PlKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment

The scavenging of extracellular macromolecules by engulfment can sustain cell growth in a nutrient depleted environment. Engulfed macromolecules are contained within vacuoles that are targeted for lysosome fusion to initiate degradation and nutrient export. We have shown that vacuoles containing engulfed material undergo mTORC1-dependent fission that redistributes degraded cargo back into the endosomal network. Here we identify the lipid kinase PlKfyve as a regulator of an alternative pathway that distributes engulfed contents in support of intracellular macromolecular synthesis during macro-pinocytosis, entosis, and phagocytosis. We find that PlKfyve regulates vacuole size in part through its downstream effector, the cationic transporter TRPML1. Furthermore, PlKfyve promotes recovery of nutrients from vacuoles, suggesting a potential link between PlKfyve activity and lysosomal nutrient export. During nutrient depletion, PlKfyve activity protects Ras-mutant cells from starvation-induced cell death and supports their proliferation. These data identify PlKfyve as a critical regulator of vacuole maturation and nutrient recovery during engulfment.