George Washington University Cancer Center, Washington, DC 20052, USA; Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Department of Oncology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Cell Rep. 2018 Dec 4;25(10):2851-2865.e3. doi: 10.1016/j.celrep.2018.11.025.
The protein deacetylase SIRT1 (Sirtuin 1) regulates many cellular processes, including cell-cycle progression, DNA damage response, and metabolism. Although the centrosome is a key regulator of cell-cycle progression and genome stability, little is known concerning SIRT1 controlled centrosome-associated events. Here we report that the centrosome protein Plk2 is acetylated and undergoes deacetylation by SIRT1. Acetylation protects Plk2 from ubiquitination, and SIRT1-mediated deacetylation promotes ubiquitin-dependent degradation of Plk2. SIRT1 controls centriole duplication by temporally modulating centrosomal Plk2 levels. AURKA phosphorylates SIRT1 and promotes the SIRT1-Plk2 interaction in mitosis. In early-mid G, phosphorylated SIRT1 deacetylates and promotes Plk2 degradation. In late G, SIRT1 is hypophosphorylated and its affinity to Plk2 is decreased, resulting in a rapid accumulation of centrosomal Plk2, which contributes to the timely initiation of centriole duplication. Collectively, our findings uncover a critical role of SIRT1 in centriole duplication and provide a mechanistic insight into SIRT1-mediated centrosome-associated functions.
蛋白去乙酰化酶 SIRT1（Sirtuin 1）调节许多细胞过程，包括细胞周期进程、DNA 损伤反应和代谢。尽管中心体是细胞周期进程和基因组稳定性的关键调节剂，但对于 SIRT1 控制的中心体相关事件知之甚少。在这里，我们报告中心体蛋白 Plk2 被 SIRT1 乙酰化，并经历去乙酰化。乙酰化保护 Plk2 免受泛素化，而 SIRT1 介导的去乙酰化促进 Plk2 的泛素依赖性降解。SIRT1 通过暂时调节中心体 Plk2 水平来控制中心体复制。AURKA 磷酸化 SIRT1 并促进有丝分裂中 SIRT1-Plk2 相互作用。在早中期 G，磷酸化的 SIRT1 去乙酰化并促进 Plk2 降解。在晚期 G，SIRT1 去磷酸化，其与 Plk2 的亲和力降低，导致中心体 Plk2 的快速积累，这有助于中心体复制的及时启动。总之，我们的研究结果揭示了 SIRT1 在中心体复制中的关键作用，并为 SIRT1 介导的中心体相关功能提供了机制见解。
