PI(3,5)P2 Regulates Vacuole Cation Transport to Mediate Cellular Osmoregulation

Abstract

Lysosomes are dynamic organelles with critical roles in cellular physiology. The lysosomal signaling lipid phosphatidylinositol 3,5‐bisphosphate (PI(3,5)P2) is a key regulator that has been implicated to control lysosome ion homeostasis, but the scope of ion transporters targeted by PI(3,5)P2 and the purpose of this regulation is not well understood. We identified loss‐of‐function mutations in the vacuolar H+‐ATPase (V‐ATPase) and in Vnx1, a vacuolar monovalent cation/proton antiporter that suppress the growth defects and osmotic swelling of vacuoles (lysosomes) in Saccharomyces cerevisiae lacking PI(3,5)P2 synthesis. The loss of PI(3,5)P2 synthesis in yeast causes a robust accumulation of multiple cations, most notably a ~3‐fold increase in cellular potassium, a primary osmolyte that regulates cellular/organellar water content. The accumulation of potassium and other cations in yeast lacking PI(3,5)P2 is relieved by Vnx1 or V‐ATPase inactivation, or by increased activation of a vacuolar cation export channel, Yvc1. Furthermore, inactivating the V‐ATPase or Vnx1 rescued several vacuole functions that are defective in PI(3,5)P2‐deficient cells. Thus, our data demonstrates that a critical function of PI(3,5)P2 signaling is to orchestrate vacuole/lysosome ion transport to maintain cellular osmoregulation and lysosome homeostasis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.