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Vol. 20, Issue 7, 1981-1991, April 1, 2009
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*Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; Biological Systems Control Team, Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan; Exploratory Research, Pharmaceutical Research Laboratory, and ||Institute of Life Sciences, Ajinomoto Co., Kawasaki 210-8681, Japan; ¶Department of Internal Medicine-MMG, University of Michigan Medical School, Ann Arbor, MI 48109; and #Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
Submitted December 30, 2008;
Revised February 3, 2009;
Accepted February 4, 2009
Monitoring Editor: Sandra L. Schmid
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.
These authors contributed equally to this work.
@ Present address: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
Address correspondence to: Noboru Mizushima (nmizu.phy2{at}tmd.ac.jp)
Abbreviations used: ATG, autophagy-related genes; FIP200, Focal adhesion kinase family interacting protein of 200 kDa; GFP, green fluorescent protein; LC3, microtubule-associated protein light chain 3; MEF, mouse embryonic fibroblast; (m)TOR, (mammalian) target of rapamycin; mTORC, mTOR complex; ULK, uncoordinated 51-like kinase.
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