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ESCRTs and Fab1 regulate distinct steps of autophagy
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Rusten, Tor Erik, Vaccari, Thomas, Lindmo, Karine, Rodahl, Lina M.W., Nezis, I. P., Sem-Jacobsen, Catherine, Wendler, Franz, Vincent, Jean-Paul, Brech, Andreas, Bilder, David and Stenmark, H. (Harald) (2007) ESCRTs and Fab1 regulate distinct steps of autophagy. Current Biology, Volume 17 (Number 20). pp. 1817-1825. doi:10.1016/j.cub.2007.09.032 ISSN 0960-9822.
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Official URL: http://dx.doi.org/10.1016/j.cub.2007.09.032
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] .
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Current Biology | ||||
Publisher: | Cell Press | ||||
ISSN: | 0960-9822 | ||||
Official Date: | October 2007 | ||||
Dates: |
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Volume: | Volume 17 | ||||
Number: | Number 20 | ||||
Page Range: | pp. 1817-1825 | ||||
DOI: | 10.1016/j.cub.2007.09.032 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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