Sestrins function as guanine nucleotide dissociation inhibitors for rag GTPases to control mTORC1 signaling Journal Article

Authors: Peng, M.; Yin, N.; Li, M. O.
Article Title: Sestrins function as guanine nucleotide dissociation inhibitors for rag GTPases to control mTORC1 signaling
Abstract: 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.
Keywords: signal transduction; controlled study; unclassified drug; gene mutation; gene translocation; nonhuman; protein function; animal cell; mouse; phenotype; allele; gene overexpression; cell growth; protein protein interaction; embryo development; in vivo study; in vitro study; phosphorylation; gene activation; regulatory mechanism; sequence alignment; gene control; cell size; alanine; gene dosage; nutrient; enzyme binding; hydrolysis; diet restriction; lysine; arginine; lysosome; null allele; cell membrane permeability; guanosine triphosphatase; mammalian target of rapamycin complex 1; hydroxymethylglutaryl coenzyme a reductase kinase; guanine nucleotide dissociation inhibitor; article; kwashiorkor; hela cell line; raga guanosine triphosphatase; ragb guanosine triphosphatase; ragc guanosine triphosphatase; sestrin
Journal Title: Cell
Volume: 159
Issue: 1
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2014-09-25
Start Page: 122
End Page: 133
Language: English
DOI: 10.1016/j.cell.2014.08.038
PROVIDER: scopus
PMCID: PMC4181352
PUBMED: 25259925
Notes: Export Date: 3 November 2014 -- Source: Scopus
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MSK Authors
  1. Min Peng
    5 Peng
  2. Ming Li
    67 Li
  3. Na Yin
    4 Yin