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Vol. 20, Issue 7, 1992-2003, April 1, 2009
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*Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455; and Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105
Submitted December 30, 2008;
Revised February 2, 2009;
Accepted February 5, 2009
Monitoring Editor: Sandra L. Schmid
Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.
Address correspondence to: Do-Hyung Kim: (dhkim{at}umn.edu)
Abbreviations used: Atg, Autophagy-related gene; FIP200, focal adhesion kinase (FAK) family interacting protein of 200 kDa; GST, glutathione S-transferase; LC3, microtubule-associated protein 1 light chain 3; MBP, myelin basic protein; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin; Rheb, Ras homolog enriched in brain; shRNA, short hairpin RNA; ULK1, Unc-51-like kinase 1; ULK2, Unc-51-like kinase 2; S6K1, S6 kinase 1.
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