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. 2019 Jun 20;7:113. doi: 10.3389/fcell.2019.00113

FIGURE 4.

FIGURE 4

Amino acid dependent regulation of mTORC1. mTORC1 activity is modulated by the levels of specific amino acids within the lumen of lysosomes and in the cytosol. Information about luminal amino acids is transduced by an inside-out mechanism to mTORC1 present on the cytosolic surface, while cytosolic amino acid levels is sensed by cytosolic complexes that associate with the lysosome surface to modulate mTORC1. The following is a simplified series of steps that modulate mTORC1 both during high (A) and low (B) levels of leucine and arginine. (A) High amino acid conditions: (1) High levels of intraluminal arginine promotes leucine transport into the lysosome via SLC38A9. (2) FLCN-mediated inhibition of PAT1 amino acid transporter staunches leucine flow out of the lysosome, helping to amass leucine within the lysosome further; (3) Higher levels of leucine promote V-ATPase activity. (4) V-ATPase and SLC38A9 then promote Ragulator and interactions with Rag heterodimers. (5) Ragulator is a GEF for RagA/B, and together with folliculin, a GAP for RagC/D, helps form GTP-RagA/B::GDP-RagC/D heterodimer. (6) Active Ragulator and Rag heterodimers now recruit and activate mTORC1 on the lysosome surface. (7) Meanwhile, in the cytosol, cytosolic leucine and arginine bind to and inhibits sestrins and CASTOR1, respectively. This prevents sestrins and CASTOR from compromising GATOR2. (8) Ultimately, this allows for GATOR2 to bind and block GATOR1, a negative modulator of mTORC1. Together, both cytosolic and luminal amino acid sensors boost mTORC1 activity on lysosomes. (B) During low levels of amino acids: (1) Low intraluminal amino acids compromise inside out mediated activation of mTORC1. (2) The absence of arginine leads to a halt in leucine import via SLC38A9. (3) With no leucine in the lumen, the V-ATPase is unable to activate Ragulator and Rag GTPase heterodimers. (4) In addition, low cytosolic leucine prompts leucine export from the lysosome via PAT1, further depleting luminal leucine. (5) Decreased levels of cytosolic amino acids relieve sestrins and CASTOR1 from inhibition. (6) Free Sestrins and CASTOR1 can now bind and handicap GATOR2, freeing GATOR1. (7) GATOR1 is then recruited to the lysosome by the lysosome-associated KICSTOR, which further suppresses Ragulator/Rag GTPases. (8) Rag heterodimers take on GDP-RagA/B::GTP-RagC/D inhibitory conformation. (9) All these changes result in the release of mTORC1 from the lysosome and its suppression, thus initiating catabolic cellular programs.