AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1

Nat Commun. 2022 Aug 17;13(1):4836. doi: 10.1038/s41467-022-32365-2.


The mechanistic target of rapamycin (mTOR) signals through the mTOR complex 1 (mTORC1) and the mTOR complex 2 to maintain cellular and organismal homeostasis. Failure to finely tune mTOR activity results in metabolic dysregulation and disease. While there is substantial understanding of the molecular events leading mTORC1 activation at the lysosome, remarkably little is known about what terminates mTORC1 signaling. Here, we show that the AAA + ATPase Thorase directly binds mTOR, thereby orchestrating the disassembly and inactivation of mTORC1. Thorase disrupts the association of mTOR to Raptor at the mitochondria-lysosome interface and this action is sensitive to amino acids. Lack of Thorase causes accumulation of mTOR-Raptor complexes and altered mTORC1 disassembly/re-assembly dynamics upon changes in amino acid availability. The resulting excessive mTORC1 can be counteracted with rapamycin in vitro and in vivo. Collectively, we reveal Thorase as a key component of the mTOR pathway that disassembles and thus inhibits mTORC1.

Publication types

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

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Amino Acids* / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Phosphorylation
  • Regulatory-Associated Protein of mTOR / metabolism
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases* / metabolism


  • Amino Acids
  • Regulatory-Associated Protein of mTOR
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • ATPases Associated with Diverse Cellular Activities
  • Sirolimus

Associated data

  • Dryad/10.5061/dryad.6wwpzgn25