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

Lundquist, Mark R.; Goncalves, Marcus D.; Loughran, Ryan M.; Possik, Elite; Vijayaraghavan, Tarika; Yang, Annan; Pauli, Chantal; Ravi, Archna; Verma, Akanksha; Yang, Zhiwei; Johnson, Jared L.; Wong, Jenny C.Y.; Ma, Yilun; Hwang, Katie Seo-Kyoung; Weinkove, David; Divecha, Nullin; Asara, John M.; Elemento, Olivier; Rubin, Mark A.; Kimmelman, Alec C.; Pause, Arnim; Cantley, Lewis C.; Emerling, Brooke M.

Authors

Mark R. Lundquist

Marcus D. Goncalves

Ryan M. Loughran

Elite Possik

Tarika Vijayaraghavan

Annan Yang

Chantal Pauli

Archna Ravi

Akanksha Verma

Zhiwei Yang

Jared L. Johnson

Jenny C.Y. Wong

Yilun Ma

Katie Seo-Kyoung Hwang

Nullin Divecha

John M. Asara

Olivier Elemento

Mark A. Rubin

Alec C. Kimmelman

Arnim Pause

Lewis C. Cantley

Brooke M. Emerling



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.

Citation

Lundquist, M. R., Goncalves, M. D., Loughran, R. M., Possik, E., Vijayaraghavan, T., Yang, A., Pauli, C., Ravi, A., Verma, A., Yang, Z., Johnson, J. L., Wong, J. C., Ma, Y., Hwang, K. S.-K., Weinkove, D., Divecha, N., Asara, J. M., Elemento, O., Rubin, M. A., Kimmelman, A. C., …Emerling, B. M. (2018). Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Molecular Cell, 70(3), 531-544.e9. https://doi.org/10.1016/j.molcel.2018.03.037

Journal Article Type Article
Acceptance Date Mar 29, 2018
Online Publication Date May 3, 2018
Publication Date 2018-05
Deposit Date May 4, 2018
Journal Molecular Cell
Print ISSN 1097-2765
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 70
Issue 3
Pages 531-544.e9
DOI https://doi.org/10.1016/j.molcel.2018.03.037
Public URL https://durham-repository.worktribe.com/output/1327399