miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis

Nat Commun. 2016 May 13;7:11422. doi: 10.1038/ncomms11422.

Abstract

The ability of the unfolded protein response, UPR, to regulate cell homeostasis through both gene expression and protein synthesis has been well documented. One primary pro-apoptotic protein that responds to both PERK and Ire1 signalling is the CHOP/GADD153 transcription factor. Although CHOP deficiency delays onset of cell death, questions remain regarding how CHOP regulates apoptosis. Here, we provide evidence demonstrating that CHOP/GADD153-dependent apoptosis reflects expression of micro-RNA, miR-216b. MiR-216b accumulation requires PERK-dependent induction of CHOP/GADD153, which then directly regulates miR-216b expression. As maximal expression of miR-216b is antagonized by Ire1, miR-216b accumulation reflects the convergence of PERK and Ire1 activities. Functionally, miR-216b directly targets c-Jun, thereby reducing AP-1-dependent transcription and sensitizing cells to ER stress-dependent apoptosis. These results provide direct insight into the molecular mechanisms of CHOP/GADD153-dependent cell death.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Unfolded Protein Response
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • DDIT3 protein, human
  • MIRN216 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor CHOP
  • EIF2AK3 protein, human
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases