title: Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival.
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 (RagA(GTP)) from its endogenous promoter. RagA(GTP/GTP) mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagA(GTP/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 RagA(GTP/GTP) neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagA(GTP/GTP) mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagA(GTP/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 RagA(GTP/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.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Alejo
authors.initials: A
authors.lastname: Efeyan
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.forename: Steven
authors.initials: S
authors.lastname: Chang
authors.forename: Iwona
authors.initials: I
authors.lastname: Gumper
authors.forename: Harriet
authors.initials: H
authors.lastname: Snitkin
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Wolfson
authors.forename: Oktay
authors.initials: O
authors.lastname: Kirak
authors.forename: David D
authors.initials: DD
authors.lastname: Sabatini
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism / Q000502:physiology*; D001343:Autophagy / Q000235:genetics*; D001786:Blood Glucose / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D055879:Gene Knock-In Techniques; D007003:Hypoglycemia / Q000235:genetics; D053208:Kaplan-Meier Estimate; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020558:GTP Phosphohydrolases