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

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

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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 throughOGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.

Original languageEnglish (US)
Pages (from-to)1655-1665
Number of pages11
JournalGenes and Development
Volume31
Issue number16
DOIs
StatePublished - Aug 15 2017

Bibliographical note

Publisher Copyright:
© 2017 Ruan et al.

Keywords

  • Autophagy
  • CaMKII
  • Glucagon
  • Glucose production
  • O-GlcNAcylation
  • ULK

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