1. Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy
- Author
-
Keisuke Tabata, Akiko Nozoe, Kanae Shirahama-Noda, Tamotsu Yoshimori, Takeshi Noda, and Shintaro Kira
- Subjects
Programmed cell death ,autophagy ,Saccharomyces cerevisiae Proteins ,GTPase-activating protein ,Mutant ,Vacuole ,GTPase ,Saccharomyces cerevisiae ,Biology ,BAG3 ,Animals ,Molecular Biology ,ATG16L1 ,Monomeric GTP-Binding Proteins ,Gtr1 ,Gtr2 ,Autophagy ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,RAG ,Basic Research Paper ,Cell biology ,TORC1 ,Biochemistry ,Protein Kinases ,Protein Binding ,Signal Transduction ,Transcription Factors - 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.
- Published
- 2014