The phospholipase D1 pathway modulates macroautophagy

Nat Commun. 2010;1:142. doi: 10.1038/ncomms1144.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Androstadienes / pharmacology
  • Animals
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy / physiology*
  • Blotting, Western
  • CHO Cells
  • Class III Phosphatidylinositol 3-Kinases / antagonists & inhibitors
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Cricetinae
  • Cricetulus
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Microscopy, Electron
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Phospholipase D / genetics
  • Phospholipase D / metabolism*
  • Sequestosome-1 Protein
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Wortmannin
  • tau Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Microtubule-Associated Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • light chain 3, human
  • tau Proteins
  • Class III Phosphatidylinositol 3-Kinases
  • Phospholipase D
  • phospholipase D1
  • Wortmannin