title: ESCRTs and Fab1 regulate distinct steps of autophagy.
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].
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, N-0310 Oslo, Norway.
authors.forename: Tor Erik
authors.initials: TE
authors.lastname: Rusten
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaccari
authors.forename: Karine
authors.initials: K
authors.lastname: Lindmo
authors.forename: Lina M W
authors.initials: LM
authors.lastname: Rodahl
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Nezis
authors.forename: Catherine
authors.initials: C
authors.lastname: Sem-Jacobsen
authors.forename: Franz
authors.initials: F
authors.lastname: Wendler
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vincent
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: David
authors.initials: D
authors.lastname: Bilder
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000502:physiology / Q000648:ultrastructure; D017344:Genes, Insect; D007814:Larva / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C511665:Vps25 protein, Drosophila; C514108:Fab1 protein, Drosophila; D017853:Phosphotransferases (Alcohol Group Acceptor)