PIKfyve 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 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.
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.
Shefali
S
Krishna
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Wilhelm
W
Palm
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yongchan
Y
Lee
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Wendy
W
Yang
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Urmi
U
Bandyopadhyay
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
Haoxing
H
Xu
Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
Oliver
O
Florey
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Craig B
CB
Thompson
Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: overhom1@mskcc.org.
Michael
M
Overholtzer
D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D013217:Starvation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000235:genetics* / Q000378:metabolism; D014617:Vacuoles / Q000235:genetics* / Q000378:metabolism
D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D050051:Transient Receptor Potential Channels; C416674:MCOLN1 protein, human; C492139:PIKFYVE protein, human