“VAC14”的意思、由来-开放百科全书

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.^[1]^[4] 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.

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.^[5] 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.^[6] Human Vac14/ArPIKfyve also interacts with the PDZ (post-synaptic density) domain of neuronal nitric oxide synthase ^[7] but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.^[8]

Lessons from VAC14 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.^[9] 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.^[10]

VAC14 and human disease

References

1. ^¹{{cite web | title = Entrez Gene: Vac14 homolog (S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55697| accessdate = }}
2. ^{{cite journal |vauthors=Davy BE, Robinson ML | title = Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene | journal = Hum. Mol. Genet. | volume = 12 | issue = 10 | pages = 1163–70 |date=May 2003 | pmid = 12719380 | doi = 10.1093/hmg/ddg122| url = | issn = }}
3. ^{{cite journal |vauthors=Sbrissa D, Ikonomov OC, Strakova J, Dondapati R, Mlak K, Deeb R, Silver R, Shisheva A | title = A mammalian ortholog of Saccharomyces cerevisiae Vac14 that associates with and up-regulates PIKfyve phosphoinositide 5-kinase activity | journal = Mol. Cell. Biol. | volume = 24 | issue = 23 | pages = 10437–47 |date=December 2004 | pmid = 15542851 | pmc = 529046 | doi = 10.1128/MCB.24.23.10437-10447.2004 }}
4. ^{{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 = J. Biol. Chem. | volume = 282 | issue = 33 | pages = 23878–91 |date=August 2007 | pmid = 17556371 | doi = 10.1074/jbc.M611678200 | url = | issn = }}
5. ^{{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 = J. Biol. Chem. | volume = 285 | issue = 35 | pages = 26760–4 |date=August 2010 | pmid = 20630877 | doi = 10.1074/jbc.C110.154658 | pmc=2930674}}
6. ^{{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 = J. Mol. Biol. | volume = 384 | issue = 4 | pages = 766–79 |date=December 2008 | pmid = 18950639 | pmc = 2756758 | doi = 10.1016/j.jmb.2008.10.009 }}
7. ^{{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 Lett. | volume = 580 | issue = 30 | pages = 6948–54 |date=December 2006 | pmid = 17161399 | doi = 10.1016/j.febslet.2006.11.061 }}
8. ^{{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 = Exp. Cell Res. | volume = 313 | issue = 11 | pages = 2404–16 |date=July 2007 | pmid = 17475247 | pmc = 2475679 | doi = 10.1016/j.yexcr.2007.03.024 }}
9. ^{{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 | title = Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 44 | pages = 17518–23 |date=October 2007 | pmid = 17956977 | pmc = 2077288 | doi = 10.1073/pnas.0702275104 }}
10. ^{{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 | title = VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse | journal = EMBO J. | volume = 27 | issue = 24 | pages = 3221–34 |date=December 2008 | pmid = 19037259 | pmc = 2600653 | doi = 10.1038/emboj.2008.248 | url = https://dash.harvard.edu/bitstream/handle/1/5311764/2600653.pdf?sequence=1 }}
11. ^{{cite web | url = http://www.wikigenes.org/e/gene/e/55697.html | title = VAC14 - Vac14 homolog (S. cerevisiae) | date = | publisher = WikiGenes | accessdate = 2011-07-16 }}

Functions and interactions

Lessons from VAC14 mouse models

VAC14 and human disease

References

Further reading