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Genes Dev. 2017 Aug 15;31(16):1655-1665. doi: 10.1101/gad.305441.117. Epub 2017 Sep 13.

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

Author information

1
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
2
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
3
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
5
Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
6
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

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.

KEYWORDS:

CaMKII; O-GlcNAcylation; Ulk; autophagy; glucagon; glucose production

PMID:
28903979
PMCID:
PMC5647936
DOI:
10.1101/gad.305441.117
[Indexed for MEDLINE]
Free PMC Article

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