2. Academic Validation
  3. PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment

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.
Shefali Krishna 1,  Wilhelm Palm 2,  Yongchan Lee 3,  Wendy Yang 3,  Urmi Bandyopadhyay 3,  Haoxing Xu 4,  Oliver Florey 5,  Craig B Thompson 2,  Michael Overholtzer 6
Affiliations

Affiliations

  • 1 Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY 10065, USA; Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
  • 5 Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
  • 6 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: overhom1@mskcc.org.
PMID: 27623384 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.

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