title: Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy.
abstract: Autophagy is an intracellular degradation process that delivers cytosolic material to lysosomes and vacuoles. To investigate the mechanisms that regulate autophagy, we performed a genome-wide screen using a yeast deletion-mutant collection, and found that Npr2 and Npr3 mutants were defective in autophagy. Their mammalian homologs, NPRL2 and NPRL3, were also involved in regulation of autophagy. Npr2-Npr3 function upstream of Gtr1-Gtr2, homologs of the mammalian RRAG GTPase complex, which is crucial for TORC1 regulation. Both npr2∆ mutants and a GTP-bound Gtr1 mutant suppressed autophagy and increased Tor1 vacuole localization. Furthermore, Gtr2 binds to the TORC1 subunit Kog1. A GDP-bound Gtr1 mutant induced autophagy even under nutrient-rich conditions, and this effect was dependent on the direct binding of Gtr2 to Kog1. These results revealed that 2 molecular mechanisms, Npr2-Npr3-dependent GTP hydrolysis of Gtr1 and direct binding of Gtr2 to Kog1, are involved in TORC1 inactivation and autophagic induction.
authors.affiliation: Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan; Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kira
authors.affiliation: Laboratory of Viral Infection; International Research Center for Infectious Diseases; Research Institute for Microbial Diseases; Osaka University; Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tabata
authors.affiliation: Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Shirahama-Noda
authors.affiliation: Graduate School of Medicine, Osaka University; Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nozoe
authors.affiliation: Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan; Graduate School of Medicine, Osaka University; Osaka, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.affiliation: Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan; Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noda
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C121263:GTR2 protein, S cerevisiae; C121262:Gtr1 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; C092275:NPR2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; C066958:NPR1 protein, S cerevisiae; D011494:Protein Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: GTPase-activating protein; Gtr1; Gtr2; RAG; TORC1; autophagy