Journal Article

Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor

Stefan, Christopher J., Nishimura, Taki, Ungermann, Christian, Numrich, Johannes, Montoro, Ayelén González, Malia, PC

2018

Overview

Lysosomes have an important role in cellular protein and organelle quality control, metabolism, and signaling. On the surface of lysosomes, the PIKfyve/Fab1 complex generates phosphatidylinositol 3,5-bisphosphate, PI-3,5-P₂, which is critical for lysosomal membrane homeostasis during acute osmotic stress and for lysosomal signaling. Here, we identify the inverted BAR protein Ivy1 as an inhibitor of the Fab1 complex with a direct influence on PI-3,5-P₂ levels and vacuole homeostasis. Ivy1 requires Ypt7 binding for its function, binds PI-3,5-P₂, and interacts with the Fab1 kinase. Colocalization of Ivy1 and Fab1 is lost during osmotic stress. In agreement with Ivy1’s role as a Fab1 regulator, its overexpression blocks Fab1 activity during osmotic shock and vacuole fragmentation. Conversely, loss of Ivy1, or lateral relocalization of Ivy1 on vacuoles away from Fab1, results in vacuole fragmentation and poor growth. Our data suggest that Ivy1 modulates Fab1-mediated PI-3,5-P₂ synthesis during membrane stress and may allow adjustment of the vacuole membrane environment.

• Publisher: National Academy of Sciences
• Subject: BAR protein / Biological Sciences / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Biology / Enzyme inhibitors / Fragmentation / Homeostasis / Inhibitors / Intracellular Membranes - metabolism / Kinases / Lysosomes / Lysosomes - genetics / Lysosomes - metabolism / Membranes / Metabolism / Osmotic shock / Osmotic stress / Phosphatidylinositol / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Phosphatidylinositol Phosphates - genetics / Phosphatidylinositol Phosphates - metabolism / Phosphoinositide-3 Kinase Inhibitors / Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors / Phosphotransferases (Alcohol Group Acceptor) - genetics / Phosphotransferases (Alcohol Group Acceptor) - metabolism / Protein turnover / Proteins / Quality control / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Saccharomyces cerevisiae - cytology / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae - metabolism / Saccharomyces cerevisiae Proteins - antagonists & inhibitors / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Signaling / Stresses / Vacuoles / Vacuoles - genetics / Vacuoles - metabolism