GCN2 phosphorylation of eIF2alpha activates NF-kappaB in response to UV irradiation

In response to UV irradiation, mammalian cells elicit a gene expression programme designed to repair damage and control cell proliferation and apoptosis. Important members of this stress response include the NF-kappaB (nuclear factor-kappaB) family. However, the mechanisms by which UV irradiation activates NF-kappaB are not well understood. In eukaryotes, a variety of environmental stresses are recognized and remediated by a family of protein kinases that phosphorylate the alpha subunit of eIF2 (eukaryotic initiation factor-2). In the present study we show that NF-kappaB in MEF (murine embryo fibroblast) cells is activated by UV-C and UV-B irradiation through a mechanism requiring eIF2alpha phosphorylation. The primary eIF2alpha kinase in response to UV is GCN2 (general control non-derepressible-2), with PEK/PERK (pancreatic eIF2alpha kinase/RNA-dependent-protein-kinase-like endoplasmic-reticulum kinase) carrying out a secondary function. Our studies indicate that lowered protein synthesis accompanying eIF2alpha phosphorylation, combined with eIF2alpha kinase-independent turnover of IkappaBalpha (inhibitor of kappaBalpha), reduces the levels of IkappaBalpha in response to UV irradiation. Release of NF-kappaB from the inhibitory IkappaBalpha would facilitate NF-kappaB entry into the nucleus and targeted transcriptional control. We also find that loss of GCN2 in MEF cells significantly enhances apoptosis in response to UV exposure similar to that measured in cells deleted for the RelA/p65 subunit of NF-kappaB. These results demonstrate that GCN2 is central to recognition of UV stress, and that eIF2alpha phosphorylation provides resistance to apoptosis in response to this environmental insult.