A major determinant of mTORC1 activity is its shuttling between the lysosomal surface and the cytoplasm, with nutrients like amino acids (AAs) and glucose promoting its recruitment to lysosomes via interactions with the Rag GTPases.

Active mTORC1 phosphorylates multiple distinct substrates to regulate various cellular functions at different subcellular locations. (See also our recent @NatureCellBio paper for more details on this 👇) nature.com/articles/s41556-0…

Importantly, how mTORC1 that is activated on lysosomes is released to meet its non-lysosomal targets elsewhere was not known. Moreover, whether mTORC1 activity itself impacts on its localization had not been investigated previously.

Here, we show that #pharmacological or #genetic inhibition of mTORC1 activity prevents its release from the lysosomal surface, even under conditions of nutrient #starvation or lysosomal dysfunction.

The increased localization of mTORC1 on lysosomes is accompanied by elevated and sustained phosphorylation of its #rapamycin-resistant, non-canonical lysosomal targets, like #TFEB.

Mechanistically, ‘inactive’ mTORC1 causes persistent activation of the #Rag dimer, particularly RagA, which in turn is responsible for the forced mTORC1 tethering on lysosomes, even upon nutrient starvation.

Therefore, not only the #recruitment but also the #release of mTORC1 from the lysosomal surface is an active process mediated by the Rags. This is a mechanism via which active mTORC1 licenses its own release from lysosomes, likely to ensure that its cycling is not futile.

Don't forget to also check the accompanying paper from the Zwartkruis group @UMCUtrecht! Congratulations to all authors! 👏 cell.com/molecular-cell/full…