Termination of autophagy and reformation of lysosomes regulated by mTOR

Nature. 2010 Jun 17;465(7300):942-6. doi: 10.1038/nature09076. Epub 2010 Jun 6.

Abstract

Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell-a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.

Publication types

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

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Cell Line
  • Chlorocebus aethiops
  • HeLa Cells
  • Homeostasis / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Nutritional Physiological Phenomena*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Vero Cells

Substances

  • Intracellular Signaling Peptides and Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Protein-Serine-Threonine Kinases