Amino Acids Regulate mTORC1 Activity Through Rag GTPase Dimer

Amino Acids Regulate mTORC1 Activity Through Rag GTPase Dimer

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Amino Acids Regulate mTORC1 Activity Through Rag GTPase Dimer

Amino Acids Regulate mTORC1 Activity Through Rag GTPase Dimer

Actually, I rarely read such purely mechanistic articles, but since mTORC1 is a classic signaling pathway, some newly discovered mechanisms may still be helpful for future explorations. The mTOR signaling pathway is recognized as a target of rapamycin, and my main focus is on adaptive immunity. In recent years, a group of scientists led by Professor Chi Hongbo has published several articles on how nutrients regulate T cell immunity through the mTOR signaling pathway, most of which are part of the CNS series. For example, the role of PI3K-AKT in regulating mTOR during proliferation has been addressed in many fields. As a cellular nutrient sensor, the mTOR signaling pathway plays an indispensable role. Today’s article mainly discusses how amino acids regulate the activity of mTORC1 through Rag GTPase. In mammals, Rag mainly consists of four proteins, forming two dimers: RagA/B and RagC/D.

The authors expressed individual Rag heterodimers in cell lines, where the differences in RagC/D determine the specificity of mTORC1 downstream sites. RagD promotes the phosphorylation of the downstream lysosomal substrates TFEB/TFE3. The authors demonstrate that different Rags perform different functions, with dimers containing RagD primarily responsible for recruiting and activating mTORC1 on lysosomes, mainly by increasing the affinity for the lysosomal LAMTOR complex, thereby more effectively recruiting mTORC1 to the lysosome. For non-lysosome-dependent functions, both RagC and D are involved in activation, such as S6K. RagA/B defines the cell’s response to amino acid signals; cells expressing RagB can resist starvation responses, maintaining lysosomal mTORC1 activity even under starvation conditions, with the dimers primarily responsible for resisting starvation. In previous studies, it was believed that the functions of these homologous pairs of Rags were somewhat redundant, suggesting that these two dimers could be interchangeable, which is quite fascinating. Various homologous family proteins may also possess such coding capabilities akin to codons, where different combinations may exert different functions.

Results:

  1. The RagC and RagD paralogues differentially regulate mTORC1;

  2. RagC and RagD differentially regulate lysosomal biogenesis;

  3. Enhanced association of RagD with lysosomes via p18/LAMTOR1;

  4. The RagC/D terminal regions define their distinct properties;

  5. Cancer-associated Rag C mutants upregulate lysosomal mTORC1;

  6. The RagA/B paralogues differently control mTORC1 in starvation;

  7. Structure-function analysis of RagA/B in AA starvation. (This part is quoted from the original text)

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Reference:

1. Gollwitzer P, Grützmacher N, Wilhelm S, Kümmel D, Demetriades C. A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids. Nat Cell Biol. 2022;24(9):1394-1406. doi:10.1038/s41556-022-00976-y

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