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

A Efeyan, R Zoncu, S Chang, I Gumper, H Snitkin… - Nature, 2013 - nature.com
A Efeyan, R Zoncu, S Chang, I Gumper, H Snitkin, RL Wolfson, O Kirak, DD Sabatini
Nature, 2013nature.com
The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal
growth in response to many environmental cues, including nutrients and growth factors. Cell-
based studies showed that mTORC1 senses amino acids through the RagA–D family of
GTPases,(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. RagA GTP/GTP mice develop …
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors. Cell-based studies showed that mTORC1 senses amino acids through the RagA–D family of GTPases, (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.
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