Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3
inactivates TORC1 and induces autophagy |
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Authors: | Shintaro Kira Keisuke Tabata Kanae Shirahama-Noda Akiko Nozoe Tamotsu Yoshimori Takeshi Noda |
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Institution: | 1.Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan;2.Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan;3.Laboratory of Viral Infection; International Research Center for Infectious Diseases; Research Institute for Microbial Diseases; Osaka University; Osaka, Japan;4.Graduate School of Medicine, Osaka University; Osaka, Japan |
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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. |
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Keywords: | autophagy GTPase-activating protein Gtr1 Gtr2 RAG TORC1 |
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