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J. Biol. Chem., Vol. 281, Issue 46, 34870-34879, November 17, 2006

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AMP-activated Protein Kinase and the Regulation of Autophagic Proteolysis^*

Daniel Meley¹, Chantal Bauvy, Judith H. P. M. Houben-Weerts, Peter F. Dubbelhuis, Mariette T. J. Helmond, Patrice Codogno, and Alfred J. Meijer²

From the INSERM U756, Faculté de Pharmacie, Université Paris-Sud 11, 92296 Châtenay-Malabry, France and the Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands

Interruption of mTOR-dependent signaling by rapamycin is known to stimulate autophagy, both in mammalian cells and in yeast. Because activation of AMPK also inhibits mTOR-dependent signaling one would expect stimulation of autophagy by AMPK activation. According to the literature, this is true for yeast but, unexpectedly, not for mammalian cells on the basis of the use of AICAR, a pharmacological activator of AMPK. In the present study, carried out with hepatocytes, HT-29 cells, and HeLa cells, we have reexamined the possible role of AMPK in the control of mammalian autophagy. Inhibition of AMPK activity by compound C or by transfection with a dominant negative form of AMPK almost completely inhibited autophagy. These results suggest that the inhibition of autophagy by AICAR is not related to its ability to activate AMPK. We conclude that in mammalian cells, as in yeast, AMPK is required for autophagy.

Received for publication, June 8, 2006 , and in revised form, September 5, 2006.

^* This work was supported by institutional funding from the Institut National de la Santé et de la Recherche Médicale (INSERM) and from the University of Paris-Sud 11, and by a grant from the Association pour la Recherche sur le Cancer (ARC) (n°3503, to P. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by an ARC Fellowship.

² To whom correspondence should be addressed: Dept. of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Tel.: 31-20-5665159; Fax: 31-20-6915519; E-mail: a.j.meijer{at}amc.uva.nl.

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