Autophagy Machinery Mediates Macroendocytic Processing and Entotic Cell Death by Targeting Single Membranes

Nat Cell Biol. 2011 Oct 16;13(11):1335-43. doi: 10.1038/ncb2363.

Abstract

Autophagy normally involves the formation of double-membrane autophagosomes that mediate bulk cytoplasmic and organelle degradation. Here we report the modification of single-membrane vacuoles in cells by autophagy proteins. LC3 (Light chain 3) a component of autophagosomes, is recruited to single-membrane entotic vacuoles, macropinosomes and phagosomes harbouring apoptotic cells, in a manner dependent on the lipidation machinery including ATG5 and ATG7, and the class III phosphatidylinositol-3-kinase VPS34. These downstream components of the autophagy machinery, but not the upstream mammalian Tor (mTor)-regulated ULK-ATG13-FIP200 complex, facilitate lysosome fusion to single membranes and the degradation of internalized cargo. For entosis, a live-cell-engulfment program, the autophagy-protein-dependent fusion of lysosomes to vacuolar membranes leads to the death of internalized cells. As pathogen-containing phagosomes can be targeted in a similar manner, the death of epithelial cells by this mechanism mimics pathogen destruction. These data demonstrate that proteins of the autophagy pathway can target single-membrane vacuoles in cells in the absence of pathogenic organisms.

Publication types

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

MeSH terms

  • Autophagy*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Cell Line, Tumor
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Endocytosis*
  • Humans
  • Intracellular Membranes / metabolism*
  • Intracellular Membranes / pathology
  • Lysosomes / metabolism
  • Membrane Fusion
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • Time Factors
  • Transfection
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism
  • Vacuoles / metabolism*
  • Vacuoles / pathology

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Microtubule-Associated Proteins
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • light chain 3, human
  • Class III Phosphatidylinositol 3-Kinases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes