Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy

Nao Hosokawa; Taichi Hara; Takeshi Kaizuka; Chieko Kishi; Akito Takamura; Yutaka Miura; Shun-ichiro Iemura; Tohru Natsume; Kenji Takehana; Naoyuki Yamada; Jun-Lin Guan; Noriko Oshiro; Noboru Mizushima

doi:10.1091/mbc.e08-12-1248

Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy

Mol Biol Cell. 2009 Apr;20(7):1981-91. doi: 10.1091/mbc.e08-12-1248. Epub 2009 Feb 11.

Authors

Nao Hosokawa¹, Taichi Hara, Takeshi Kaizuka, Chieko Kishi, Akito Takamura, Yutaka Miura, Shun-ichiro Iemura, Tohru Natsume, Kenji Takehana, Naoyuki Yamada, Jun-Lin Guan, Noriko Oshiro, Noboru Mizushima

Affiliation

¹ Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*

Substances

ATG13 protein, human
Adaptor Proteins, Signal Transducing
Amino Acids
Autophagy-Related Proteins
Intracellular Signaling Peptides and Proteins
Multiprotein Complexes
Proteins
Rb1cc1 protein, mouse
Transcription Factors
Protein Kinases
MTOR protein, human
mTOR protein, mouse
Autophagy-Related Protein-1 Homolog
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
Ulk1 protein, mouse