Rag GTPases regulate cellular amino acid homeostasis

Amino acids are essential sources for synthesizing proteins, being precursors for hormones/neurotransmitters and key anaplerotic metabolites for the tricarboxylic acid cycle and gluconeogenesis. While mammalian cells can synthesize the majority of amino acids from other metabolic intermediates, among the 20 proteinogenic l-amino acids, 9 amino acids are required to be absorbed from nutrients, called essential amino acids. Our body possesses multiple layered systemic amino acid homeostatic regulations to ensure a constant and sufficient amino acid supply by maintaining plasma amino acid concentrations through intestine/kidney-mediated absorption and liver/muscle-mediated secretion. Hence, short-term fasting (up to 48 h) generally does not decrease plasma concentrations of amino acids except alanine, which is utilized for hepatic gluconeogenesis, and even long-term fasting (up to 6 wk) only decreases amino acids modestly (1). However, it has been known that chronic malnutrition, such as Kwashiorkor, significantly decreases amino acid concentrations in blood (2). In addition to the systemic regulations of amino acid homeostasis, cells also maintain intracellular concentrations of amino acids through multiple mechanisms, including transporter/endocytosis-mediated absorption, biosynthesis, and proteasome/lysosome-mediated proteolysis. Moreover, cellular amino acids can regulate their sensing pathways, which also modulate amino acid production, consumption, and temporal storage in organelles such as lysosomes. This storage mechanism may have important roles in adjusting concentrations of cytoplasmic proteinogenic amino acids (e.g., essential amino acids), preventing their oxidation and supplying building blocks for needed protein synthesis. Recent studies mainly using HEK293T cells demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1), which is activated by amino acids, controls the abundance of amino acids, particularly essential amino acids, in lysosomes in response to amino acid availability in a manner … [↵][1]1To whom correspondence may be addressed. Email: inokik{at}umich.edu or kuguan{at}ucsd.edu. [1]: #xref-corresp-1-1