PMID- 35977929 OWN - NLM STAT- MEDLINE DCOM- 20220819 LR - 20231107 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Aug 17 TI - AAA + ATPase Thorase inhibits mTOR signaling through the disassembly of the mTOR complex 1. PG - 4836 LID - 10.1038/s41467-022-32365-2 [doi] LID - 4836 AB - 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. CI - (c) 2022. The Author(s). FAU - Umanah, George K E AU - Umanah GKE AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. FAU - Abalde-Atristain, Leire AU - Abalde-Atristain L AUID- ORCID: 0000-0002-6292-7886 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Vollum Institute, Oregon Health & Science University, Portland, OR, 97239, USA. FAU - Khan, Mohammed Repon AU - Khan MR AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Mitra, Jaba AU - Mitra J AUID- ORCID: 0000-0001-6569-6203 AD - Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. AD - Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Dar, Mohamad Aasif AU - Dar MA AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Chang, Melissa AU - Chang M AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Tangella, Kavya AU - Tangella K AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - McNamara, Amy AU - McNamara A AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Bennett, Samuel AU - Bennett S AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Chen, Rong AU - Chen R AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Aggarwal, Vasudha AU - Aggarwal V AUID- ORCID: 0000-0001-9856-1292 AD - Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Cortes, Marisol AU - Cortes M AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Worley, Paul F AU - Worley PF AD - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Ha, Taekjip AU - Ha T AUID- ORCID: 0000-0003-2195-6258 AD - Departments of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD, 21205, USA. FAU - Dawson, Ted M AU - Dawson TM AUID- ORCID: 0000-0002-6459-0893 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. AD - Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. AD - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. AD - Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. FAU - Dawson, Valina L AU - Dawson VL AUID- ORCID: 0000-0002-2915-3970 AD - Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. AD - Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. AD - Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. AD - Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. AD - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. LA - eng SI - Dryad/10.5061/dryad.6wwpzgn25 GR - P30 AG066507/AG/NIA NIH HHS/United States GR - T32 GM007445/GM/NIGMS NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - P50 DA000266/DA/NIDA NIH HHS/United States GR - R35 NS097966/NS/NINDS NIH HHS/United States GR - P50 DA044123/DA/NIDA NIH HHS/United States GR - R35 GM122569/GM/NIGMS NIH HHS/United States GR - K01 NS099362/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20220817 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Amino Acids) RN - 0 (Regulatory-Associated Protein of mTOR) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - ATPases Associated with Diverse Cellular Activities/metabolism MH - *Amino Acids/metabolism MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Phosphorylation MH - Regulatory-Associated Protein of mTOR/metabolism MH - Sirolimus/pharmacology MH - *TOR Serine-Threonine Kinases/metabolism PMC - PMC9385847 COIS- The authors declare no competing interests. EDAT- 2022/08/18 06:00 MHDA- 2022/08/20 06:00 PMCR- 2022/08/17 CRDT- 2022/08/17 23:14 PHST- 2022/04/14 00:00 [received] PHST- 2022/07/26 00:00 [accepted] PHST- 2022/08/17 23:14 [entrez] PHST- 2022/08/18 06:00 [pubmed] PHST- 2022/08/20 06:00 [medline] PHST- 2022/08/17 00:00 [pmc-release] AID - 10.1038/s41467-022-32365-2 [pii] AID - 32365 [pii] AID - 10.1038/s41467-022-32365-2 [doi] PST - epublish SO - Nat Commun. 2022 Aug 17;13(1):4836. doi: 10.1038/s41467-022-32365-2.