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

George K. E. Umanah, Leire Abalde-Atristain, Mohammed Repon Khan, Jaba Mitra, Mohamad Aasif Dar, Melissa Chang, Kavya Tangella, Amy McNamara, Samuel Bennett, Rong Chen, Vasudha Aggarwal, Marisol Cortes, Paul F. Worley, Taekjip Ha, Ted M. Dawson () and Valina L. Dawson ()
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George K. E. Umanah: Johns Hopkins University School of Medicine
Leire Abalde-Atristain: Johns Hopkins University School of Medicine
Mohammed Repon Khan: Johns Hopkins University School of Medicine
Jaba Mitra: University of Illinois at Urbana-Champaign
Mohamad Aasif Dar: Johns Hopkins University School of Medicine
Melissa Chang: Johns Hopkins University School of Medicine
Kavya Tangella: Johns Hopkins University School of Medicine
Amy McNamara: Johns Hopkins University School of Medicine
Samuel Bennett: Johns Hopkins University School of Medicine
Rong Chen: Johns Hopkins University School of Medicine
Vasudha Aggarwal: Johns Hopkins University
Marisol Cortes: Johns Hopkins University School of Medicine
Paul F. Worley: Johns Hopkins University School of Medicine
Taekjip Ha: JHU Howard Hughes Medical Institute
Ted M. Dawson: Johns Hopkins University School of Medicine
Valina L. Dawson: Johns Hopkins University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32365-2

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