PIKfyve Regulates Vacuole Maturation and Nutrient Recovery Following Engulfment

Dev Cell. 2016 Sep 12;38(5):536-47. doi: 10.1016/j.devcel.2016.08.001.

Abstract

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 PIKfyve as a regulator of an alternative pathway that distributes engulfed contents in support of intracellular macromolecular synthesis during macropinocytosis, entosis, and phagocytosis. We find that PIKfyve regulates vacuole size in part through its downstream effector, the cationic transporter TRPML1. Furthermore, PIKfyve promotes recovery of nutrients from vacuoles, suggesting a potential link between PIKfyve activity and lysosomal nutrient export. During nutrient depletion, PIKfyve activity protects Ras-mutant cells from starvation-induced cell death and supports their proliferation. These data identify PIKfyve as a critical regulator of vacuole maturation and nutrient recovery during engulfment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Cell Line, Tumor
  • Endosomes / genetics
  • Endosomes / metabolism
  • Humans
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Phagocytosis / genetics
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Starvation
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transient Receptor Potential Channels / genetics*
  • Transient Receptor Potential Channels / metabolism
  • Vacuoles / genetics*
  • Vacuoles / metabolism

Substances

  • MCOLN1 protein, human
  • Multiprotein Complexes
  • Transient Receptor Potential Channels
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • PIKFYVE protein, human
  • Mechanistic Target of Rapamycin Complex 1