Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy throughOGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.
Bibliographical noteFunding Information:
We thank Ira Tabas and Lale Ozcan (Columbia University) for providing liver tissues of Camk2g-LKO and CA-CaMKII mice, E. Olson and J. Backs (University of Texas Southwestern) for providing Camk2gF/F mice, A.R. Marks (Columbia University) for providing Itpr1F/F mice, A. Iwasaki and G.I. Shulman (Yale University) for providing Atg5F/F mice, T. Melia (Yale University) for providing HeLa cells expressing YFP-LC3, X. Yu (University of Michigan) for providing Myc-OGT plasmids, and H. Singer (Albany Medical College) for providing CaMKII plasmids and adenovirus. We thank Michael Jurczak for technical assistance. This work was supported by the National Institutes of Health (NIH; grants R01DK089098, R01DK102648, and CT DPH2014-0139), the American Cancer Society, and the Ellison Medical Foundation to X.Y.; NIH grant P01DK57751 to A.M.B., B.E.E., M.H.N.,
and X.Y.; and NIH grant P30DK34989 and American Heart Association grant 14SDG20120052 to H.-B.R.
© 2017 Ruan et al.
- Glucose production