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

Abstract

Highlights d JAZF1 localizes in the nucleus in high-glucose and metabolic stress conditions d JAZF1 mediates metabolic stress via endoplasmic reticulum and p53 stress pathways d JAZF1 regulates ribosome biogenesis and aminoacyl-tRNA synthetases d JAZF1 is a direct negative regulator of insulin gene transcription

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

“…The molecular function of the JAZF1 protein is largely unexplored. It is a transcription factor with three C2H2 zinc fingers, and studies have linked it to glucose production, lipid metabolism, ribosome biogenesis, metabolic disorders and pancreatic cancer (Kobiita et al, 2020; Liao et al, 2019; Nakajima et al, 2004; Zhou et al, 2020). The JAZF1 protein has a homolog in S. cerevisiae called Sfp1 (Figure 6A), an essential transcription factor involved in regulation of ribosomal protein (RP), ribosomal biogenesis(RiBi) and cell cycle genes, responding to nutrients and stress through regulation by TORC1 (Lempiainen et al, 2009; Marion et al, 2004).…”

Association of the JAZF1 Variant in Adults With a Parental History of Type 2 Diabetes Mellitus In Pakistan

“…Kobiita et al conducted a study regarding the role of JAZF1 in the homeostatic control of ribosome biogenesis and function in metabolic stress. They found that SNP rs1635852 located in intron X of JAZF1 is a key factor in pancreatic beta-cell for mediating metabolic stress signals and regulating protein translation in response to increased demand for insulin [ 27 ].…”

tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

“…These findings suggest that some T2D gene variants increase T2D risk by altering aaRS expression. Kobiita et al also found reduced JAZF1 expression in islets from two T1D patients when compared to four nondiabetic individuals, as well as in islets from eight-week-old NOD mice, a model of autoimmune diabetes [149]. RNA sequencing by Russell et al of FACS-purified pancreatic β-cells from four T1D patients and thirteen nondiabetic individuals showed no changes in JAZF1 or GARS1 expression and a nonsignificant trend for reduced DARS1 levels in T1D β-cells [130].…”

“…Kobiita et al recently demonstrated that the T2D susceptibility gene JAZF1, the expression of which is reduced in pancreatic islets of T2D patients, is a transcriptional activator of several aaRS-encoding genes [149]. Interestingly, Jazf1 deficiency in mouse β-cells resulted in reduced expression of Dars and Gars [149], the latter being the aaRS with highest expression in human pancreas [150]. Moreover, they also showed that Gars levels are reduced by 50% in db/db mouse islets, and Gars and Dars silencing sensitize pancreatic β-cells to ER stress-induced apoptosis.…”