Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Cell |
| Year | 2014 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cell.2014.01.024 · PMID 24529380 · Free full text (PMC4346203) |
TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1.
| Intervention | Biochemical/genetic (Rag / TSC2) |
| Target | TORC1 / Rag GTPases / TSC2 |
| Model | Mammalian cells |
| Effect | Upon amino-acid starvation the Rag GTPases recruit TSC2 to the lysosome to inactivate TORC1 |