Autocrine Tumor Necrosis Factor Alpha Links Endoplasmic Reticulum Stress to the Membrane Death Receptor Pathway through IRE1α-Mediated NF-κB Activation and Down-Regulation of TRAF2 Expression

Abstract

NF-κB 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-κB 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 IRE1α through the adapter protein TRAF2. ER stress-induced NF-κB activation is impaired in IRE1α knockdown cells and IRE1α^−/− MEFs. We found, however, that inhibiting NF-κB significantly decreased 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-α) was IRE1α and NF-κB 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-α-induced activation of NF-κB and c-Jun N-terminal kinase and turns TNF-α from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-α induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.

We thank B. M. J. Foxwell for adenoviral vector containing human TNF-α promoter (−1173bp) with the 3′ untranslated region of the human TNF-α gene and D. W. Ballard for mutant IκB, IKK-α, IKK-β, and IKK-γ plasmids.

Portions of this work were supported by grant DK 42394 from NIH.