The Diabetes Gene JAZF1 Is Essential for the Homeostatic Control of Ribosome Biogenesis and Function in Metabolic Stress

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. [Display omitted] •JAZF1 localizes in the nucleus in high-glucose and metabolic stress conditions•JAZF1 mediates metabolic stress via endoplasmic reticulum and p53 stress pathways•JAZF1 regulates ribosome biogenesis and aminoacyl-tRNA synthetases•JAZF1 is a direct negative regulator of insulin gene transcription JAZF1 has been identified in several GWASs as a type 2 diabetes susceptibility gene. Kobiita et al. demonstrate that JAZF1 is a transcriptional regulator that is translocated in the nucleus upon metabolic stress and in diabetes. The study also reveals numerous functions of JAZF1 in the regulation of genes involved in ribosome biogenesis and protein translation, including insulin gene transcription.