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

Abstract

The Rags represent a unique family of evolutionarily conserved, heterodimeric, lysosome-localized small GTPases that play an indispensible role in regulating cellular metabolism in response to various amino acid signaling mechanisms. Rapid progress in the field 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 mTORC1 signaling in the presence of abundant amino acids. Conversely, Rag inactivation plays an indispensible role 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.

Keywords: Rags; TFE3; TFEB; autophagy; lysosomes; mTOR.

Figure 1.

Rags localize to the lysosome surface and serve as a signaling scaffold for mTORC1 activation in response to cellular nutrient levels. Under nutrient rich conditions, Rags promote mTORC1 lysosomal localization where it is activated and promotes an anabolic signaling environment to promote cellular growth and proliferation. Under conditions of low nutrient availability, mTORC1 dissociates from the Rags at the lysosome surface and the cell switches to a catabolic metabolic program featuring increased autophagy and lysosome biogenesis, which serves to restore cellular nutrient pools.

Figure 2.

Rags signal amino acid availability through a variety of nutrient sensors that modulate nucleotide binding status. Positive regulators of Rag signaling are shown in green while negative regulators are shown in red.

Figure 3.

Rags coordinate lysosome biogenesis and autophagy induction at the lysosome surface. The Rag GTPases sense amino acid availability and serve as a signal integration hub for mTORC1 activation. Another small GTPase, Rheb, coordinates signaling in response to growth factor signals and cellular energy level cues via AKT and AMPK, which positively and negatively regulate Rheb through TSC. Under anabolic signaling conditions, mTORC1 activates protein synthesis through phosphorylation of intermediaries such as 4EBP1 and S6K. Under catabolic conditions, autophagy and lysosomal biogenesis is induced via de-repression of TFEB and TFE3 at the lysosome surface.