Rag GTPases regulate cellular amino acid homeostasis

Amino acids are essential sources for protein synthesis, being precursors of 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 acids I-amino acids, 9 amino acids need to be absorbed from nutrients, called essential amino acids. Our body has several systemic amino acid homeostatic regulations to ensure a constant and sufficient supply of amino acids by maintaining plasma concentrations of amino acids through absorption by the intestine/kidney and secretion by the liver/muscle. Therefore, short-term fasting (up to 48 h) generally does not decrease plasma amino acid concentrations, with the exception of alanine, which is used for hepatic gluconeogenesis, and even long-term fasting term (up to 6 weeks) only modestly decreases amino acids (1). However, chronic malnutrition, such as Kwashiorkor, is known to significantly decrease blood amino acid concentrations (2). In addition to systemic regulations of amino acid homeostasis, cells also maintain intracellular amino acid concentrations by multiple mechanisms, including transporter/endocytosis-mediated uptake, biosynthesis, and proteasome-mediated proteolysis. /lysosome. Additionally, 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 can play an important role in adjusting the concentrations of cytoplasmic proteinogenic amino acids (eg, essential amino acids), preventing their oxidation and providing building blocks for necessary protein synthesis.

Recent studies using primarily HEK293T cells have demonstrated that the mechanistic target rapamycin complex 1 (mTORC1), which is activated by amino acids, controls the abundance of amino acids, especially essential amino acids, in lysosomes in response to the availability of amino acids in a way…

1To whom correspondence may be addressed. E-mail: inokik{at}umich.edu Where kuguan{at}ucsd.edu.

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