.au=Meisler, MH&rft.au=Weisman, LS&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600653&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 27292112.188-194&rft.date=2016-07&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005439#id-name=PMC&rft_id=info:pmid/27292112&rft_id=info:doi/10.1016/j.ajhg.2016.05.008&rft.aulast=Lenk&rft.aufirst=GM&rft.au=Szymanska, K&rft.au=Debska-Vielhaber, G&rft.au=Rydzanicz, M&rft.au=Walczak, A&rft.au=Bekiesinska-Figatowska, M&rft.au=Vielhaber, S&rft.au=Hallmann, K&rft.au=Stawinski, P&rft.au=Buehring, S&rft.au=Hsu, DA&rft.au=Kunz, WS&rft.au=Meisler, MH&rft.au=Ploski, R&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005439&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">
  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 237615479.4959-4973&rft.date=2021-11&rft_id=https://api.semanticscholar.org/CorpusID:237615479#id-name=S2CID&rft_id=info:pmid/34554760&rft_id=info:doi/10.1021/acs.jproteome.1c00408&rft.aulast=Qiu&rft.aufirst=S&rft.au=Lavallée-Adam, M&rft.au=Côté, M&rft_id=https://doi.org/10.1021%2Facs.jproteome.1c00408&rfr_id=info:sid/en.wikipedia.org:VAC14" class="Z3988">

Further reading

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