Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival

Mice expressing a constitutively active form of RagA are unable to inhibit mTORC1 after birth and to trigger autophagy, and succumb perinatally. The mTOR complex 1 (mTORC1) pathway is a major regulator of growth in eukaryotes and a drug target for common diseases including cancer and neurodegeneration. It is known that mTORC1 senses amino acids through the Rag family of GTPases, but their physiological importance is unknown. David M. Sabatini and colleagues show that following birth, which stops the maternal nutrient supply, mTORC1 is inhibited in mice in a Rag-dependent fashion. This inhibition triggers autophagy, which promotes the release of amino acids needed to sustain plasma glucose levels via gluconeogenesis between birth and suckling. Thus the Rag pathway acts as a general nutrient sensor, and through its regulation of mTORC1, helps maintain nutrient homeostasis and survival in neonates. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors1. Cell-based studies showed that mTORC1 senses amino acids through the RagA–D family of GTPases2,3 (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagAGTP) from its endogenous promoter. RagAGTP/GTP mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagAGTP/GTP neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-acid concentrations. In contrast, mTORC1 inhibition does not occur in RagAGTP/GTP neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagAGTP/GTP mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagAGTP/GTP neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagAGTP/GTP neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagAGTP/GTP fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.