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Dryad
Published August 29, 2022 | Version v1
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AAA+ ATPase Thorase Inhibits mTOR Signaling Through the Disassembly of the mTOR Complex 1

Creators

  • 1. Johns Hopkins Medicine

Description

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.

Notes

Funding provided by: National Institute of Neurological Disorders and Stroke
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000065
Award Number: NS099362

Funding provided by: National Institute of Neurological Disorders and Stroke
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000065
Award Number: R35NS09796

Funding provided by: National Institute of General Medical Sciences
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000057
Award Number: GM122569

Funding provided by: National Institute on Drug Abuse
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000026
Award Number: DA000266

Funding provided by: National Institute on Drug Abuse
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000026
Award Number: DA044123

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Additional details

Related works

Is cited by
10.1038/s41467-022-32365-2 (DOI)
Is derived from
10.5061/dryad.6wwpzgn25 (DOI)