Essential role for the myotubularin-related phosphatase ymrlp and the synaptojanin-like phosphatases Sjl2p and Sjl3p in regulation of phosphatidylinositol 3-phosphate in yeast
Essential role for the myotubularin-related phosphatase ymrlp and the synaptojanin-like phosphatases Sjl2p and Sjl3p in regulation of phosphatidylinositol 3-phosphate in yeast
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DOI：
10.1091/mbc.e04-03-0209
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发表时间：
2004-08-01
影响因子：
3.3
通讯作者：
Emr, SD
中科院分区：
文献类型：
--
作者：
Parrish, WR;Stefan, CJ;Emr, SD
Vps 34 p是酿酒酵母中唯一的磷脂酰肌醇（PI）3-激酶，用于蛋白质分选到酵母中的液泡的需要已经例证了磷酸肌醇（PI的磷酸化衍生物）在膜运输中的重要作用。为了更好地理解调节PI 3-磷酸[PI（3）P]介导的信号传导的机制，研究了酵母肌微管蛋白相关的PI（3）P磷酸酶Ymr 1 p的作用。我们发现，Ymr 1 p和synaptojanin样磷酸酶Sjl 3 p作为PI（3）P的定位和水平的关键调节器。我们的数据表明，ymr 1Delta sjl 3Delta双突变体异常积累PI（3）P，并证明了这种脂质的稳态再分配，导致液泡膜上的富集。这导致液泡蛋白分选缺陷、液泡碎片化和PI（3）P特异性效应物的失调。YMR 1、SJL 2和SJL 3的三重缺失是致死性的，这表明磷酸酶介导的PI（3）P调节是必需的。与此一致，通过PI（3）P靶向Sac 1 p结构域嵌合体（GFP-Sac 1DeltaC-FYVEEEA 1）恢复ymr 1Deltasjl 2Deltasjl 3Delta三重突变体的生长，该嵌合体使PI（3）P恢复到与野生型细胞相当的水平。总之，这项研究表明，Ymr 1 p，一个肌管蛋白磷酸酶家族成员，在PI（3）P依赖性信号转导的控制和维持内体系统的完整性的功能。此外，这项工作确定了一个重要的重叠作用，脂质磷酸酶的3'磷酸肌醇在酵母中的调节。
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 ymr1Delta sjl3Delta 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 ymr1Delta sjl2Delta sjl3Delta triple mutant by a PI(3)P-targeted Sac1p domain chimera (GFP-Sac1DeltaC-FYVEEEA1) 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.