Authors: Hildegard I.D. Mack, Bin Zheng, John Asara and Sheila M. Thomas

Hildegard I.D. Mack

Cancer Biology Program; Division of Hematology/Oncology; Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School; Boston, MA USA; Institute of Pathology; Technische Universität München; Munich, Germany; Current affiliation: The Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

Bin Zheng

Institute for Cancer Genetics; Departments of Dermatology and Pathology & Cell Biology; Herbert Irving Comprehensive Cancer Center; Columbia University; New York, NY USA

John Asara

Division of Signal Transduction; Department of Medicine; Beth Israel Deaconess Medical Center; Boston, MA USA

Sheila M. Thomas

Corresponding author: sthomas@fas.harvard.edu
Cancer Biology Program; Division of Hematology/Oncology; Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School; Boston, MA USA; Division of Medical Sciences; Graduate School of Arts and Sciences; Harvard University; Cambridge, MA USA

Abstract:
Autophagy is activated in response to a variety of cellular stresses including metabolic stress. While elegant genetic studies in yeast have identified the core autophagy machinery, the signaling pathways that regulate this process are less understood. AMPK is an energy sensing kinase and several studies have suggested that AMPK is required for autophagy. The biochemical connections between AMPK and autophagy, however, have not been elucidated. In this report, we identify a biochemical connection between a critical regulator of autophagy, ULK1, and the energy sensing kinase, AMPK. ULK1 forms a complex with AMPK, and AMPK activation results in ULK1 phosphorylation. Moreover, we demonstrate that the immediate effect of AMPK-dependent phosphorylation of ULK1 results in enhanced binding of the adaptor protein YWHAZ/14-3-3ζ; and this binding alters ULK1 phosphorylation in vitro. Finally, we provide evidence that both AMPK and ULK1 regulate localization of a critical component of the phagophore, ATG9, and that some of the AMPK phosphorylation sites on ULK1 are important for regulating ATG9 localization. Taken together these data identify an ULK1-AMPK signaling cassette involved in regulation of the autophagy machinery.

Received: August 9, 2011; Accepted: May 2, 2012; Published Online: August 1, 2012

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