Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling

• Published in: Cell Vol. 159; no. 1; pp. 122 - 133
• Main Authors: Peng, Min, Yin, Na, Li, Ming O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2014
• Subjects: Amino Acid Sequence; Amino Acids - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Animals, Newborn; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Embryo, Mammalian - cytology; Female; Fibroblasts - metabolism; Gene Knock-In Techniques; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Molecular Sequence Data; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pregnancy; Sequence Alignment; Signal Transduction; Starvation - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.08.038

Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here, we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino-acid-induced Rag guanine nucleotide exchange and mTORC1 translocation to the lysosome. Mutation of the conserved GDI motif creates a dominant-negative form of Sestrin that renders mTORC1 activation insensitive to amino acid deprivation, whereas a cell-permeable peptide containing the GDI motif inhibits mTORC1 signaling. Mice deficient in all Sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting. These findings reveal a nonredundant mechanism by which the Sestrin family of GDIs regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling. [Display omitted] •Sestrins prevent amino-acid-induced mTORC1 recruitment to the lysosome•Sestrins are guanine nucleotide dissociation inhibitors for RagA and RagB•A cell-permeable peptide containing the GDI motif inhibits mTORC1 activation•Sestrin deficiency renders mTORC1 signaling insensitive to nutrient status in vivo Sestrins inhibits GDP dissociation from Rags GTPases, thereby modulating the role of mTORC1 in nutrient sensing.