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

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Science  16 Oct 2020:
Vol. 370, Issue 6514, pp. 351-356
DOI: 10.1126/science.aaz0863

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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


The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR–Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase–independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.

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