ESCRTs and Fab1 Regulate Distinct Steps of Autophagy

Curr Biol. 2007 Oct 23;17(20):1817-25. doi: 10.1016/j.cub.2007.09.032. Epub 2007 Oct 11.

Abstract

Eukaryotes use autophagy to turn over organelles, protein aggregates, and cytoplasmic constituents. The impairment of autophagy causes developmental defects, starvation sensitivity, the accumulation of protein aggregates, neuronal degradation, and cell death [1, 2]. Double-membraned autophagosomes sequester cytoplasm and fuse with endosomes or lysosomes in higher eukaryotes [3], but the importance of the endocytic pathway for autophagy and associated disease is not known. Here, we show that regulators of endosomal biogenesis and functions play a critical role in autophagy in Drosophila melanogaster. Genetic and ultrastructural analysis showed that subunits of endosomal sorting complex required for transport (ESCRT)-I, -II and -III, as well as their regulatory ATPase Vps4 and the endosomal PtdIns(3)P 5-kinase Fab1, all are required for autophagy. Although the loss of ESCRT or Vps4 function caused the accumulation of autophagosomes, probably because of inhibited fusion with the endolysosomal system, Fab1 activity was necessary for the maturation of autolysosomes. Importantly, reduced ESCRT functions aggravated polyglutamine-induced neurotoxicity in a model for Huntington's disease. Thus, this study links ESCRT function with autophagy and aggregate-induced neurodegeneration, thereby providing a plausible explanation for the fact that ESCRT mutations are involved in inherited neurodegenerative disease in humans [4].

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Autophagy / genetics
  • Autophagy / physiology*
  • Base Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • DNA Primers / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology*
  • Drosophila melanogaster / ultrastructure
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / physiology
  • Endosomes / ultrastructure
  • Genes, Insect
  • Larva / ultrastructure
  • Microscopy, Electron, Transmission
  • Models, Biological
  • Mutation
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*

Substances

  • Carrier Proteins
  • DNA Primers
  • Drosophila Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Vps25 protein, Drosophila
  • Fab1 protein, Drosophila
  • Phosphotransferases (Alcohol Group Acceptor)