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Gene Review

VAC14  -  Vac14 homolog (S. cerevisiae)

Homo sapiens

Synonyms: ArPIKfyve, FLJ10305, Protein VAC14 homolog, TAX1BP2, TRX, ...
 
 
 

Disease Relevance

The medical relevance of the human VAC14 gene is currently unclear.

A possible role in human lymphomas is based on the reported association of a protein product comprised of 167 amino acids (aa) with the human T-cell lymphotropic virus type-I Tax1 protein (1). The first 123 aa of the Tax1 binding protein are identical with aa 244-366 of the full-length human Vac14 (782 aa). However, the interaction of the full-length protein with the viral Tax1 protein remains unknown.

Increased human VAC14 transcript levels are associated with chronic fatigue syndrome in women (2). This finding is yet to be confirmed.

Mutations in the coding sequence of the human VAC14 gene are not detected in a screen of 95 patients with Charcot-Marie-Tooth peripheral neuropathy and a member of a family with neurological SCA4 disorder (3).

Database search for single nucleotide polymorphisms (SNPs) reveals 1094 human SNPs in the VAC14 gene. No published research is linked to any of them. However, in several VAC14 databases there is a report using genomic SNPs constellation in the individualized prediction of smoking cessation success (4). Even if some Vac14 SNPs participate in the genomic SNPs constellation associated with better prognosis of smoking cessation, the role of the VAC14 gene is currently unclear.

 

Overview

The first evidence for the existence of this gene is published in 1996, when a partial human cDNA sequence (corresponding to 167 aa) is identified in a search of proteins interacting with the T-cell lymphotropic virus type-I Tax1 protein (1). Therefore, the gene was initially named as TAX1BP2 or TRX (1). It should be pointed out that the old name TAX1BP2 is used also for a VAC14-unrelated protein (5). The first detailed characterization of the human protein is published in 2004 (6). Human Vac14 protein physically interacts with the kinase PIKFYVE, up-regulating the PIKfyve phosphatidylinositol (PtdIns) (3,5)P2 synthesizing activity (6). Based on these general characteristics, the human protein is called ArPIKfyve (associated regulator of PIKfyve) (6,7). The current human gene symbol is VAC14, which is identical with the name of the gene in S. cerevisiae (budding yeast).

 

High impact information on ArPIKfyve

  • ArPIKfyve is a widespread protein of 82 kDa (6).
  • Small-interfering (si) RNA-directed gene silencing approach to selectively ablate endogenous ArPIKfyve renders HEK293 cells susceptible to formation of vacuoles similar to those observed upon expression of PIKfyve mutants deficient in PtdIns(3,5)P2 production. Decreased in vitro PIKfyve kinase activity but unaltered PIKfyve protein levels are detected under these conditions (6).
  • Endogenous ArPIKfyve forms a stable ternary complex with PIKfyve and the PtdIns (3,5)P2-specific phosphatase Sac3 (6,8). The complex is thus called the PAS complex (from PIKfyve-ArPIKfyve-Sac3) (8,9).
  • ArPIKfyve is the principal organizer of the PAS complex (9). It interacts with both Sac3 and PIKfyve, whereas Sac3 is permissive for maximal PIKfyve-ArPIKfyve association (9).
  • ArPIKfyve scaffolds the PAS complex due to its ability to homooligomerize via its conserved C-terminal domain (9). Introduction of the C-terminal peptide fragment of the ArPIKfyve-ArPIKfyve contact sites effectively disassembles the PAS complex and reduces the in vitro PIKfyve lipid kinase activity (9).
  • ArPIKfyve interacts with the Sac3 phosphatase independently of PIKfyve to make a stable ArPIKfyve-Sac3 heterooligomer (9,10)
  • ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation (11). A failure of this mechanism is considered to be the primary molecular defect in the pathogenesis of Charcot-Marie-Tooth peripheral neuropathy 4J, associated with Sac3I41T mutation (11).
 

Other interactions of ArPIKfyve

  • An interaction between the PDZ domain of neuronal nitric oxide synthase (nNOS) and ArPIKfyve (human Vac14) has been described (12). Binding assays using various Vac14 deletion constructs reveals a beta-finger independent interaction that is based on a novel internal motif. Mutational analyses reveal essential residues within the motif, thus defining a new type of PDZ domain interaction.
 

Functions of ArPIKfyve

  • ArPIKfyve serves as a scaffold of the interactions between the PIKfyve kinase and the Sac3 phosphatase, thereby assembling core protein machinery to execute both synthesis and turnover of PtdIns(3,5)P2 (8-10).
  • The PAS complex is essential for endomembrane homeostasis and multivesicular body (MVB) formation (8). siRNA-mediated ablation of endogenous ArPIKfyve severely reduces the MVB formation as studied by reconstitution assays (8);
  • siRNA-mediated selective ablation of ArPIKfyve prevents the PtdIns(3,5)P2 increase in 3T3L1 adipocytes under hyperosmotic stress (7);
  • ArPIKfyve is implicated in insulin signaling in differentiated 3T3L1 adipocytes (13). siRNAs-mediated selective ablation of ArPIKfyve in this cell type depletes the PtdIns(3,5)P2 pool and reduces insulin-activated glucose uptake to a comparable degree. Combined loss of PIKfyve and ArPIKfyve causes further PtdIns(3,5)P2 ablation that correlates with greater attenuation in insulin responsiveness. Loss of PIKfyve-ArPIKfyve reduces insulin-stimulated protein kinase Akt (PKB) phosphorylation and the cell surface accumulation of the glucose transporter 4 (GLUT4) or insulin-regulated aminopeptidase (IRAP), but not GLUT1-containing vesicles. Noteworthy, the overall expression of these proteins is not affected (13).
  • Ectopic expression of the ArPIKfyve C-terminal peptide inhibits insulin-induced GLUT4 surface accumulation in 3T3L1 adipocytes, further underscoring the important role of this ArPIKfyve region in the assembly of the PAS complex (9).
 

Transgenic mice

  • Mice lacking Vac14/ArPIKfyve die at, or shortly after birth. Fibroblasts from these mice have ~50 % lower levels of PtdIns(3,5)P2 and PtdIns(5)P vs. controls (14).
  • The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts (14).
  • Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective (14).
  • Mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14/ArPIKfyve that prevents the association with PIKfyve, thus generating a partial complex (3).
  • ArPIKfyve, similarly to PIKfyve, is also required in the synthesis of another rare phosphoinositide, i.e., PtdIns(5)P, as evidenced by studies in knockout mice models of PIKfyve or ArPIKfyve (14,15).
 

References:

1. Mireskandari A, Reid RL, Kashanchi F, Dittmer J, Li WB, Brady JN. Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic virus type-I Tax1 binding protein. Biochim Biophys Acta. 1996 Apr 10;1306(1):9-13. PMID: 8611628

2. Carmel L., Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan M. Gene expression profile of empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics 2006, 7(3): 375

3. 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. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J. 2008 Dec 17;27(24):3221-34. Epub 2008 Nov 27. PMID:19037259

4. Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR. Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Mol Med. 2010 Jul-Aug;16(7-8):247-53. Epub 2010 Mar 17. PMID: 20379614

5. Ching YP, Chan SF, Jeang KT, Jin DY. The retroviral oncoprotein Tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nat Cell Biol. 2006 Jul;8(7):717-24. Epub 2006 Jun 11. PMID: 16767081

6. Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A. A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity. Mol Cell Biol. 2004 Dec;24(23):10437-47.PMID:15542851

7. Sbrissa D, Shisheva A. Acquisition of unprecedented phosphatidylinositol 3,5-bisphosphate rise in hyperosmotically stressed 3T3-L1 adipocytes, mediated by ArPIKfyve-PIKfyve pathway. J Biol Chem. 2005 Mar 4;280(9):7883-9. Epub 2004 Nov 16.PMID:15546865

8. Sbrissa D, Ikonomov OC, Fu Z, Ijuin T, Gruenberg J, Takenawa T, Shisheva A. 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. 2007 Aug 17;282(33):23878-91. Epub 2007 Jun 7.PMID:17556371

9. Sbrissa D, Ikonomov OC, Fenner H, Shisheva A. ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol. 2008 Dec 26;384(4):766-79. Epub 2008 Oct 11. PMID:18950639

10. Ikonomov OC, Sbrissa D, Fenner H, Shisheva A. PIKfyve-ArPIKfyve-Sac3 core complex: Contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis J. Biol. Chem. 2009 Dec 18;284(51):35794-806. Epub 2009 Oct 19. PMID: 19840946

11. Ikonomov OC, Sbrissa D, Fligger J, Delvecchio K, Shisheva A. ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder. J Biol Chem. 2010 Aug 27;285(35):26760-4. Epub 2010 Jul 14. PMID:20630877

12. Lemaire JF, McPherson, PS. Binding of Vac14 to neuronal nitric oxide synthase: Characterization of a new internal PDZ-recognition motif. FEBS Letters 2006, 580: 6948-6954. PMID: 17161399

13. Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A. ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes. Exp Cell Res. 2007 Jul 1;313(11):2404-16. Epub 2007 Mar 30.PMID:17475247

14. Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS. 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. 2007 Oct 30;104(44):17518-23. Epub 2007 Oct 23.PMID:17956977

15. Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y., Jin J-P, Rappolee D, Shisheva A. The phosphoinositide kinase PIKfyve is vital in early embryonic development: Preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. J Biol Chem 2011 Apr 15; 286: 13404-13. Epub 2011 Feb 24. PMID: 21349843

 
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