Amino acid-dependent regulation of autophagy by mTORC1 Amino acid-dependent regulation of autophagy by mTORC1 Schematic representation of the cellular signalling pathways governed by amino acids in the regulation of autophagy via mTORC1. Amino acid sufficiency activates the mTORC1 pathway which inhibits autophagy at multiple steps. Although the best-characterized mechanism via which mTORC1 inhibits autophagy involves the direct control of ULK1, mTORC1 also regulates Atg14-containing Vps34 complex and TFEB. In amino acid-rich conditions, mTORC1 binds to, phosphorylates and thereby inactivates the autophagy initiators ULK1 and Atg13, which are present in a complex with FIP200 and Atg101. Likewise, mTORC1 phosphorylates TFEB and TFE3 and this event facilitates the interaction between TFEB and TFE3 and the cytosolic chaperone 14-3-3 which retains them in the cytoplasm. In the absence of activating stimuli, autophagy is induced through the dissociation of mTORC1 from the ULK1 complex, thus relieving the inhibition of ULK1 which is then responsible of its own phosphorylation as well as phosphorylation of Atg13, FIP200 and Raptor. ULK1 is then able to activate this PI3K complex and promote autophagosome synthesis. In addition, mTORC1 inactivation leads to relocalization of TFEB and TFE3 to the nucleus where they cause the expression of multiple lysosomal and autophagy-related genes. This allows the cell to maintain a critical level of energy and metabolites for surviving the starvation condition. Yoana Rabanal-Ruiz et al. Essays Biochem. 2017;61:565-584 ©2017 by Portland Press Ltd