Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy

被引：2096

作者：

Egan, Daniel F. ^{[1
]}

Shackelford, David B. ^{[1
]}

Mihaylova, Maria M. ^{[1
,2
]}

Gelino, Sara ^{[4
]}

Kohnz, Rebecca A. ^{[1
]}

Mair, William ^{[1
]}

Vasquez, Debbie S. ^{[1
]}

Joshi, Aashish ^{[5
]}

Gwinn, Dana M. ^{[1
]}

Taylor, Rebecca ^{[1
]}

Asara, John M. ^{[6
,7
]}

Fitzpatrick, James ^{[3
]}

Dillin, Andrew ^{[1
,2
]}

Viollet, Benoit ^{[8
]}

Kundu, Mondira ^{[5
]}

Hansen, Malene ^{[4
]}

Shaw, Reuben J. ^{[1
,2
]}

机构：

[1] Salk Inst Biol Studies, Dulbecco Ctr Canc Res, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[2] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Waitt Adv Biophoton Ctr, La Jolla, CA 92037 USA

[4] Sanford Burnham Med Res Inst, Del E Webb Neurosci Aging & Stem Cell Res Ctr, Grad Sch Biomed Sci, La Jolla, CA 92037 USA

[5] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[6] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Univ Paris 05, CNRS, Inst Cochin, INSERM,U1016,UMR 8104, Paris, France

来源：

SCIENCE | 2011年 / 331卷 / 6016期

关键词：

CATALYTIC SUBUNIT; AUTOPHAGY; COMPLEX; ROLES; METABOLISM; DOMAINS; TARGET; LIVER;

D O I：

10.1126/science.1196371

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.

引用

页码：456 / 461

页数：6

共 32 条

[1] Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin [J].

Andreelli, F ;

Foretz, M ;

Knauf, C ;

Cani, PD ;

Perrin, C ;

Iglesias, MA ;

Pillot, B ;

Bado, A ;

Tronche, F ;

Mithieux, G ;

Vaulont, S ;

Burcelin, R ;

Viollet, B .

ENDOCRINOLOGY, 2006, 147 (05) :2432-2441

[2] Network organization of the human autophagy system [J].

Behrends, Christian ;

Sowa, Mathew E. ;

Gygi, Steven P. ;

Harper, J. Wade .

NATURE, 2010, 466 (7302) :68-U84

[3] mTORC1 Phosphorylates the ULK1-mAtg13-FIP200 Autophagy Regulatory Complex [J].

Chan, Edmond Y. .

SCIENCE SIGNALING, 2009, 2 (84)

[4] Kinase-Inactivated ULK Proteins Inhibit Autophagy via Their Conserved C- Terminal Domains Using an Atg13-Independent Mechanism [J].

Chan, Edmond Y. W. ;

Longatti, Andrea ;

McKnight, Nicole C. ;

Tooze, Sharon A. .

MOLECULAR AND CELLULAR BIOLOGY, 2009, 29 (01) :157-171

[5] An Atg1/Atg13 Complex with Multiple Roles in TOR-mediated Autophagy Regulation [J].

Chang, Yu-Yun ;

Neufeld, Thomas P. .

MOLECULAR BIOLOGY OF THE CELL, 2009, 20 (07) :2004-2014

[6] Functional domains of the α1 catalytic subunit of the AMP-activated protein kinase [J].

Crute, BE ;

Seefeld, K ;

Gamble, J ;

Kemp, BE ;

Witters, LA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (52) :35347-35354

[7] Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer [J].

Fogarty, S. ;

Hardie, D. G. .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2010, 1804 (03) :581-591

[8] ULK1•ATG13•FIP200 Complex Mediates mTOR Signaling and Is Essential for Autophagy [J].

Ganley, Ian G. ;

Lam, Du H. ;

Wang, Junru ;

Ding, Xiaojun ;

Chen, She ;

Jiang, Xuejun .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (18) :12297-12305

[9] PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 [J].

Geisler, Sven ;

Holmstroem, Kira M. ;

Skujat, Diana ;

Fiesel, Fabienne C. ;

Rothfuss, Oliver C. ;

Kahle, Philipp J. ;

Springer, Wolfdieter .

NATURE CELL BIOLOGY, 2010, 12 (02) :119-U70

[10] AMPK phosphorylation of raptor mediates a metabolic checkpoint [J].

Gwinn, Dana M. ;

Shackelford, David B. ;

Egan, Daniel F. ;

Mihaylova, Maria M. ;

Mery, Annabelle ;

Vasquez, Debbie S. ;

Turk, Benjamin E. ;

Shaw, Reuben J. .

MOLECULAR CELL, 2008, 30 (02) :214-226

← 1 2 3 4 →