Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability

Nat Commun. 2020 Mar 17;11(1):1416. doi: 10.1038/s41467-020-15156-5.

Abstract

The kinase mTOR complex 1 (mTORC1) promotes cellular growth and is frequently dysregulated in cancers. In response to nutrients, mTORC1 is activated on lysosomes by Rag and Rheb guanosine triphosphatases (GTPases) and drives biosynthetic processes. How limitations in nutrients suppress mTORC1 activity remains poorly understood. We find that when amino acids are limited, the Rap1-GTPases confine lysosomes to the perinuclear region and reduce lysosome abundance, which suppresses mTORC1 signaling. Rap1 activation, which is independent of known amino acid signaling factors, limits the lysosomal surface available for mTORC1 activation. Conversely, Rap1 depletion expands the lysosome population, which markedly increases association between mTORC1 and its lysosome-borne activators, leading to mTORC1 hyperactivity. Taken together, we establish Rap1 as a critical coordinator of the lysosomal system, and propose that aberrant changes in lysosomal surface availability can impact mTORC1 signaling output.

Publication types

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

MeSH terms

  • Amino Acids / metabolism*
  • Humans
  • Lysosomes / enzymology
  • Lysosomes / genetics
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Signal Transduction
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / metabolism*
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • Amino Acids
  • RAP1A protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • RAP1B protein, human
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins