title: eIF4A inactivates TORC1 in response to amino acid starvation.
abstract: Amino acids regulate TOR complex 1 (TORC1) via two counteracting mechanisms, one activating and one inactivating. The presence of amino acids causes TORC1 recruitment to lysosomes where TORC1 is activated by binding Rheb. How the absence of amino acids inactivates TORC1 is less well understood. Amino acid starvation recruits the TSC1/TSC2 complex to the vicinity of TORC1 to inhibit Rheb; however, the upstream mechanisms regulating TSC2 are not known. We identify here the eIF4A-containing eIF4F translation initiation complex as an upstream regulator of TSC2 in response to amino acid withdrawal in Drosophila We find that TORC1 and translation preinitiation complexes bind each other. Cells lacking eIF4F components retain elevated TORC1 activity upon amino acid removal. This effect is specific for eIF4F and not a general consequence of blocked translation. This study identifies specific components of the translation machinery as important mediators of TORC1 inactivation upon amino acid removal.
authors.affiliation: Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Foivos-Filippos
authors.initials: FF
authors.lastname: Tsokanos
authors.affiliation: Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Albert
authors.affiliation: Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Demetriades
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics and Heidelberg University, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Spirohn
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics and Heidelberg University, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
authors.affiliation: Division of Signal Transduction in Cancer and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany a.teleman@dkfz.de.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D000596:Amino Acids; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C533414:NAT1 protein, Drosophila; C570998:TORC1 protein complex, Drosophila; D014157:Transcription Factors; C117726:gig protein, Drosophila; D039601:Eukaryotic Initiation Factor-4A
keywords: lysosomes; mTOR; mTORC1; stress; translation