The GATOR–Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids

Intricacies of amino acid sensing The way in which cells sense amino acids derived from external proteins taken up by micropinocytosis and then degraded in the lysosome turns out to be different from the way in which they sense external amino acids taken up through transporters in the plasma membrane. Both sources of amino acids end up activating the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase complex. However, Hesketh et al. found that cultured human cells sense amino acids derived from exogenous proteins in late endosomes by a mechanism independent of the Rag guanosine triphosphatases (GTPases) that control mTORC1 activation in response to external amino acids. Furthermore, the GATOR GTPase had an inhibitory effect on mTORC1 activation in response to proteins processed through the lysosome, opposite to its role in sensing amino acids taken up across the plasma membrane. Science , this issue p. 351