Home LiteratureArticle Details
PMID: 21266992 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The phospholipase D1 pathway modulates macroautophagy.

Nature communications ·Vol. 1 ·2010-00-00 ·Pages 142

Dall'Armi C, Hurtado-Lorenzo A, Tian H, Morel E, Nezu A, Chan RB, Yu WH, Robinson KS, Yeku O, Small SA, Duff K, Frohman MA, Wenk MR, Yamamoto A, Di Paolo G

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Androstadienes/pharmacology Animals Autophagy/drug effects,genetics,physiology Blotting, Western CHO Cells Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors,metabolism Cricetinae Cricetulus Fluorescent Antibody Technique HeLa Cells Humans Mice Mice, Knockout Microscopy, Confocal Microscopy, Electron Microtubule-Associated Proteins/genetics,metabolism Phospholipase D/genetics,metabolism Sequestosome-1 Protein Signal Transduction/drug effects,genetics Wortmannin tau Proteins/metabolism
Chemicals
Adaptor Proteins, Signal Transducing Androstadienes MAP1LC3A protein, human Microtubule-Associated Proteins SQSTM1 protein, human Sequestosome-1 Protein tau Proteins Class III Phosphatidylinositol 3-Kinases Phospholipase D phospholipase D1 Wortmannin
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Dall'Armi Claudia
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
Hurtado-Lorenzo Andrés
Tian Huasong
Morel Etienne
Nezu Akiko
Chan Robin B
Yu W Haung
Robinson Kimberly S
Yeku Oladapo
Small Scott A
Duff Karen
Frohman Michael A
Wenk Markus R
Yamamoto Akitsugu
Di Paolo Gilbert
References (57)
57 references, click to expand
  1. Regulation of autophagy by phosphatidylinositol 3-phosphate.
    FEBS Lett. 2010 Apr 2;584(7):1302-12 PMID: 20074568
  2. mTOR signaling: PLD takes center stage.
    Cell Cycle. 2008 Oct;7(20):3118-23 PMID: 18927511
  3. Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs.
    J Cell Biol. 2003 Jul 21;162(2):305-15 PMID: 12876278
  4. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum.
    J Cell Biol. 2008 Aug 25;182(4):685-701 PMID: 18725538
  5. Phospholipase D1 regulates secretagogue-stimulated insulin release in pancreatic beta-cells.
    J Biol Chem. 2004 Jun 25;279(26):27534-41 PMID: 15087463
  6. Loss of autophagy in the central nervous system causes neurodegeneration in mice.
    Nature. 2006 Jun 15;441(7095):880-4 PMID: 16625205
  7. Autophagy fights disease through cellular self-digestion.
    Nature. 2008 Feb 28;451(7182):1069-75 PMID: 18305538
  8. Phospholipase D1 production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granules at a late stage.
    J Biol Chem. 2007 Jul 27;282(30):21746-57 PMID: 17540765
  9. Intracellular localization of phospholipase D1 in mammalian cells.
    Mol Biol Cell. 2001 Apr;12(4):943-55 PMID: 11294898
  10. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network.
    EMBO Rep. 2001 Apr;2(4):330-5 PMID: 11306555
  11. An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure.
    Mol Biol Cell. 2008 Nov;19(11):4651-9 PMID: 18768752
  12. Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes.
    J Biol Chem. 1998 Aug 21;273(34):21883-92 PMID: 9705327
  13. Phospholipase D and the SNARE Sso1p are necessary for vesicle fusion during sporulation in yeast.
    J Cell Sci. 2006 Apr 1;119(Pt 7):1406-15 PMID: 16554438
  14. Regulation of mTOR by phosphatidic acid?
    Cancer Res. 2007 Jan 1;67(1):1-4 PMID: 17210675
  15. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation.
    J Cell Biol. 2010 Feb 22;188(4):537-46 PMID: 20156962
  16. Insulin-stimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by phospholipase D1.
    Mol Biol Cell. 2005 Jun;16(6):2614-23 PMID: 15772157
  17. Molecular mechanisms of PLD function in membrane traffic.
    Traffic. 2008 Aug;9(8):1233-9 PMID: 18422860
  18. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation.
    Nat Cell Biol. 2009 Dec;11(12):1433-7 PMID: 19898463
  19. Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells.
    J Biol Chem. 2000 Jan 14;275(2):992-8 PMID: 10625637
  20. The role of autophagy during the early neonatal starvation period.
    Nature. 2004 Dec 23;432(7020):1032-6 PMID: 15525940
  21. Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits.
    J Neurosci. 2010 Dec 8;30(49):16419-28 PMID: 21147981
  22. Phospholipase D1 is an effector of Rheb in the mTOR pathway.
    Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8286-91 PMID: 18550814
  23. Retroviruses human immunodeficiency virus and murine leukemia virus are enriched in phosphoinositides.
    J Virol. 2008 Nov;82(22):11228-38 PMID: 18799574
  24. In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome.
    J Cell Biol. 1990 Aug;111(2):329-45 PMID: 2166050
  25. Regulation of macroautophagy by mTOR and Beclin 1 complexes.
    Biochimie. 2008 Feb;90(2):313-23 PMID: 17928127
  26. WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy.
    Oncogene. 2004 Dec 16;23(58):9314-25 PMID: 15602573
  27. Mechanism of membrane binding of the phospholipase D1 PX domain.
    J Biol Chem. 2004 Dec 24;279(52):54918-26 PMID: 15475361
  28. Organotypic slice cultures from transgenic mice as disease model systems.
    J Mol Neurosci. 2002 Dec;19(3):317-20 PMID: 12540058
  29. A diacylglycerol-dependent signaling pathway contributes to regulation of antibacterial autophagy.
    Cell Host Microbe. 2010 Aug 19;8(2):137-46 PMID: 20674539
  30. Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1.
    Sci Signal. 2010 Jan 05;3(103):ra1 PMID: 20051593
  31. Regulation of membrane traffic by phosphoinositide 3-kinases.
    J Cell Sci. 2006 Feb 15;119(Pt 4):605-14 PMID: 16467569
  32. Phospholipase D1 localises to secretory granules and lysosomes and is plasma-membrane translocated on cellular stimulation.
    Curr Biol. 1998 Jul 2;8(14):835-8 PMID: 9663393
  33. Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy.
    J Cell Biol. 2002 Aug 19;158(4):761-72 PMID: 12186856
  34. 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis.
    Mol Pharmacol. 2009 Mar;75(3):437-46 PMID: 19064628
  35. Bap31 is an itinerant protein that moves between the peripheral endoplasmic reticulum (ER) and a juxtanuclear compartment related to ER-associated Degradation.
    Mol Biol Cell. 2008 May;19(5):1825-36 PMID: 18287538
  36. Analysis of intact phosphoinositides in biological samples.
    J Lipid Res. 2006 Jul;47(7):1588-96 PMID: 16632799
  37. Autophagy gone awry in neurodegenerative diseases.
    Nat Neurosci. 2010 Jul;13(7):805-11 PMID: 20581817
  38. Phospholipase D in brain function and Alzheimer's disease.
    Biochim Biophys Acta. 2010 Aug;1801(8):799-805 PMID: 20399893
  39. Autophagosome formation: core machinery and adaptations.
    Nat Cell Biol. 2007 Oct;9(10):1102-9 PMID: 17909521
  40. Potential therapeutic applications of autophagy.
    Nat Rev Drug Discov. 2007 Apr;6(4):304-12 PMID: 17396135
  41. A role for phosphatidic acid in COPI vesicle fission yields insights into Golgi maintenance.
    Nat Cell Biol. 2008 Oct;10(10):1146-53 PMID: 18776900
  42. Phospholipase D1 is specifically required for regulated secretion of von Willebrand factor from endothelial cells.
    Blood. 2009 Jan 22;113(4):973-80 PMID: 18945966
  43. Evidence for fusion between multilamellar endosomes and autophagosomes in HeLa cells.
    Eur J Cell Biol. 1997 Apr;72(4):307-13 PMID: 9127730
  44. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes.
    J Cell Biol. 2009 Sep 21;186(6):773-82 PMID: 19797076
  45. Molecular dissection of autophagy: two ubiquitin-like systems.
    Nat Rev Mol Cell Biol. 2001 Mar;2(3):211-6 PMID: 11265251
  46. Inhibition of autophagic-lysosomal delivery and autophagic lactolysis by asparagine.
    J Cell Biol. 1991 Jun;113(6):1305-12 PMID: 1904444
  47. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway.
    Proc Natl Acad Sci U S A. 2010 May 18;107(20):9424-9 PMID: 20439739
  48. Phosphoinositides in phagolysosome and autophagosome biogenesis.
    Biochem Soc Symp. 2007;(74):141-8 PMID: 17233587
  49. Autophagy and multivesicular bodies: two closely related partners.
    Cell Death Differ. 2009 Jan;16(1):70-8 PMID: 19008921
  50. Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.
    Nat Chem Biol. 2009 Feb;5(2):108-17 PMID: 19136975
  51. The regulation and function of Class III PI3Ks: novel roles for Vps34.
    Biochem J. 2008 Feb 15;410(1):1-17 PMID: 18215151
  52. Measurement of phospholipase D activity.
    Anal Biochem. 1997 Oct 1;252(1):1-9 PMID: 9324933
  53. Phospholipase D: a lipid centric review.
    Cell Mol Life Sci. 2005 Oct;62(19-20):2305-16 PMID: 16143829
  54. Phospholipase D in calcium-regulated exocytosis: lessons from chromaffin cells.
    Biochim Biophys Acta. 2009 Sep;1791(9):936-41 PMID: 19289180
  55. Toward unraveling membrane biogenesis in mammalian autophagy.
    Curr Opin Cell Biol. 2008 Aug;20(4):401-7 PMID: 18472412
  56. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms.
    J Neurochem. 2003 Aug;86(3):582-90 PMID: 12859672
  57. Regulation of membrane biogenesis in autophagy via PI3P dynamics.
    Semin Cell Dev Biol. 2010 Sep;21(7):671-6 PMID: 20403452
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms1144
Published
2010-00-00
Pages
142
Language
English
Region
England
NLM ID
101528555
PMCID
PMC3328354
Subset
IM
Grants
NIGMS NIH HHS · R01 GM071520 · United States
NIGMS NIH HHS · R01 GM71520 · United States
NINDS NIH HHS · R01 NS056049-04 · United States
NINDS NIH HHS · R01 NS056049-03 · United States
NINDS NIH HHS · R01 NS056049-05 · United States
NINDS NIH HHS · R01 NS056049 · United States
NIGMS NIH HHS · T32 GM007367 · United States
NIA NIH HHS · P50 AG008702 · United States
External Links
PubMed source DOI: 10.1038/ncomms1144 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2