RRC ID 72405
Author Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N.
Title Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy.
Journal Mol Biol Cell
Abstract Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the approximately 3-MDa ULK1-Atg13-FIP200 complex.
Volume 20(7)
Pages 1981-91
Published 2009-4-1
DOI 10.1091/mbc.e08-12-1248
PII E08-12-1248
PMID 19211835
PMC PMC2663915
MeSH Adaptor Proteins, Signal Transducing / metabolism* Amino Acids / deficiency Amino Acids / pharmacology* Animals Autophagy / drug effects* Autophagy-Related Protein-1 Homolog Autophagy-Related Proteins Cell Line Cell Membrane / drug effects Cell Membrane / enzymology Cell Membrane / ultrastructure Humans Intracellular Signaling Peptides and Proteins / metabolism* Mechanistic Target of Rapamycin Complex 1 Mice Molecular Weight Multiprotein Complexes Phosphorylation / drug effects Protein Binding / drug effects Protein Kinases / metabolism Protein Serine-Threonine Kinases / metabolism* Protein Transport / drug effects Proteins TOR Serine-Threonine Kinases Transcription Factors / metabolism*
IF 3.791
DNA material pMXs-IP-EGFP-hATG13 (RDB19625) pME18s-HA-hFIP200 (RDB19769) pEGFP-C1-hAtg13 (RDB19770) p3xFLAG-CMV10-hAtg13 (RDB19771) p3xFLAG-CMV14-mULK1 (RDB19772)