| Background |
PIKFYVE is a lipid kinase that phosphorylates position 5 of PIP (phosphatidylinositol) or PIP (phosphatidylinositol 3-phosphate) to form PI5P or PIP2 The normal cellular levels of the latter two lipids are important in maintaining the functional responses of endosomes, lysosomes, and autophagosomes, as well as the regulation of cell cycle, stress response, T cell activation, and chromatin remodeling PIKFYVE functions within a regulatory complex including the PIKFYVE kinase, a scaffold protein Vac14, and a lipid phosphatase Fig4 (Sac) The complex localizes to endosomes and lysosomes, regulating endosome-to-TGN retrograde transport, lysosome fission, and lysosomal related autophagy. Targeted disruption of the PIKFYVE gene is embryonic lethal, indicating the vital role of the kinase in early embryonic development. Inhibition of PIKFYVE disrupts lysosome function in autophagy and can selectively kill certain cancer cells. PIKFYVE inhibition also potentiates immune response to checkpoint blockade in the tumor microenvironment.
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