The importance of PI(3,5)P2 in mitotic exit

Phosphoinositides are evolutionarily conserved signaling lipids that are critical for many aspects of cellular biology. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), one of the rarest phosphoinositides, is synthesized on vacuole/lysosome membranes through the phosphorylation of Phosphatidylinositol-3-phosphate (PI3P) by the Fab1 kinase. PI(3,5)P2 plays key roles in various cellular processes, including vacuole/lysosome structure and function, stress response, autophagy, transcriptional regulation, and membrane trafficking. Dysregulation of PI(3,5)P2 production has been implicated in various human diseases such as amyotrophic lateral sclerosis and cancer, highlighting the significance of PI(3,5)P2 for human health. The work presented in this thesis discovers that PI(3,5)P2 is crucial for a timely mitotic exit in budding yeast. Our data shows that reduced levels of PI(3,5)P2 results in delayed mitotic exit and lethality in cells with compromised mitotic exit activity. Conversely, overproduction of PI(3,5)P2 rescues the prolonged anaphase and lethality of mitotic exit mutants. Mechanistically, we find that PI(3,5)P2 regulates the localization of the mitotic exit inhibitor Kin4. Accordingly, high levels of PI(3,5)P2 causes recruitment of Kin4 to the vacuole periphery. We further show that this process is dependent on Atg18, a known effector of PI(3,5)P2. Thus, this study unravels a novel link between PI(3,5)P2 and cell cycle progression in budding yeast.