Roles of PIKfyve in multiple cellular pathways

Abstract

Phosphoinositide signaling lipids are crucial for eukaryotes and regulate many aspects of cell function. These signaling molecules are difficult to study because they are extremely low abundance. Here, we focus on two of the lowest abundance phosphoinositides, PI(3,5)P₂ and PI(5)P, which play critical roles in cellular homeostasis, membrane trafficking and transcription. Their levels are tightly regulated by a protein complex that includes PIKfyve, Fig4 and Vac14. Importantly, mutations in this complex that decrease PI(3,5)P₂ and PI(5)P are linked to human diseases, especially those of the nervous system. Paradoxically, PIKfyve inhibitors which decrease PI(3,5)P₂ and PI(5)P, are currently being tested for some neurodegenerative diseases, as well as other diverse diseases including some cancers, and as a treatment for SARS-CoV2 infection. A more comprehensive picture of the pathways that are regulated by PIKfyve will be critical to understand the roles of PI(3,5)P₂ and PI(5)P in normal human physiology and in disease.

Keywords: Fig4; PIKfyve; Vac14; endomembrane trafficking; endosomes; phosphoinositide.

Figure 1

PI(3,5)P₂ levels acutely and transiently rise and fall in response to hyperosmotic stress. Yeast grown in normal media were transferred to hyperosmotic media (containing 0.9 M NaCl) at time zero (perpendicular arrow) and left in 0.9 M salt for the rest of the experiment (parallel arrow). Although there were no further perturbations to the external environment, the levels of PI(3,5)P₂ (relative to PI(4,5)P₂) rapidly increase, plateau and rapidly decrease. These findings indicate that the levels of PI(3,5)P₂ are tightly controlled. Within 5 min, PI(3,5)P₂ levels rise over 20-fold, plateau for 10 min, then rapidly return to basal levels. Multiple layers of regulations within the Fab1 complex, which includes both the lipid kinase Fab1/PIKfyve and lipid phosphatase Fig4 provide tight control of PI(3,5)P₂ synthesis and turnover. Data modified from [7].

Figure 2

Schematic of the cellular localization of the two lipids products downstream of PIKfyve activity, PI(3,5)P₂ and PI(5)P, as well as the precursor PI(3)P. Due to the lack of suitable and/or sufficiently sensitive bioprobes, the localization of endogenous levels of PI(3,5)P₂ and PI(5)P is inferred from the localization of PIKfyve. PI(3,5)P₂ localizes on early endosomes, late endosomes and lysosomes. PI(5)P may also be present at all or some of these locations. CME: Clathrin-mediated endocytosis. CIE: Clathrin-independent endocytosis. EE: Early endosome. LE: Late endosome. MVB: Multivesicular body. EA: Endoplasmic reticulum. ERC: Early recycling compartment. TGN: Trans-Golgi network.