Rags connect mTOR and autophagy

Abstract

mTOR, the master regulator of protein metabolism, is activated by growth factor signaling, amino acids and other nutrients. Emerging evidence indicates that an unexpected physical association between mTOR and lysosomes plays a critical role in amino acid mediated mTOR activation. Rag GTPases, together with a multi-protein complex called Ragulator, mediate amino acid-mediated mTOR recruitment to the lysosome surface where mTOR becomes activated. Furthermore, mTOR is also recruited to a unique cytoplasmic compartment composed of autolysosomes, which is observed in oncogenic Ras-induced senescent (RIS) cells. Formation of this TOR-autophagy spatial coupling compartment (TASCC) seems to allow activation of mTOR and autophagy in a mutually reinforcing manner. Proper formation of the TASCC also requires active Rag proteins. Interestingly, inhibition of activity of Rag proteins also suppresses acute induction of secretory protein synthesis during RIS. Thus, the TASCC provides evidence for the functional relevance of the Rag-mediated association between lysosomes and mTOR, and provides a mechanism for the simultaneous activation of anabolic and catabolic processes. © 2012 Landes Bioscience.