the association of ampk with ulk1 regulates autophagyampk的协会ulk1调节自噬.pdfVIP

The Association of AMPK with ULK1 Regulates Autophagy Jong Woo Lee, Sungman Park, Yoshinori Takahashi, Hong-Gang Wang* Department of Pharmacology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America Abstract Autophagy is a highly orchestrated intracellular bulk degradation process that is activated by various environmental stresses. The serine/threonine kinase ULK1, like its yeast homologue Atg1, is a key initiator of autophagy that is negatively regulated by the mTOR kinase. However, the molecular mechanism that controls the inhibitory effect of mTOR on ULK1- mediated autophagy is not fully understood. Here we identified AMPK, a central energy sensor, as a new ULK1-binding partner. We found that AMPK binds to the PS domain of ULK1 and this interaction is required for ULK1-mediated autophagy. Interestingly, activation of AMPK by AICAR induces 14-3-3 binding to the AMPK-ULK1-mTORC1 complex, which coincides with raptor Ser792 phosphorylation and mTOR inactivation. Consistently, AICAR induces autophagy in TSC2-deficient cells expressing wild-type raptor but not the mutant raptor that lacks the AMPK phosphorylation sites (Ser722 and Ser792). Taken together, these results suggest that AMPK association with ULK1 plays an important role in autophagy induction, at least in part, by phosphorylation of raptor to lift the inhibitory effect of mTOR on the ULK1 autophagic complex. Citation: Lee JW, Park S, Takahashi Y, Wang H-G (2010) The Association of AMPK with ULK1 Regulates Autophagy. PLoS ONE 5(11): e15394. doi:10.1371/ journal.pone.0015394 Editor: Gen Sheng Wu, Wayne State University School of Medicine, United States of America Received July 26, 2010; Accepted September 4, 2010; Published November 3, 2010 Copyright: 2010 Lee et a