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; Valina L Dawson

doi:10.1038/s41467-022-32365-2

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.

Authors

George K E Umanah^#^{1

2

3}, Leire Abalde-Atristain^#^{1

2

4

5}, Mohammed Repon Khan^#^{1

2}, Jaba Mitra^{6

7}, Mohamad Aasif Dar^{1

2}, Melissa Chang^{1

2}, Kavya Tangella^{1

2}, Amy McNamara^{1

2}, Samuel Bennett^{1

2}, Rong Chen^{1

2}, Vasudha Aggarwal⁷, Marisol Cortes^{1

2}, Paul F Worley⁸, Taekjip Ha⁹, Ted M Dawson^{10

11

12

13

14}, Valina L Dawson^{15

16

17

18

19}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
³ Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁵ Vollum Institute, Oregon Health & Science University, Portland, OR, 97239, USA.
⁶ Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
⁷ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA.
⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁹ Departments of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD, 21205, USA.
¹⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹² Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹³ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹⁴ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.
¹⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu.
¹⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu.
¹⁷ Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu.
¹⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu.
¹⁹ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu.

^# Contributed equally.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding