Rags to riches: Amino acid sensing by the Rag GTPases in health and disease

摘要

The Rags represent a unique family of evolutionary conserved, heterodimeric, lysosome-iocalized small GTPases that play an indispensible role in regulating cellular metabolism in response to various amino acid signaling mechanisms. Rapid progress in thefield has begun to unveil a picture in which Rags act as central players in translating information regarding cellular amino acid levels by modulating their nucleotide binding status through an ensemble of support proteins localized in and around the lysosomes. By cooperating with other signaling pathways that converge on the lysosomes, Rags promote anabolic processes through positively affecting mTORG signaling in the presence of abundant amino acids. Conversely, Rag inactivation plays an indispensiblerole in switching cellular metabolism into a catabolic paradigm by promoting the activity of the master lysosomal/autophagic transcription factors TFEB and TFE3. Precise control of Rag signaling is necessary for cells to adapt to constantly changing cellular demands and emerging evidence has highlighted their importance in a wide variety of developmental and pathological conditions.