Activation Signal of Nuclear Factor-κB in Response to Endoplasmic Reticulum Stress is Transduced via IRE1 and Tumor Necrosis Factor Receptor-Associated Factor 2

• Published in: Biological & pharmaceutical bulletin 2003, Vol.26(7), pp.931-935
• Main Authors: Kaneko, Masayuki, Niinuma, Yoshifumi, Nomura, Yasuyuki
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Line; Cell physiology; Effects of physical and chemical agents; endoplasmic reticulum (ER) stress; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoribonucleases; Fundamental and applied biological sciences. Psychology; Humans; IRE1; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular and cellular biology; NF-kappa B - genetics; NF-kappa B - metabolism; nuclear transcription factor-κB (NF-κB); Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins - genetics; Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Thapsigargin - toxicity; TNF Receptor-Associated Factor 2; TRAF2
• ISSN: 0918-6158; 1347-5215
• 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-κB (NF-κB) 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-κB induced by ER stress. NF-κB 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-κB by ER stress. These results suggest that ER stress-induced NF-κB activation is also mediated by the IRE1-TRAF2 pathway, as well as JNK activation.