title: The Vam6 GEF controls TORC1 by activating the EGO complex.
abstract: The target of rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is activated by a variety of hormones (e.g., insulin) and nutrients (e.g., amino acids) and is deregulated in various cancers. Here, we report that the yeast Rag GTPase homolog Gtr1, a component of the vacuolar-membrane-associated EGO complex (EGOC), interacts with and activates TORC1 in an amino-acid-sensitive manner. Expression of a constitutively active (GTP-bound) Gtr1(GTP), which interacted strongly with TORC1, rendered TORC1 partially resistant to leucine deprivation, whereas expression of a growth inhibitory, GDP-bound Gtr1(GDP), caused constitutively low TORC1 activity. We also show that the nucleotide-binding status of Gtr1 is regulated by the conserved guanine nucleotide exchange factor (GEF) Vam6. Thus, in addition to its regulatory role in homotypic vacuolar fusion and vacuole protein sorting within the HOPS complex, Vam6 also controls TORC1 function by activating the Gtr1 subunit of the EGO complex.
authors.affiliation: Department of Medicine, University of Fribourg, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Binda
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Péli-Gulli
authors.forename: Grégory
authors.initials: G
authors.lastname: Bonfils
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panchaud
authors.forename: Jörg
authors.initials: J
authors.lastname: Urban
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sturgill
authors.forename: Robbie
authors.initials: R
authors.lastname: Loewith
authors.forename: Claudio
authors.initials: C
authors.lastname: De Virgilio
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D026905:Amino Acid Transport Systems / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000201:enzymology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D026905:Amino Acid Transport Systems; D000596:Amino Acids; D004268:DNA-Binding Proteins; C491145:GAP1 protein, S cerevisiae; C121263:GTR2 protein, S cerevisiae; C121262:Gtr1 protein, S cerevisiae; D020662:Guanine Nucleotide Exchange Factors; C501979:MEH1 protein, S cerevisiae; D046912:Multiprotein Complexes; D011500:Protein Synthesis Inhibitors; C062214:SWI4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C485218:Tco89 protein, S cerevisiae; D014157:Transcription Factors; C406817:VAM6 protein, S cerevisiae; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; C530964:SCH9 protein, S cerevisiae; C500749:target of rapamycin protein, S cerevisiae; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus