mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination

Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination. Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination. The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiencyGe et al.Cell MetabolismNovember 17, 2023In BriefGe et al. unravel a novel mechanism of amino acid sensing by mTORC1, in which amino acid depletion-caused accumulation of uncharged tRNAs stimulates GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at K2066 to inhibit mTORC1 kinase activity by preventing substrate recruitment. Full-Text PDF