PDF(Pubmed)
Abstract：
Regulation of SIRT1 activity is vital to energy homeostasis and plays important roles in many diseases. We previously showed that insulin triggers the epigenetic regulator DBC1 to prime SIRT1 for repression by the multifunctional trafficking protein PACS-2. Here, we show that liver DBC1/PACS-2 regulates the diurnal inhibition of SIRT1, which is critically important for insulin-dependent switch in fuel metabolism from fat to glucose oxidation. We present the x-ray structure of the DBC1 S1-like domain that binds SIRT1 and an NMR characterization of how the SIRT1 N-terminal region engages DBC1. This interaction is inhibited by acetylation of K112 of DBC1 and stimulated by the insulin-dependent phosphorylation of human SIRT1 at S162 and S172, catalyzed sequentially by CK2 and GSK3, resulting in the PACS-2-dependent inhibition of nuclear SIRT1 enzymatic activity and translocation of the deacetylase in the cytoplasm. Finally, we discuss how defects in the DBC1/PACS-2-controlled SIRT1 inhibitory pathway are associated with disease, including obesity and non-alcoholic fatty liver disease.
摘要：
SIRT1活性的调节对能量稳态至关重要，在许多疾病中起着重要作用。我们先前表明，胰岛素触发表观遗传调节剂DBC1以引发SIRT1，以抑制多功能运输蛋白PACS-2。这里,我们显示肝脏DBC1/PACS-2调节SIRT1的昼夜抑制，这对于胰岛素依赖性燃料代谢从脂肪到葡萄糖氧化的转变至关重要。我们介绍了结合SIRT1的DBC1S1样结构域的X射线结构，以及SIRT1N末端区域如何与DBC1接合的NMR表征。这种相互作用被DBC1的K112乙酰化抑制，并被人SIRT1在S162和S172的胰岛素依赖性磷酸化刺激，由CK2和GSK3依次催化，导致PACS-2依赖性抑制核SIRT1酶活性和脱乙酰酶在细胞质中的易位。最后,我们讨论了DBC1/PACS-2控制的SIRT1抑制途径中的缺陷如何与疾病相关，包括肥胖和非酒精性脂肪性肝病。
