2. Academic Validation
  3. Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy

Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy

  • Mol Cell. 2018 May 3;70(3):531-544.e9. doi: 10.1016/j.molcel.2018.03.037.
Mark R Lundquist 1,  Marcus D Goncalves 1,  Ryan M Loughran 2,  Elite Possik 3,  Tarika Vijayaraghavan 3,  Annan Yang 4,  Chantal Pauli 5,  Archna Ravi 2,  Akanksha Verma 6,  Zhiwei Yang 1,  Jared L Johnson 1,  Jenny C Y Wong 1,  Yilun Ma 1,  Katie Seo-Kyoung Hwang 1,  David Weinkove 7,  Nullin Divecha 8,  John M Asara 9,  Olivier Elemento 6,  Mark A Rubin 5,  Alec C Kimmelman 10,  Arnim Pause 3,  Lewis C Cantley 11,  Brooke M Emerling 12
Affiliations

Affiliations

  • 1 Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 2 Sanford Burnham Prebys Medical Discovery Institute, Cancer Metabolism and Signaling Networks Program, La Jolla, CA 92037, USA.
  • 3 Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada.
  • 4 Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10065, USA.
  • 6 Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 7 School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, UK.
  • 8 The Inositide Laboratory, Centre for Biological Sciences, Southampton University, Southampton, SO17 1BJ, UK.
  • 9 Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Perlmutter Cancer Center, Department of Radiation Oncology, NYU Medical School, New York, NY 10016, USA.
  • 11 Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: [email protected].
  • 12 Sanford Burnham Prebys Medical Discovery Institute, Cancer Metabolism and Signaling Networks Program, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 29727621 DOI: 10.1016/j.molcel.2018.03.037
Abstract

While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P2) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P2, a small fraction can be made by phosphorylating phosphatidylinositol-5-phosphate (PI-5-P). The physiological relevance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active Enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrichment in lipid droplets and in autophagic vesicles during fasting. These changes are due to a defect in the clearance of autophagosomes that halts Autophagy and reduces the supply of nutrients salvaged through this pathway. Similar defects in Autophagy are seen in nutrient-starved Pip4k2a-/-Pip4k2b-/- mouse embryonic fibroblasts and in C. elegans lacking the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P2 synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.

Keywords

PI5P4K; TFEB; autophagy; lipid kinase; lysosome; mTORC1; metabolism; phospholipid.

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