title: mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle.
abstract: In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2α eIF2α phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115 USA.
authors.forename: Issam
authors.initials: I
authors.lastname: Ben-Sahra
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115 USA.
authors.forename: Gerta
authors.initials: G
authors.lastname: Hoxhaj
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115 USA.
authors.forename: Stéphane J H
authors.initials: SJH
authors.lastname: Ricoult
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115 USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000235:genetics; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011687:Purines / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D015852:Eukaryotic Initiation Factor-2; D046912:Multiprotein Complexes; D011687:Purines; D013763:Tetrahydrofolates; D051701:Activating Transcription Factor 4; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D045064:Methenyltetrahydrofolate Cyclohydrolase