Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation.

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.

• Authors: Hai-Bin Ruan, Yina Ma, Sara Torres, Bichen Zhang, Colleen Feriod, Ryan M Heck, Kevin Qian, Minnie Fu, Xiuqi Li, Michael H Nathanson, Anton M Bennett, Yongzhan Nie, Barbara E Ehrlich, Xiaoyong Yang
• Journal: Genes & development (Genes Dev) Vol. 31 Issue 16 Pg. 1655-1665 (08 15 2017) ISSN: 1549-5477 [Electronic] United States
• PMID: 28903979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 Ruan et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• Atg5 protein, mouse
• Autophagy-Related Protein 5
• Inositol 1,4,5-Trisphosphate Receptors
• Glucagon
• N-Acetylglucosaminyltransferases
• Autophagy-Related Protein-1 Homolog
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Adaptation, Biological
• Animals
• Autophagy
• Autophagy-Related Protein 5 (physiology)
• Autophagy-Related Protein-1 Homolog (metabolism)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Cells, Cultured
• Glucagon (pharmacology)
• HEK293 Cells
• HeLa Cells
• Humans
• Inositol 1,4,5-Trisphosphate Receptors (metabolism)
• Liver (drug effects, enzymology, metabolism)
• Mice, Inbred C57BL
• N-Acetylglucosaminyltransferases (metabolism, physiology)
• Nutritional Physiological Phenomena