AI Article Synopsis
- Scientists found that when cells lack amino acids, a process happens that causes a protein called mTOR to get a special tag (ubiquitination), which stops it from doing its job.
- This happens because without enough amino acids, a type of molecule called tRNAs build up, which signals another protein called GCN2 to interact with mTOR.
- Their research shows a new way that cells can sense whether they have enough amino acids through a specific pathway involving GCN2 and another protein, FBXO22.
Article 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.
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| http://dx.doi.org/10.1016/j.cmet.2023.10.016 | DOI Listing |
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