Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation
- Hai-Bin Ruan1,2,7,
- Yina Ma3,7,
- Sara Torres1,
- Bichen Zhang1,3,
- Colleen Feriod3,4,
- Ryan M. Heck2,
- Kevin Qian1,
- Minnie Fu1,
- Xiuqi Li1,
- Michael H. Nathanson5,
- Anton M. Bennett1,4,
- Yongzhan Nie6,
- Barbara E. Ehrlich3,4 and
- Xiaoyong Yang1,3
- 1Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 2Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455, USA;
- 3Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 4Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 5Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
- 6State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
- Corresponding author: xiaoyong.yang{at}yale.edu
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↵7 These authors contributed equally to this work.
Abstract
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 through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.305441.117.
- Received December 23, 2016.
- Accepted August 14, 2017.
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