AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.
Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92130, USA.
Joungmok
J
Kim
Mondira
M
Kundu
Benoit
B
Viollet
Kun-Liang
KL
Guan
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D012694:Serine; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
PLoS One. 2010 Nov 03;5(11):e15394
21072212
J Cell Biol. 2000 Sep 18;150(6):1507-13
10995454
Circ Res. 2007 Mar 30;100(6):914-22
17332429
Mol Cell. 2008 Apr 25;30(2):214-26
18439900
Mol Biol Cell. 2009 Apr;20(7):2004-14
19225150
Nature. 2010 Jul 1;466(7302):68-76
20562859
Curr Biol. 2003 May 13;13(10):797-806
12747827
Autophagy. 2008 Feb;4(2):151-75
18188003
Biochem Soc Trans. 2009 Feb;37(Pt 1):232-6
19143638
J Biol Chem. 2007 Aug 31;282(35):25464-74
17595159
Cell. 2003 Nov 26;115(5):577-90
14651849
Autophagy. 2009 Aug;5(6):758-65
19411825
Nat Cell Biol. 2003 Jun;5(6):578-81
12771962
Curr Opin Cell Biol. 2010 Apr;22(2):226-33
19945837
J Cell Sci. 2006 Sep 15;119(Pt 18):3888-900
16940348
Annu Rev Genet. 2009;43:67-93
19653858
J Biol Chem. 2009 May 1;284(18):12297-305
19258318
Curr Top Microbiol Immunol. 2004;279:73-84
14560952
J Clin Invest. 2001 Oct;108(8):1167-74
11602624
Curr Biol. 2010 Jun 22;20(12):1093-8
20537536
Nat Cell Biol. 2007 Feb;9(2):218-24
17237771
J Biol Chem. 2006 Nov 17;281(46):34870-9
16990266
Curr Opin Cell Biol. 2010 Apr;22(2):132-9
20056399
Diabetes. 2002 Aug;51(8):2420-5
12145153
Mol Cell Proteomics. 2006 Apr;5(4):749-57
16340016
Nat Rev Mol Cell Biol. 2009 Jul;10(7):458-67
19491929
FEBS Lett. 2010 Apr 2;584(7):1417-26
20096689
Cell Microbiol. 2010 Jan;12(1):10-8
19888990
Nutr Rev. 2009 Dec;67(12):677-89
19941614
Nat Cell Biol. 2002 Sep;4(9):648-57
12172553
EMBO J. 2009 Mar 18;28(6):677-85
19197243
J Cell Biol. 2008 May 5;181(3):497-510
18443221
FEBS J. 2008 Sep;275(17):4263-70
18637946
Genes Dev. 2003 Aug 1;17(15):1829-34
12869586
J Biol Chem. 2010 Mar 19;285(12):9100-13
20080969
Curr Opin Drug Discov Devel. 2010 Jan;13(1):31-40
20047144
Curr Top Microbiol Immunol. 2009;335:141-67
19802564
Curr Top Microbiol Immunol. 2009;335:107-21
19802562
Cell Cycle. 2007 Aug 1;6(15):1837-49
17671424
Nat Cell Biol. 2007 Oct;9(10):1102-9
17909521
Mol Biol Cell. 2005 May;16(5):2544-53
15743910
Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85
17712357
FEBS Lett. 2010 Apr 2;584(7):1287-95
20083114
J Mol Biol. 2002 Mar 22;317(2):309-23
11902845
Mol Biol Cell. 2009 Apr;20(7):1992-2003
19225151
Semin Cell Dev Biol. 2010 Sep;21(7):664-70
20359542
Mol Cell Biol. 2010 Feb;30(4):1049-58
19995911
Gene. 1997 Jun 19;192(2):207-13
9224892
Mol Biol Cell. 2009 Apr;20(7):1981-91
19211835
Autophagy. 2009 Oct;5(7):973-9
19597335
Cell. 2006 Feb 10;124(3):471-84
16469695