FIGURE 3.

mTORC1 in amino acid regulation. In high amino acid conditions, Sestrin2 and CASTOR1 bind leucine and arginine, respectively. This induces their dissociation from GATOR2. Once released, GATOR2 inhibits by an unknown mechanism the activity of GATOR1, thereby preventing activation of the GTPase activity of RagA and RagB. In addition, high arginine levels sensed through the lysosomal transceptor SLC38A9 induce the release of GDP from RagA and RagB. High amino acid levels therefore maintain the binding of RagA and RagB to GTP. This allows Rags to recruit the mTORC1 complex to the lysosomal membrane, thereby allowing activation of the mTOR kinase by Rheb. The mTOR activation contributes to amino acid storage and consumption by activating protein synthesis through the phosphorylation of S6K and 4E-BP1. mTOR activation also blocks autophagy by phosphorylating the ULK1-ATG13-FIP200 complex, stopping the recycling and release of amino acids. Conversely, in low amino acid conditions, the mTORC1 complex remains free and inactive in the cytosol. Absence of S6K and 4E-BP1 phosphorylation impairs protein synthesis, contributing to amino acid saving. Dephosphorylation of the ULK1-ATG13-FIP200 complex initiates autophagy and lysosomal protein degradation, releasing free amino acids.