Format

Send to

Choose Destination
Autophagy. 2014 Sep;10(9):1565-78. doi: 10.4161/auto.29397. Epub 2014 Jun 30.

Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy.

Author information

1
Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan; Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan.
2
Laboratory of Viral Infection; International Research Center for Infectious Diseases; Research Institute for Microbial Diseases; Osaka University; Osaka, Japan.
3
Center for Frontier Oral Science; Graduate School of Dentistry; Osaka University, Osaka, Japan.
4
Graduate School of Medicine, Osaka University; Osaka, Japan.
5
Graduate School of Frontier Bioscience; Osaka University; Osaka, Japan; Graduate School of Medicine, Osaka University; Osaka, Japan.

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.

KEYWORDS:

GTPase-activating protein; Gtr1; Gtr2; RAG; TORC1; autophagy

PMID:
25046117
PMCID:
PMC4206535
DOI:
10.4161/auto.29397
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center