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Vol. 13, Issue 4, 1238-1251, April 2002
and
*Department of Cellular and Molecular Medicine and the Howard
Hughes Medical Institute, University of California at San Diego, School
of Medicine, La Jolla, California 92093-0668; and
The Saccharomyces cerevisiae FAB1 gene encodes the
sole phosphatidylinositol 3-phosphate [PtdIns(3)P] 5-kinase
responsible for synthesis of the polyphosphoinositide
PtdIns(3,5)P2. VAC7 encodes a 128-kDa
transmembrane protein that localizes to vacuolar membranes. Both
vac7 and fab1 null mutants have
dramatically enlarged vacuoles and cannot grow at elevated
temperatures. Additionally, vac7Department of Biochemistry, University of Iowa, Iowa
City, Iowa 52242
mutants have nearly
undetectable levels of PtdIns(3,5)P2, suggesting that Vac7
functions to regulate Fab1 kinase activity. To test this hypothesis, we
isolated a fab1 mutant allele that bypasses the
requirement for Vac7 in PtdIns(3,5)P2 production. Expression of this fab1 allele in vac7
mutant cells suppresses the temperature sensitivity, vacuolar
morphology, and PtdIns(3,5)P2 defects normally exhibited by
vac7 mutants. We also identified a mutant allele of
FIG4, whose gene product contains a Sac1
polyphosphoinositide phosphatase domain, which suppresses
vac7 mutant phenotypes. Deletion of
FIG4 in vac7 mutant cells suppresses
the temperature sensitivity and vacuolar morphology defects, and
dramatically restores PtdIns(3,5)P2 levels. These results
suggest that generation of PtdIns(3,5)P2 by the Fab1 lipid
kinase is regulated by Vac7, whereas turnover of
PtdIns(3,5)P2 is mediated in part by the
Sac1 polyphosphoinositide phosphatase family member Fig4.
These authors contributed equally to this study.
§
Corresponding author. E-mail address:
semr{at}ucsd.edu.
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