Discovery of Atg5/Atg7-independent alternative macroautophagy

Nature. 2009 Oct 1;461(7264):654-8. doi: 10.1038/nature08455.

Abstract

Macroautophagy is a process that leads to the bulk degradation of subcellular constituents by producing autophagosomes/autolysosomes. It is believed that Atg5 (ref. 4) and Atg7 (ref. 5) are essential genes for mammalian macroautophagy. Here we show, however, that mouse cells lacking Atg5 or Atg7 can still form autophagosomes/autolysosomes and perform autophagy-mediated protein degradation when subjected to certain stressors. Although lipidation of the microtubule-associated protein light chain 3 (LC3, also known as Map1lc3a) to form LC3-II is generally considered to be a good indicator of macroautophagy, it did not occur during the Atg5/Atg7-independent alternative process of macroautophagy. We also found that this alternative process of macroautophagy was regulated by several autophagic proteins, including Unc-51-like kinase 1 (Ulk1) and beclin 1. Unlike conventional macroautophagy, autophagosomes seemed to be generated in a Rab9-dependent manner by the fusion of isolation membranes with vesicles derived from the trans-Golgi and late endosomes. In vivo, Atg5-independent alternative macroautophagy was detected in several embryonic tissues. It also had a function in clearing mitochondria during erythroid maturation. These results indicate that mammalian macroautophagy can occur through at least two different pathways: an Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Autophagy-Related Protein-1 Homolog
  • Beclin-1
  • Etoposide / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Food Deprivation
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Atg5 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, mouse
  • Microtubule-Associated Proteins
  • Etoposide
  • Phosphatidylinositol 3-Kinases
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • Ulk1 protein, mouse
  • rab9 protein, mouse
  • rab GTP-Binding Proteins
  • Autophagy-Related Protein 7