The unfolded protein response is shaped by the NMD pathway

EMBO Rep. 2015 May;16(5):599-609. doi: 10.15252/embr.201439696. Epub 2015 Mar 25.


Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), an essential adaptive intracellular pathway that relieves the stress. Although the UPR is an evolutionarily conserved and beneficial pathway, its chronic activation contributes to the pathogenesis of a wide variety of human disorders. The fidelity of UPR activation must thus be tightly regulated to prevent inappropriate signaling. The nonsense-mediated RNA decay (NMD) pathway has long been known to function in RNA quality control, rapidly degrading aberrant mRNAs, and has been suggested to regulate subsets of normal mRNAs. Here, we report that the NMD pathway regulates the UPR. NMD increases the threshold for triggering the UPR in vitro and in vivo, thereby preventing UPR activation in response to normally innocuous levels of ER stress. NMD also promotes the timely termination of the UPR. We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1α, whose NMD-dependent degradation partly underpins this process. Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD's ability to regulate normal mRNAs.

Keywords: ER stress; IRE1; NMD; UPR; cancer.

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum Stress / genetics
  • Endoribonucleases / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Gene Order
  • Genetic Vectors / genetics
  • Mice
  • Mice, Knockout
  • Nonsense Mediated mRNA Decay*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Unfolded Protein Response / genetics*


  • DNA-Binding Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases