2. Academic Validation
  3. The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency

The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency

  • Cell Metab. 2023 Nov 11:S1550-4131(23)00385-6. doi: 10.1016/j.cmet.2023.10.016.
Meng-Kai Ge 1,  Cheng Zhang 2,  Na Zhang 3,  Ping He 2,  Hai-Yan Cai 4,  Song Li 5,  Shuai Wu 3,  Xi-Li Chu 3,  Yu-Xue Zhang 3,  Hong-Ming Ma 3,  Li Xia 3,  Shuo Yang 3,  Jian-Xiu Yu 3,  Shi-Ying Yao 6,  Xiao-Long Zhou 6,  Bing Su 7,  Guo-Qiang Chen 8,  Shao-Ming Shen 9
Affiliations

Affiliations

  • 1 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer and Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No. 2019RU043), Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China.
  • 2 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer and Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No. 2019RU043), Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China.
  • 3 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China.
  • 4 Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 5 Shanghai Institute of Immunology, Department of Immunology and Microbiology, SJTU-SM, Shanghai 200025, China.
  • 6 State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, SJTU-SM, Shanghai 200025, China. Electronic address: bingsu@sjtu.edu.cn.
  • 8 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer and Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No. 2019RU043), Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Hainan Academy of Medical Sciences, Hainan Medical University, Hainan 571199, China. Electronic address: chengq@shsmu.edu.cn.
  • 9 Institute of Aging & Tissue Regeneration, State Key Laboratory of Systems Medicine for Cancer and Stress and Cancer Research Unit of Chinese Academy of Medical Sciences (No. 2019RU043), Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200127, China; Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, China. Electronic address: smshen@shsmu.edu.cn.
PMID: 37979583 DOI: 10.1016/j.cmet.2023.10.016
Abstract

Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular Amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.

Keywords

FBXO22; GCN2; amino acids; mTOR; mTORC1; ubiquitination; uncharged tRNA.

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