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

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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 in volved 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 TRE1- TRAF2 pathway, as well as JNK activation.
公益社団法人日本薬学会の論文
2003-07-01