Ruan Hai-Bin, Ma Yina, Torres Sara, Zhang Bichen, Feriod Colleen, Heck Ryan M, Qian Kevin, Fu Minnie, Li Xiuqi, Nathanson Michael H, Bennett Anton M, Nie Yongzhan, Ehrlich Barbara E, Yang Xiaoyong
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Genes Dev. 2017 Aug 15;31(16):1655-1665. doi: 10.1101/gad.305441.117. Epub 2017 Sep 13.
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.
饥饿诱导肝脏自噬，人们认为自噬可为其他器官提供营养物质，从而维持全身的稳态。在此，我们证明O-连接β-N-乙酰葡糖胺（O-GlcNAc）转移酶（OGT）是胰高血糖素刺激的肝脏自噬和对饥饿的代谢适应所必需的。小鼠肝脏中OGT的基因敲除会降低自噬通量以及葡萄糖和酮体的产生。在胰高血糖素诱导的钙信号传导过程中，钙/钙调蛋白依赖性激酶II（CaMKII）使OGT磷酸化，进而通过增强AMPK依赖性磷酸化来促进O-GlcNAc修饰和Ulk蛋白的激活。这些发现揭示了一种信号级联反应，即饥饿通过OGT磷酸化促进自噬，并确立了O-GlcNAc信号在将肝脏自噬与营养稳态相耦合中的重要性。
