Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy

Molecular Biology of the Cell - Tập 20 Số 7 - Trang 1981-1991 - 2009
Nao Hosokawa1, Taichi Hara1, Takeshi Kaizuka1, Chieko Kishi1, Akito Takamura1, Yutaka Miura1, Shun-ichiro Iemura2, Tohru Natsume2, Kenji Takehana3, Naoyuki Yamada4,5, Jun‐Lin Guan6, Noriko Oshiro7, Noboru Mizushima1
1Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
2Biological Systems Control Team, Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan;
3Exploratory Research, Pharmaceutical Research Laboratory, and
4Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114
5Institute of Life Sciences, Ajinomoto Co., Kawasaki 210-8681, Japan;
6Department of Internal Medicine-MMG, University of Michigan Medical School, Ann Arbor, MI 48109; and
7Biosignal Research Center, Kobe University, Kobe 657-8501, Japan

Tóm tắt

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 ∼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 ∼3-MDa ULK1–Atg13–FIP200 complex.

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Molecular Biology of the Cell

Tập 20 Số 7

1981-1991

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