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J. Biol. Chem., Vol. 277, Issue 46, 44100-44107, November 15, 2002
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From the Departments of Pediatrics and Biochemistry and Molecular
Biology, Atlantic Research Centre, IWK Health Centre, Dalhousie
University, Halifax, Nova Scotia B3H 4H7, Canada
Phosphatidylcholine is the most abundant
phospholipid in eukaryotic cells, comprising 50% of total cellular
phospholipid, and thus plays a major role in cellular and organellar
biogenesis. In this study, we have used both nutritional deprivation as
well as a conditional temperature sensitive allele of PCT1
(CTP:phosphocholine cytidylyltransferase) coupled with an inactivated
phosphatidylethanolamine methylation pathway to determine how
cells respond to inactivation of phosphatidylcholine synthesis.
Metabolic studies determined that phosphatidylcholine biosynthesis
decreased to negligible levels within 1 h upon shift to the
nonpermissive temperature for the temperature-sensitive
PCT1 allele. Phosphatidylcholine mass decreased to
negligible levels upon removal of choline from the medium or growth at
the nonpermissive temperature, with the levels of the other major
phospholipids increasing slightly. Cell growth rate visibly slowed upon
cessation of phosphatidylcholine synthesis. Cells remained viable for
7-8 h after phosphatidylcholine synthesis was prevented; however, at
time points beyond 8 h, viability was significantly reduced but
only if the cells had been previously grown at 37 °C and not
25 °C. The inhibition of phosphatidylcholine synthesis at 37 °C
did not alter Golgi-derived vesicle transport to the vacuole as
monitored by carboxypeptidase Y processing or to the plasma membrane as
determined by invertase secretion. Immunofluorescence microscopy
localized Pct1p to the nucleus and nuclear membrane. Pct1p activity is
regulated by Sec14p, a cytoplasm/Golgi localized phosphatidylcholine/phosphatidylinositol binding protein that regulates
Golgi-derived vesicle transport partially through its ligand-dependent regulation of PCT1 derived
enzyme activity. Our nuclear localization of Pct1p indicates that the
regulation of Pct1p by Sec14p is indirect.
Cessation of Growth to Prevent Cell Death Due to Inhibition of
Phosphatidylcholine Synthesis Is Impaired at 37 °C in
Saccharomyces cerevisiae*
*
This work was supported by an operating grant from the
National Sciences and Engineering Research Council, a senior clinical scholar award from the IWK Health Centre (to C. R. M.), and an IWK
Health Centre graduate studentship (to A. G. H.).
To whom correspondence should be addressed. Tel.: 902-494-7066;
Fax: 902-494-1394; E-mail: cmcmaste@is.dal.ca.
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