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

George K E Umanah1,2,3, Leire Abalde-Atristain1,2,4,5, Mohammed Repon Khan1,2

  • 1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Nature Communications
|August 17, 2022
PubMed

Insights

The AAA+ ATPase Thorase directly binds mTOR, inhibiting mTORC1 signaling by orchestrating complex disassembly. This discovery reveals Thorase as a crucial component in regulating mTORC1 activity and cellular homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is crucial for cellular and organismal homeostasis.
  • Dysregulation of mTOR activity leads to metabolic disorders.
  • While mTORC1 activation is well-studied, the mechanisms terminating mTORC1 signaling remain largely unknown.

Purpose of the Study:

  • To identify novel regulators of mTORC1 signaling termination.
  • To elucidate the molecular mechanisms by which mTORC1 signaling is inactivated.

Main Methods:

  • Biochemical assays to study protein-protein interactions.
  • Cellular models to investigate mTORC1 dynamics.
  • In vitro and in vivo experiments to assess Thorase function.

Main Results:

  • The AAA+ ATPase Thorase directly binds to mTOR.
  • Thorase facilitates the disassembly and inactivation of mTORC1 by disrupting the mTOR-Raptor interaction at the mitochondria-lysosome interface.
  • Loss of Thorase leads to persistent mTORC1 signaling and altered dynamics in response to amino acid availability.
  • Excessive mTORC1 signaling due to Thorase deficiency can be inhibited by rapamycin.

Conclusions:

  • Thorase is a key regulator that actively disassembles and inhibits mTORC1.
  • Understanding Thorase's role provides new insights into controlling mTORC1 signaling and metabolic diseases.

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