Regulation of TORC1 in Response to Amino Acid Starvation via Lysosomal Recruitment of TSC2
Menées in vitro, ces deux études mettent en évidence des mécanismes par lesquels le complexe suppresseur de tumeurs TSC1-TSC2 régule la désactivation de mTORC1
TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1. "TSC2 is recruited by the Rag GTPases to lysosomes upon amino acid starvation "TSC2 is required for complete inactivation of TORC1 upon amino acid starvation "Loss of TSC2 causes Rheb-mediated lysosomal retention of mTOR upon aa starvation "TSC2 is required for the correct physiological response of cells to aa starvation Localization of the TORC1 inhibitor TSC2 to the lysosomes facilitates inactivation of both Rheb and Rag GTPases and allows TORC1 to be released from the lysosome.
Cell 2014