PIKfyve governs endoplasmic reticulum-lysosome contacts to modulate endoplasmic reticulum dynamics

Lysosomes are essential to clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P ₂ ] and promotes lysosome fission since lysosomes coalesce into larger, but fewer organelles in PIKfyve defective cells. Here, we reveal a role for PIKfyve in regulating endoplasmic reticulum (ER) dynamics. We show the ER is less reticulated and motile in cells acutely inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules via microtubule-based movement. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin’s FYVE domain. Thus, our findings reveal that PIKfyve activity balances phosphoinositides at ER-lysosome contact sites to govern ER properties and has significant implications to our understanding of disease linked to PIKfyve dysfunction such as neurodegeneration.