Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, HPL H36, 8093 Zürich, Switzerland.
MWSchmid GmbH, Möhrlistrasse 25, 8006 Zurich, Switzerland.
Cell Rep. 2020 Jul 7;32(1):107846. doi: 10.1016/j.celrep.2020.107846.
The ability of pancreatic β-cells to respond to increased demands for insulin during metabolic stress critically depends on proper ribosome homeostasis and function. Excessive and long-lasting stimulation of insulin secretion can elicit endoplasmic reticulum (ER) stress, unfolded protein response, and β-cell apoptosis. Here we show that the diabetes susceptibility gene JAZF1 is a key transcriptional regulator of ribosome biogenesis, global protein, and insulin translation. JAZF1 is excluded from the nucleus, and its expression levels are reduced upon metabolic stress and in diabetes. Genetic deletion of Jazf1 results in global impairment of protein synthesis that is mediated by defects in ribosomal protein synthesis, ribosomal RNA processing, and aminoacyl-synthetase expression, thereby inducing ER stress and increasing β-cell susceptibility to apoptosis. Importantly, JAZF1 function and its pleiotropic actions are impaired in islets of murine T2D and in human islets exposed to metabolic stress. Our study identifies JAZF1 as a central mediator of metabolic stress in β-cells.
胰岛β细胞在代谢应激时响应胰岛素需求增加的能力，主要取决于核糖体的稳态和功能。胰岛素分泌的过度和持久刺激会引发内质网（ER）应激、未折叠蛋白反应和β细胞凋亡。在这里，我们发现糖尿病易感基因 JAZF1 是核糖体生物发生、整体蛋白和胰岛素翻译的关键转录调节剂。JAZF1 从核中被排除，并且其表达水平在代谢应激和糖尿病中降低。Jazf1 的基因缺失会导致蛋白质合成的全面障碍，这是由核糖体蛋白合成、核糖体 RNA 加工和氨酰-tRNA 合成酶表达的缺陷介导的，从而诱导 ER 应激并增加β细胞对凋亡的易感性。重要的是，JAZF1 的功能及其多效性作用在 T2D 小鼠胰岛和暴露于代谢应激的人胰岛中受到损害。我们的研究将 JAZF1 确定为β细胞代谢应激的中心介质。
