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.

胰腺β细胞在代谢应激过程中对胰岛素需求增加的反应能力主要取决于核糖体的体内稳态和功能。过度和持久地刺激胰岛素分泌会引起内质网（ER）应激，未反应的蛋白反应和β细胞凋亡。在这里，我们显示糖尿病易感基因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因子。JAZF1被排除在细胞核之外，在代谢压力和糖尿病中其表达水平降低。Jazf1的基因删除导致蛋白质合成的整体损害，这种损害是由核糖体蛋白质合成，核糖体RNA加工和氨酰基合成酶表达的缺陷介导的，从而诱导内质网应激并增加β细胞对凋亡的敏感性。重要的是，在小鼠T2D胰岛和暴露于代谢应激的人类胰岛中，JAZF1功能及其多效性作用受到损害。我们的研究确定JAZF1是β细胞中代谢应激的主要介质。