Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
Center for RNA Research, Institute for Basic Science, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
Cell Rep. 2018 Dec 4;25(10):2878-2890.e4. doi: 10.1016/j.celrep.2018.11.042.
Unc-51-like-kinase 1 (ULK1) is a target of both the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), whose role is to facilitate the initiation of autophagy in response to starvation. Upon glucose starvation, dissociation of mTOR from ULK1 and phosphorylation by AMPK leads to the activation of ULK1 activity. Here, we provide evidence that ULK1 is the attachment of O-linked N-acetylglucosamine (O-GlcNAcylated) on the threonine 754 site by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation. ULK1 O-GlcNAcylation occurs after dephosphorylation of adjacent mTOR-dependent phosphorylation on the serine 757 site by protein phosphatase 1 (PP1) and phosphorylation by AMPK. ULK1 O-GlcNAcylation is crucial for binding and phosphorylation of ATG14L, allowing the activation of lipid kinase VPS34 and leading to the production of phosphatidylinositol-(3)-phosphate (PI(3)P), which is required for phagophore formation and initiation of autophagy. Our findings provide insights into the crosstalk between dephosphorylation and O-GlcNAcylation during autophagy and specify a molecular framework for potential therapeutic intervention in autophagy-related diseases.
UNC-51 样激酶 1（ULK1）是雷帕霉素靶蛋白（mTOR）和 AMP 激活的蛋白激酶（AMPK）的共同靶标，其作用是促进自噬的起始以响应饥饿。在葡萄糖饥饿时，mTOR 与 ULK1 解离并被 AMPK 磷酸化，导致 ULK1 活性的激活。在这里，我们提供证据表明，葡萄糖饥饿时，O-连接的 N-乙酰葡萄糖胺转移酶（OGT）将 O-连接的 N-乙酰葡萄糖胺（O-GlcNAc）连接到 ULK1 的苏氨酸 754 位上。ULK1 的 O-GlcNAcylation 发生在丝氨酸 757 位上的 mTOR 依赖性磷酸化被蛋白磷酸酶 1（PP1）去磷酸化以及 AMPK 磷酸化之后。ULK1 的 O-GlcNAcylation 对于结合和磷酸化 ATG14L 至关重要，从而激活脂质激酶 VPS34，导致产生磷脂酰肌醇-3-磷酸（PI（3）P），这对于吞噬体的形成和自噬的起始是必需的。我们的发现深入了解了自噬过程中去磷酸化和 O-GlcNAcylation 之间的串扰，并为自噬相关疾病的潜在治疗干预提供了分子框架。
