title: Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2.
abstract: Rag GTPases assemble into heterodimeric complexes consisting of RagA or RagB and RagC or RagD in higher eukaryotes, or Gtr1 and Gtr2 in yeast, to relay amino acid signals toward the growth-regulating target of rapamycin complex 1 (TORC1). The TORC1-stimulating state of Rag GTPase heterodimers, containing GTP- and GDP-loaded RagA/B/Gtr1 and RagC/D/Gtr2, respectively, is maintained in part by the FNIP-Folliculin RagC/D GAP complex in mammalian cells. Here, we report the existence of a similar Lst4-Lst7 complex in yeast that functions as a GAP for Gtr2 and that clusters at the vacuolar membrane in amino acid-starved cells. Refeeding of amino acids, such as glutamine, stimulated the Lst4-Lst7 complex to transiently bind and act on Gtr2, thereby entailing TORC1 activation and Lst4-Lst7 dispersal from the vacuolar membrane. Given the remarkable functional conservation of the RagC/D/Gtr2 GAP complexes, our findings could be relevant for understanding the glutamine addiction of mTORC1-dependent cancers.
authors.affiliation: Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Péli-Gulli
authors.affiliation: Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sardu
authors.affiliation: Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panchaud
authors.affiliation: Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
authors.forename: Serena
authors.initials: S
authors.lastname: Raucci
authors.affiliation: Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland. Electronic address: claudio.devirgilio@unifr.ch.
authors.forename: Claudio
authors.initials: C
authors.lastname: De Virgilio
mesh_terms: D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D015966:Gene Expression Regulation, Fungal; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; C121263:GTR2 protein, S cerevisiae; C121262:Gtr1 protein, S cerevisiae; C513355:LST4 protein, S cerevisiae; C513356:LST7 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D005973:Glutamine; D020559:Monomeric GTP-Binding Proteins