VAC14

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.{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A | title = 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 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 33 | pages = 23878–23891 | date = August 2007 | pmid = 17556371 | doi = 10.1074/jbc.M611678200 | doi-access = free }} 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.{{cite journal | vauthors = Schulze U, Vollenbröker B, Braun DA, Van Le T, Granado D, Kremerskothen J, Fränzel B, Klosowski R, Barth J, Fufezan C, Wolters DA, Pavenstädt H, Weide T | display-authors = 6 | title = The Vac14-interaction network is linked to regulators of the endolysosomal and autophagic pathway | journal = Molecular & Cellular Proteomics | volume = 13 | issue = 6 | pages = 1397–1411 | date = June 2014 | pmid = 24578385 | pmc = 4047462 | doi = 10.1074/mcp.M113.034108 | doi-access = free }}

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.{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A | title = ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder | journal = The Journal of Biological Chemistry | volume = 285 | issue = 35 | pages = 26760–26764 | date = August 2010 | pmid = 20630877 | pmc = 2930674 | doi = 10.1074/jbc.C110.154658 | doi-access = free }} 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.{{cite journal | vauthors = Sbrissa D, Ikonomov OC, Fenner H, Shisheva A | title = ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality | journal = Journal of Molecular Biology | volume = 384 | issue = 4 | pages = 766–779 | date = December 2008 | pmid = 18950639 | pmc = 2756758 | doi = 10.1016/j.jmb.2008.10.009 }} Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase {{cite journal | vauthors = Lemaire JF, McPherson PS | title = Binding of Vac14 to neuronal nitric oxide synthase: Characterisation of a new internal PDZ-recognition motif | journal = FEBS Letters | volume = 580 | issue = 30 | pages = 6948–6954 | date = December 2006 | pmid = 17161399 | doi = 10.1016/j.febslet.2006.11.061 | s2cid = 40346432 | url = https://escholarship.mcgill.ca/concern/theses/6t053m55c }} but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.{{cite journal | vauthors = Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A | title = ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes | journal = Experimental Cell Research | volume = 313 | issue = 11 | pages = 2404–2416 | date = July 2007 | pmid = 17475247 | pmc = 2475679 | doi = 10.1016/j.yexcr.2007.03.024 }}

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.{{cite journal | vauthors = Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS | display-authors = 6 | title = Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 44 | pages = 17518–17523 | date = October 2007 | pmid = 17956977 | pmc = 2077288 | doi = 10.1073/pnas.0702275104 | doi-access = free | bibcode = 2007PNAS..10417518Z }} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse | journal = The EMBO Journal | volume = 27 | issue = 24 | pages = 3221–3234 | date = December 2008 | pmid = 19037259 | pmc = 2600653 | doi = 10.1038/emboj.2008.248 }}

In 2016, a new condition caused by mutations of the gene was discovered and named childhood-onset striatonigral degeneration (OMIM 617054){{cite journal | vauthors = Lenk GM, Szymanska K, Debska-Vielhaber G, Rydzanicz M, Walczak A, Bekiesinska-Figatowska M, Vielhaber S, Hallmann K, Stawinski P, Buehring S, Hsu DA, Kunz WS, Meisler MH, Ploski R | display-authors = 6 | title = Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease | journal = American Journal of Human Genetics | volume = 99 | issue = 1 | pages = 188–194 | date = July 2016 | pmid = 27292112 | pmc = 5005439 | doi = 10.1016/j.ajhg.2016.05.008 }} 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.{{cite journal | vauthors = Qiu S, Lavallée-Adam M, Côté M | title = Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID | journal = Journal of Proteome Research | volume = 20 | issue = 11 | pages = 4959–4973 | date = November 2021 | pmid = 34554760 | doi = 10.1021/acs.jproteome.1c00408 | s2cid = 237615479 | doi-access = free }}

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