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Vol. 12, Issue 8, 2396-2411, August 2001
Division of Cellular and Molecular Medicine, The Howard Hughes
Medical Institute, University of California, San Diego, School of
Medicine, La Jolla, California 92093-0668
Synthesis and turnover of phosphoinositides are tightly regulated
processes mediated by a set of recently identified kinases and
phosphatases. We analyzed the primary role of the phosphoinositide phosphatase Sac1p in Saccharomyces cerevisiae with the
use of a temperature-sensitive allele of this gene. Our analysis
demonstrates that inactivation of Sac1p leads to a specific increase in
the cellular levels of phosphatidylinositol 4-phosphate
(PtdIns(4)P), accompanied by changes in vacuole morphology and an
accumulation of lipid droplets. We have found that the majority of
Sac1p localizes to the endoplasmic reticulum, and this localization is
crucial for the efficient turnover of PtdIns(4)P. By generating double mutant strains harboring the sac1ts allele
and one of two temperature-sensitive PtdIns 4-kinase genes, stt4ts or pik1ts,
we have demonstrated that the bulk of PtdIns(4)P that accumulates in
sac1 mutant cells is generated by the Stt4 PtdIns
4-kinase, and not Pik1p. Consistent with these findings, inactivation
of Sac1p partially rescued defects associated with
stt4ts but not
pik1ts mutant cells. To analyze potential
overlapping functions between Sac1p and other homologous
phosphoinositide phosphatases, sac1ts mutant
cells lacking various other synaptojanin-like phosphatases were
generated. These double and triple mutants exacerbated the accumulation
of intracellular phosphoinositides and caused defects in Golgi
function. Together, our results demonstrate that Sac1p primarily turns
over Stt4p-generated PtdIns(4)P and that the membrane localization of
Sac1p is important for its function in vivo. Regulation of this
PtdIns(4)P pool appears to be crucial for the maintenance of vacuole
morphology, regulation of lipid storage, Golgi function, and actin
cytoskeleton organization.
Corresponding author. E-mail address: semr{at}ucsd.edu.
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