Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2

Numerous stressful conditions activate kinases that phosphorylate the alpha subunit of translation initiation factor 2 (eIF2alpha), thus attenuating mRNA translation and activating a gene expression program known as the integrated stress response. It has been noted that conditions associated with eIF2alpha phosphorylation, notably accumulation of unfolded proteins in the endoplasmic reticulum (ER), or ER stress, are also associated with activation of nuclear factor kappa B (NF-B-K) and that eIF2alpha phosphorylation is required for NF-B-K activation by ER stress. We have used a pharmacologically activable version of pancreatic ER kinase (PERK, an ER stress-responsive eIF2alpha kinase) to uncouple eIF2alpha phosphorylation from stress and found that phosphorylation of eIF2alpha is both necessary and sufficient to activate both NF-KB DNA binding and an NF-B-K reporter gene. eIF2alpha phosphorylation-dependent NF-B-K activation correlated with decreased levels of the inhibitor I(K)Balpha protein. Unlike canonical signaling pathways that promote I(K)Balpha phosphorylation and degradation, eIF2alpha phosphorylation did not increase phosphorylated I(K)Balpha levels or affect the stability of the protein. Pulse-chase labeling experiments indicate instead that repression of I(K)Balpha translation plays an important role in NF-B-K activation in cells experiencing high levels of eIF2alpha phosphorylation. These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-B-K during ER stress.