p27 controls Ragulator and mTOR activity in amino acid-deprived cells to regulate the autophagy-lysosomal pathway and coordinate cell cycle and cell growth

Nat Cell Biol. 2020 Sep;22(9):1076-1090. doi: 10.1038/s41556-020-0554-4. Epub 2020 Aug 17.

Abstract

Autophagy is a catabolic process whereby cytoplasmic components are degraded within lysosomes, allowing cells to maintain energy homeostasis during nutrient depletion. Several studies reported that the CDK inhibitor p27Kip1 promotes starvation-induced autophagy by an unknown mechanism. Here we find that p27 controls autophagy via an mTORC1-dependent mechanism in amino acid-deprived cells. During prolonged starvation, a fraction of p27 is recruited to lysosomes, where it interacts with LAMTOR1, a component of the Ragulator complex required for mTORC1 activation. Binding of p27 to LAMTOR1 prevents Ragulator assembly and mTORC1 activation, promoting autophagy. Conversely, p27-/- cells exhibit elevated mTORC1 signalling as well as impaired lysosomal activity and autophagy. This is associated with cytoplasmic sequestration of TFEB, preventing induction of the lysosomal genes required for lysosome function. LAMTOR1 silencing or mTOR inhibition restores autophagy and induces apoptosis in p27-/- cells. Together, these results reveal a direct coordinated regulation between the cell cycle and cell growth machineries.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Autophagy / physiology*
  • Cell Cycle / physiology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Signal Transduction / physiology*
  • Starvation / metabolism
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acids
  • Proliferating Cell Nuclear Antigen
  • p27 antigen
  • MTOR protein, human
  • TOR Serine-Threonine Kinases