Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p

doi:10.1083/jcb.200201002

Published online 11 March 2002. doi:10.1083/jcb.200201002

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© The Rockefeller University Press, 0021-9525/2002/3/1015 $5.00
The Journal of Cell Biology, Volume 156, Number 6, March 18, 2002 1015-1028

Article

Osmotic stress–induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p

Cecilia J. Bonangelino¹, Johnathan J. Nau¹, Jason E. Duex¹, Mikala Brinkman¹, Andrew E. Wurmser², Jonathan D. Gary², Scott D. Emr² and Lois S. Weisman¹

¹ Department of Biochemistry, University of Iowa, Iowa City, IA 52242
² Division of Cellular and Molecular Medicine and Howard Hughes Institute, University of California at San Diego, School of Medicine, La Jolla, CA 92093

Address correspondence to Lois S. Weisman, Department of Biochemistry, University of Iowa, Iowa City, IA 52242. Tel.: (319) 335-8581. Fax: (319) 335-9570. E-mail: lois-weisman{at}uiowa.edu

Phosphatidylinositol 3,5-bisphosphate (PtdIns[3,5]P₂) was firstidentified as a nonabundant phospholipid whose levels increasein response to osmotic stress. In yeast, Fab1p catalyzes formationof PtdIns(3,5)P₂ via phosphorylation of PtdIns(3)P. We haveidentified Vac14p, a novel vacuolar protein that regulates PtdIns(3,5)P₂synthesis by modulating Fab1p activity in both the absence andpresence of osmotic stress. We find that PtdIns(3)P levels arealso elevated in response to osmotic stress, yet, only the elevationof PtdIns(3,5)P₂ levels are regulated by Vac14p. Under basalconditions the levels of PtdIns(3,5)P₂ are 18–28-foldlower than the levels of PtdIns(3)P, PtdIns(4)P, and PtdIns(4,5)P₂.After a 10 min exposure to hyperosmotic stress the levels ofPtdIns(3,5)P₂ rise 20-fold, bringing it to a cellular concentrationthat is similar to the other phosphoinositides. This suggeststhat PtdIns(3,5)P₂ plays a major role in osmotic stress, perhapsvia regulation of vacuolar volume. In fact, during hyperosmoticstress the vacuole morphology of wild-type cells changes dramatically,to smaller, more highly fragmented vacuoles, whereas mutantsunable to synthesize PtdIns(3,5)P₂ continue to maintain a singlelarge vacuole. These findings demonstrate that Vac14p regulatesthe levels of PtdIns(3,5)P₂ and provide insight into why PtdIns(3,5)P₂levels rise in response to osmotic stress.

Key Words: VAC14; FAB1; PtdIns(3,5)P₂; vacuole; phosphatidylinositol

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