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

TitlePhosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy.
Publication TypeJournal Article
Year of Publication2018
AuthorsLundquist MR, Goncalves MD, Loughran RM, Possik E, Vijayaraghavan T, Yang A, Pauli C, Ravi A, Verma A, Yang Z, Johnson JL, C Y Wong J, Ma Y, Hwang KSeo-Kyoung, Weinkove D, Divecha N, Asara JM, Elemento O, Rubin MA, Kimmelman AC, Pause A, Cantley LC, Emerling BM
JournalMol Cell
Volume70
Issue3
Pagination531-544.e9
Date Published2018 05 03
ISSN1097-4164
KeywordsAnimals, Autophagosomes, Autophagy, Caenorhabditis elegans, Cell Line, Fasting, Fibroblasts, HEK293 Cells, Humans, Lipid Metabolism, Liver, Mice, Phosphatidylinositol Phosphates, Phosphotransferases (Alcohol Group Acceptor), Signal Transduction
Abstract

While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P, 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 Pip4k2aPip4k2b mouse embryonic fibroblasts and in C. elegans lacking the PI5P4K ortholog. These results suggest that this alternative pathway for PI-4, 5-P synthesis evolved, in part, to enhance the ability of multicellular organisms to survive starvation.

DOI10.1016/j.molcel.2018.03.037
Alternate JournalMol. Cell
PubMed ID29727621
PubMed Central IDPMC5991623
Grant ListP01 CA117969 / CA / NCI NIH HHS / United States
U54 CA210184 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
R01 CA157490 / CA / NCI NIH HHS / United States
R01 GM095567 / GM / NIGMS NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
R01 CA188048 / CA / NCI NIH HHS / United States