Genes Dev. 31, 1655–1665 (2017)

In the liver, autophagy is thought to maintain systemic nutrient and energy balance upon starvation. Whereas glucagon is known to induce autophagy, the physiological function and mechanisms of glucagon-related autophagy are not well defined. O-linked β-N-acetylglucosamine (O-GlnNAc) signalling is critical to liver metabolism, and O-GlcNAc has been proposed to function as a nutrient sensor. Yang and colleagues find that O-GlcNAc transferase (OGT) is required for liver autophagy upon glucagon stimulation and in response to starvation.

Experiments with mice deficient for hepatic Atg5 showed Atg5-mediated autophagy in the liver was required for glucagon to induce the starvation response. Treatment with O-GlcNAcase inhibitor suggested that OGT promoted autophagy. Liver-specific OGT knockout indicated that hepatic OGT mediated metabolic adaptations to starvation. Further studies suggested calcium/calmodulin-dependent kinase II (CaMKII) phosphorylated OGT to promote autophagy, and this was confirmed in CAMKII liver-specific knockout mice. The authors then showed that O-GlcNAcylation controls autophagy by modulating Ulk1 phosphorylation and activity.

This study delineates that glucagon induces calcium signalling, leading to CAMKII phosphorylation of OGT, which promotes Ulk1 O-GlcNAcylation and autophagy, linking liver autophagy to systemic nutrient homeostasis.