The phospholipase D1 pathway modulates macroautophagy.
Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. Here, we show that phospholipase D1 (PLD1), which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation. The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of Tau and p62 aggregates in organotypic brain slices. Our in vitro and in vivo findings establish a role for PLD1 in autophagy.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
Claudia
C
Dall'Armi
Andrés
A
Hurtado-Lorenzo
Huasong
H
Tian
Etienne
E
Morel
Akiko
A
Nezu
Robin B
RB
Chan
W Haung
WH
Yu
Kimberly S
KS
Robinson
Oladapo
O
Yeku
Scott A
SA
Small
Karen
K
Duff
Michael A
MA
Frohman
Markus R
MR
Wenk
Akitsugu
A
Yamamoto
Gilbert
G
Di Paolo
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D016466:CHO Cells; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077191:Wortmannin; D016875:tau Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016875:tau Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; C106801:phospholipase D1; D000077191:Wortmannin
FEBS Lett. 2010 Apr 2;584(7):1302-12
20074568
Cell Cycle. 2008 Oct;7(20):3118-23
18927511
J Cell Biol. 2003 Jul 21;162(2):305-15
12876278
J Cell Biol. 2008 Aug 25;182(4):685-701
18725538
J Biol Chem. 2004 Jun 25;279(26):27534-41
15087463
Nature. 2006 Jun 15;441(7095):880-4
16625205
Nature. 2008 Feb 28;451(7182):1069-75
18305538
J Biol Chem. 2007 Jul 27;282(30):21746-57
17540765
Mol Biol Cell. 2001 Apr;12(4):943-55
11294898
EMBO Rep. 2001 Apr;2(4):330-5
11306555
Mol Biol Cell. 2008 Nov;19(11):4651-9
18768752
J Biol Chem. 1998 Aug 21;273(34):21883-92
9705327
J Cell Sci. 2006 Apr 1;119(Pt 7):1406-15
16554438
Cancer Res. 2007 Jan 1;67(1):1-4
17210675
J Cell Biol. 2010 Feb 22;188(4):537-46
20156962
Mol Biol Cell. 2005 Jun;16(6):2614-23
15772157
Traffic. 2008 Aug;9(8):1233-9
18422860
Nat Cell Biol. 2009 Dec;11(12):1433-7
19898463
J Biol Chem. 2000 Jan 14;275(2):992-8
10625637
Nature. 2004 Dec 23;432(7020):1032-6
15525940
J Neurosci. 2010 Dec 8;30(49):16419-28
21147981
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8286-91
18550814
J Virol. 2008 Nov;82(22):11228-38
18799574
J Cell Biol. 1990 Aug;111(2):329-45
2166050
Biochimie. 2008 Feb;90(2):313-23
17928127
Oncogene. 2004 Dec 16;23(58):9314-25
15602573
J Biol Chem. 2004 Dec 24;279(52):54918-26
15475361
J Mol Neurosci. 2002 Dec;19(3):317-20
12540058
Cell Host Microbe. 2010 Aug 19;8(2):137-46
20674539
Sci Signal. 2010 Jan 05;3(103):ra1
20051593
J Cell Sci. 2006 Feb 15;119(Pt 4):605-14
16467569
Curr Biol. 1998 Jul 2;8(14):835-8
9663393
J Cell Biol. 2002 Aug 19;158(4):761-72
12186856
Mol Pharmacol. 2009 Mar;75(3):437-46
19064628
Mol Biol Cell. 2008 May;19(5):1825-36
18287538
J Lipid Res. 2006 Jul;47(7):1588-96
16632799
Nat Neurosci. 2010 Jul;13(7):805-11
20581817
Biochim Biophys Acta. 2010 Aug;1801(8):799-805
20399893
Nat Cell Biol. 2007 Oct;9(10):1102-9
17909521
Nat Rev Drug Discov. 2007 Apr;6(4):304-12
17396135
Nat Cell Biol. 2008 Oct;10(10):1146-53
18776900
Blood. 2009 Jan 22;113(4):973-80
18945966
Eur J Cell Biol. 1997 Apr;72(4):307-13
9127730
J Cell Biol. 2009 Sep 21;186(6):773-82
19797076
Nat Rev Mol Cell Biol. 2001 Mar;2(3):211-6
11265251
J Cell Biol. 1991 Jun;113(6):1305-12
1904444
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9424-9
20439739
Biochem Soc Symp. 2007;(74):141-8
17233587
Cell Death Differ. 2009 Jan;16(1):70-8
19008921
Nat Chem Biol. 2009 Feb;5(2):108-17
19136975
Biochem J. 2008 Feb 15;410(1):1-17
18215151
Anal Biochem. 1997 Oct 1;252(1):1-9
9324933
Cell Mol Life Sci. 2005 Oct;62(19-20):2305-16
16143829
Biochim Biophys Acta. 2009 Sep;1791(9):936-41
19289180
Curr Opin Cell Biol. 2008 Aug;20(4):401-7
18472412
J Neurochem. 2003 Aug;86(3):582-90
12859672
Semin Cell Dev Biol. 2010 Sep;21(7):671-6
20403452