Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1-Mediated NF-B Activation and

NF-B is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-B and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1 through the adapter protein TRAF2. ER stress-induced NF-B activation is impaired in IRE1 knockdown cells and IRE1/ MEFs. We found, however, that inhibiting NF-B significantly de-creased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-) was IRE1 and NF-B dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF--induced activation of NF-B and c-Jun N-terminal kinase and turns TNF- from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF- induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor. The endoplasmic reticulum (ER) is the organelle where protein folding occurs prior to transport to the extracellula