Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, HPL H36, 8093 Zurich, Switzerland.
Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, HPL H36, 8093 Zurich, Switzerland; Medical Faculty, University of Zurich, Zurich, Switzerland.
Cell Rep. 2019 Sep 10;28(11):2892-2904.e7. doi: 10.1016/j.celrep.2019.08.025.
Cyclin-dependent kinases (CDKs) contribute to vital cellular processes including cell cycle regulation. Loss of CDKs is associated with impaired insulin secretion and β cell survival; however, the function of CDK8 in β cells remains elusive. Here, we report that genetic ablation of Cdk8 improves glucose tolerance by increasing insulin secretion. We identify OSBPL3 as a CDK8-dependent phosphoprotein, which acts as a negative regulator of insulin secretion in response to glucose. We also show that embryonic gene silencing of neuropeptide Y in β cells is compromised in Cdk8-null mice, leading to continued expression into adulthood. Cdk8 ablation in β cells aggravates apoptosis and induces de novo expression of neuropeptides upon oxidative stress. Moreover, pancreatic islets exposed to stress display augmented apoptosis in the presence of these same neuropeptides. Our results reveal critical roles for CDK8 in β cell function and survival during metabolic stress that are in part mediated through de novo expression of neuropeptides.
细胞周期蛋白依赖性激酶（CDKs）参与包括细胞周期调控在内的重要细胞过程。CDKs 的缺失与胰岛素分泌受损和β细胞存活有关；然而，CDK8 在β细胞中的功能仍然难以捉摸。在这里，我们报告说，Cdk8 的基因缺失通过增加胰岛素分泌来改善葡萄糖耐量。我们确定 OSBPL3 是一种 CDK8 依赖性磷酸化蛋白，它作为葡萄糖反应中胰岛素分泌的负调节剂。我们还表明，β 细胞中神经肽 Y 的胚胎基因沉默在 Cdk8 缺失小鼠中受到损害，导致其在成年后持续表达。β 细胞中 Cdk8 的缺失会加剧细胞凋亡，并在氧化应激时诱导新的神经肽表达。此外，在存在这些相同神经肽的情况下，暴露于应激的胰岛会显示出增强的细胞凋亡。我们的研究结果揭示了 CDK8 在代谢应激期间β细胞功能和存活中的关键作用，这些作用部分是通过新表达神经肽介导的。
