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

Cell Rep. 2020 Jul 7;32(1):107846. doi: 10.1016/j.celrep.2020.107846.

Abstract

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.

Keywords: ER stress; Jazf1; aminoacyl-tRNA synthetase; apoptosis; diabetes; insulin; rRNA processing; ribosomal proteins; ribosome biogenesis; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / metabolism
  • Animals
  • Apoptosis
  • Base Sequence
  • Cell Nucleus / metabolism*
  • Co-Repressor Proteins / genetics*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Susceptibility
  • Endoplasmic Reticulum Stress
  • Genetic Variation
  • Genome, Human
  • Homeostasis*
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Male
  • Mice
  • Protein Biosynthesis
  • Protein Transport
  • RNA Processing, Post-Transcriptional / genetics
  • RNA, Ribosomal / genetics
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomes / metabolism*
  • Signal Recognition Particle / metabolism
  • Stress, Physiological / genetics*
  • Transcription, Genetic

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Insulin
  • JAZF1 protein, human
  • JAZF1 protein, mouse
  • RNA, Ribosomal
  • Ribosomal Proteins
  • SRP54 protein, human
  • Signal Recognition Particle
  • Amino Acyl-tRNA Synthetases