Figure 5.

Role of lysosomes in amino acid sensing. Amino acids transporters, such as PAT1 and SLC38A9, regulate amino acids efflux from lysosomes and their concentration in the lysosomal lumen. Lysosomal vATPase acts as an amino acid sensor. Increased amino acid levels weaken the interaction between vATPase and Ragulator, promoting the exchange of GTP for GDP on RagC/D by Ragulator. Additionally, SLC38A9 acts as GEF towards RagA/B, whereas FLCN-FNIP2 exhibits GAP activity towards RagC/D. RagA/B is negatively regulated by GATOR1, whose activity is, in turn, antagonized by GATOR2. In presence of cytoplasmic amino acids, Sestrin2 and CASTOR1 suppress Rags and GATOR2 activities, respectively. KICKSTOR docks GATOR1 on lysosomal surface in an amino acid-independent manner. Met metabolism is sensed by SAMTOR, disrupting the SAMTOR–GATOR1–KICKSTOR complex and preventing mTORC1 inactivation by GATOR1. Furthermore, Rags activity may be controlled directly by Leu and Gln metabolism. Once activated, the Rag complex (RagA/B-GTP/RagC/D-GDP) recruits mTORC1 to lysosomal membranes in close proximity to its upstream activator, Rheb, leading to mTORC1 activation. Within minutes following mTORC1 activation, Rags are released from the lysosomal surface to the cytoplasm, thereby controlling the extent of mTORC1 response.