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

被引：75

作者：

Lundquist, Mark R. ^{[1
]}

Goncalves, Marcus D. ^{[1
]}

Loughran, Ryan M. ^{[2
]}

Possik, Elite ^{[3
,4
]}

Vijayaraghavan, Tarika ^{[3
,4
]}

Yang, Annan ^{[5
]}

Pauli, Chantal ^{[1
,6
]}

Ravi, Archna ^{[2
]}

Verma, Akanksha ^{[1
,7
]}

Yang, Zhiwei ^{[1
]}

Johnson, Jared L. ^{[1
]}

Wong, Jenny C. Y. ^{[1
]}

Ma, Yilun ^{[1
]}

Hwang, Katie Seo-Kyoung ^{[1
]}

Weinkove, David ^{[8
]}

Divecha, Nullin ^{[9
]}

Asara, John M. ^{[10
]}

Elemento, Olivier ^{[1
,7
]}

Rubin, Mark A. ^{[1
,6
]}

Kimmelman, Alec C. ^{[11
]}

Pause, Arnim ^{[3
,4
]}

Cantley, Lewis C. ^{[1
]}

Emerling, Brooke M. ^{[2
]}

机构：

[1] Weill Cornell Med, Meyer Canc Ctr, Dept Med, New York, NY 10065 USA

[2] Sanford Burnham Prebys Med Discovery Inst, Canc Metab & Signaling Networks Program, La Jolla, CA 92037 USA

[3] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada

[4] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[5] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA

[6] New York Presbyterian Hosp, Weill Cornell Med, Englander Inst Precis Med, New York, NY 10065 USA

[7] Weill Cornell Med, Inst Computat Biomed, New York, NY 10065 USA

[8] Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England

[9] Southampton Univ, Ctr Biol Sci, Inositide Lab, Southampton SO17 1BJ, Hants, England

[10] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Signal Transduct, Dept Med, Boston, MA 02115 USA

[11] NYU, Med Sch, Perlmutter Canc Ctr, Dept Radiat Oncol, 550 1St Ave, New York, NY 10016 USA

来源：

MOLECULAR CELL | 2018年 / 70卷 / 03期

基金：

英国生物技术与生命科学研究理事会;

关键词：

P70; S6; KINASE; TRANSCRIPTIONAL CONTROL; LYSOSOME FUSION; INHIBITS GROWTH; MTORC1; DELETION; COMPLEX; SYSTEM; ROLES;

D O I：

10.1016/j.molcel.2018.03.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P2) in mammalian cells is generated by the conversion of phosphatidylinositol4-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.

引用

页码：531 / +

页数：22

共 49 条

[1] Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV [J].

Akil, Abdellah ;

Peng, Juan ;

Omrane, Mohyeddine ;

Gondeau, Claire ;

Desterke, Christophe ;

Marin, Mickael ;

Tronchere, Helene ;

Taveneau, Cyntia ;

Sar, Sokhavuth ;

Briolotti, Philippe ;

Benjelloun, Soumaya ;

Benjouad, Abdelaziz ;

Maurel, Patrick ;

Thiers, Valerie ;

Bressanelli, Stphane ;

Samuel, Didier ;

Brechot, Christian ;

Gassama-Diagne, Ama .

NATURE COMMUNICATIONS, 2016, 7

[2]

Ban H, 2004, INT J MOL MED, V13, P537

[3] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4]

BRENNER S, 1974, GENETICS, V77, P71

[5] PIKfyve Regulation of Endosome-Linked Pathways [J].

de Lartigue, Jane ;

Polson, Hannah ;

Feldman, Morri ;

Shokat, Kevan ;

Tooze, Sharon A. ;

Urbe, Sylvie ;

Clague, Michael J. .

TRAFFIC, 2009, 10 (07) :883-893

[6] Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL (vol 18, pg 339, 2016) [J].

De Leo, Maria Giovanna ;

Staiano, Leopoldo ;

Vicinanza, Mariella ;

Luciani, Alessandro ;

Carissimo, Annamaria ;

Mutarelli, Margherita ;

Di Campli, Antonella ;

Polishchuk, Elena ;

Di Tullio, Giuseppe ;

Morra, Valentina ;

Levtchenko, Elena ;

Oltrabella, Francesca ;

Starborg, Tobias ;

Santoro, Michele ;

Di Bernardo, Diego ;

Devuyst, Olivier ;

Lowe, Martin ;

Medina, Diego L. ;

Ballabio, Andrea ;

De Matteis, Maria Antonietta .

NATURE CELL BIOLOGY, 2016, 18 (08) :839-+

[7] Signal integration by mTORC1 coordinates nutrient input with biosynthetic output [J].

Dibble, Christian C. ;

Manning, Brendan D. .

NATURE CELL BIOLOGY, 2013, 15 (06) :555-564

[8] Amino acids and mTORC1: from lysosomes to disease [J].

Efeyan, Alejo ;

Zoncu, Roberto ;

Sabatini, David M. .

TRENDS IN MOLECULAR MEDICINE, 2012, 18 (09) :524-533

[9] Depletion of a Putatively Druggable Class of Phosphatidylinositol Kinases Inhibits Growth of p53-Null Tumors [J].

Emerling, Brooke M. ;

Hurov, Jonathan B. ;

Poulogiannis, George ;

Tsukazawa, Kazumi S. ;

Choo-Wing, Rayman ;

Wulf, Gerburg M. ;

Bell, Eric L. ;

Shim, Hye-Seok ;

Lamia, Katja A. ;

Rameh, Lucia E. ;

Bellinger, Gary ;

Sasaki, Atsuo T. ;

Asara, John M. ;

Yuan, Xin ;

Bullock, Andrea ;

DeNicola, Gina M. ;

Song, Jiaxi ;

Brown, Victoria ;

Signoretti, Sabina ;

Cantley, Lewis C. .

CELL, 2013, 155 (04) :844-857

[10] Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis [J].

Guo, Jessie Yanxiang ;

Karsli-Uzunbas, Gizem ;

Mathew, Robin ;

Aisner, Seena C. ;

Kamphorst, Jurre J. ;

Strohecker, Anne M. ;

Chen, Guanghua ;

Price, Sandy ;

Lu, Wenyun ;

Teng, Xin ;

Snyder, Eric ;

Santanam, Urmila ;

DiPaola, Robert S. ;

Jacks, Tyler ;

Rabinowitz, Joshua D. ;

White, Eileen .

GENES & DEVELOPMENT, 2013, 27 (13) :1447-1461

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