Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2

Biol Pharm Bull. 2003 Jul;26(7):931-5. doi: 10.1248/bpb.26.931.


Conditions that perturb the function of the endoplasmic reticulum (ER) lead to an accumulation of proteins and subsequent induction of several responses, such as an increased expression of ER-resident chaperones involved in protein folding and activation of c-jun N-terminal kinase (JNK). These responses are mediated by a transmembrane kinase/ribonuclease, IRE1, which transduces the signal from the ER lumen to the cytosol. Although nuclear transcription factor-kappaB (NF-kappaB) is also activated by ER stress, whether this response depends on IRE1 is unknown. In this study, we show that IRE1 is involved in the activation of NF-kappaB induced by ER stress. NF-kappaB was activated by ER stress-inducing agents, thapsigargin and tunicamycin. The activation was inhibited by a dominant-negative IRE1. In addition, a dominant-negative TRAF2 also suppressed the activation of NF-kappaB by ER stress. These results suggest that ER stress-induced NF-kappaB activation is also mediated by the IRE1-TRAF2 pathway, as well as JNK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoribonucleases
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 2
  • Thapsigargin / toxicity


  • Membrane Proteins
  • NF-kappa B
  • Proteins
  • TNF Receptor-Associated Factor 2
  • Thapsigargin
  • ERN2 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases