Proton-Assisted Amino Acid Transporter PAT1 Complexes with Rag GTPases and Activates TORC1 on Late Endosomal and Lysosomal Membranes

摘要: Mammalian Target of Rapamycin Complex 1 (mTORC1) is activated by growth factor-regulated phosphoinositide 3-kinase (PI3K)/Akt/Rheb signalling and extracellular amino acids (AAs) to promote proliferation. These AAs induce translocation mTOR late endosomes lysosomes (LELs), subsequent activation via mechanisms involving the presence intralumenal AAs, interaction between mTORC1 a multiprotein assembly containing Rag GTPases heterotrimeric Ragulator complex. However, which control these different aspects are not well understood. We have recently shown that intracellular Proton-assisted Amino acid Transporter (PAT1)/SLC36A1 an essential mediator AA-dependent activation. Here we demonstrate in Human Embryonic Kidney (HEK-293) cells PAT1 primarily located on LELs, physically interacts with required for normal relocalisation. also use powerful vivo genetic methodologies available Drosophila investigate regulation PAT1/Rag/Ragulator show GFP-tagged PATs reside at both cell surface LELs vivo, mirroring distribution several mammalian types. Elevated PI3K/Akt/Rheb increases levels synergistically enhances PAT-induced mechanism requiring endocytosis. In light recent identification vacuolar H(+)-ATPase as another Rag-interacting component, propose model function part AA-sensing engine drives from LEL compartments.