Essential role for phosphoinositide phosphatases in the regulation of PI(3)P in yeast.
William Parrish, Christopher Stefan, Scott Emr
Cellular and Molecular Medicin, UCSD, 9500 Gilman Dr., San Diego, CA, 92093-0668, USA
The requirement of Vps34, the sole phosphatidylinositol (PI) 3-kinase in S. cerevisiae, for vacuole protein sorting exemplified the important role for phosphoinositides, phosphorylated derivatives of PI, in membrane trafficking. To better understand the regulation of PI 3' phosphate (PI(3)P)-mediated signaling pathways, the yeast myotubularin-related PI(3)P phosphatase, Ymr1, was investigated. We found that Ymr1 and the synaptojanin-like phosphatase Sjl3 function as key regulators of the localization and cellular 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 mis-regulation of PI(3)P-specific effectors. Triple deletion of YMR1, SJL2, and SJL3 was lethal, suggesting an essential role for phosphatase-mediated PI(3)P regulation. Consistent with this, growth was restored to a ymr1 sjl2 sjl3 triple mutant by a chimeric PI(3)P-targeted Sac1 phosphatase domain that returned PI(3)P to levels comparable to wildtype cells. Taken together, we have demonstrated that Ymr1, in conjunction with Sjl2 and Sjl3, functions in the control of PI(3)P signaling and the maintenance of endosomal system integrity. Furthermore, this work has defined an essential role for lipid phosphatases in the regulation of 3' phosphoinositides in yeast.
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