Amino Acids in Autophagy: Regulation and Function.

Autophagy is a dynamic process in which the eukaryotic cells break down intracellular components by lysosomal degradation. Under the normal condition, the basal level of autophagy removes damaged organelles, misfolded proteins, or protein aggregates to keep cells in a homeostatic condition. Deprivation of nutrients (e.g., removal of amino acids) stimulates autophagy activity, promoting lysosomal degradation and the recycling of cellular components for cell survival. Importantly, insulin and amino acids are two main inhibitors of autophagy. They both activate the mTOR complex 1 (mTORC1) signaling pathway to inhibit the autophagy upstream of the uncoordinated-51 like kinase 1/2 (ULK1/2) complex that triggers autophagosome formation. In particular, insulin activates mTORC1 via the PI3K class I-AKT pathway; while amino acids activate mTORC1 either through the PI3K class III (hVps34) pathway or through a variety of amino acid sensors located in the cytosol or lysosomal membrane. These amino acid sensors control the translocation of mTORC1 from the cytosol to the lysosomal surface where mTORC1 is activated by Rheb GTPase, therefore regulating autophagy and the lysosomal protein degradation.