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Vol. 15, Issue 8, 3567-3579, August 2004

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Essential Role for the Myotubularin-related Phosphatase Ymr1p and the Synaptojanin-like Phosphatases Sjl2p and Sjl3p in Regulation of Phosphatidylinositol 3-Phosphate in Yeast

Department of Cellular and Molecular Medicine and the Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, La Jolla, California 92093-0668

Submitted March 12, 2004; Revised May 6, 2004; Accepted May 18, 2004
Monitoring Editor: Suzanne Pfeffer

The requirement of Vps34p, the sole phosphatidylinositol (PI) 3-kinase in Saccharomyces cerevisiae, for protein sorting to the vacuole in yeast has exemplified the essential role for phosphoinositides, phosphorylated derivatives of PI, in membrane trafficking. To better understand mechanisms that regulate PI 3-phosphate [PI(3)P]-mediated signaling, the role of the yeast myotubularin-related PI(3)P phosphatase Ymr1p was investigated. We found that Ymr1p and the synaptojanin-like phosphatase Sjl3p function as key regulators of the localization and levels of PI(3)P. Our data indicated that the ymr1 sjl3 double mutant aberrantly accumulated PI(3)P and demonstrated a steady-state redistribution of this lipid that leads to enrichment on the vacuolar membrane. This resulted in vacuole protein sorting defects, vacuolar fragmentation, and the misregulation of PI(3)P-specific effectors. Triple deletion of YMR1, SJL2, and SJL3 was lethal, suggesting an essential requirement for phosphatase-mediated PI(3)P regulation. Consistent with this, growth was restored to a ymr1 sjl2 sjl3 triple mutant by a PI(3)P-targeted Sac1p domain chimera (GFP-Sac1C-FYVE_EEA1) that returned PI(3)P to levels comparable with wild-type cells. Together, this study demonstrated that Ymr1p, a myotubularin phosphatase family member, functions in the control of PI(3)P-dependent signaling and the maintenance of endosomal system integrity. In addition, this work defined an essential overlapping role for lipid phosphatases in the regulation of 3' phosphoinositides in yeast.

Abbreviations used: Ape1, aminopeptidase 1; CPS, carboxypeptidase S; CPY, carboxypeptidase Y; CVT, cytoplasm-to-vacuole; 5-FOA, 5-fluorooroic acid; GFP, green fluorescent protein; HPLC, high performance liquid chromatography; MVB, multivesicular body; PCR, polymerase chain reaction; PI, phosphatidylinositol; PI(3)P, phosphatidylinositol 3-phosphate; PI(4)P, phosphatidylinositol 4-phosphate; PI(3,5)P₂, phosphatidylinositol 3,5-bisphosphate; PI(4,5)P₂, phosphatidylinositol 4,5-bisphosphate; vps, vacuole protein sorting.

^* Corresponding author. E-mail address: semr{at}ucsd.edu.

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