GCN2 phosphorylation of eIF2α activates NF-κB in response to UV irradiation

Hao Yuan Jiang, Ronald C. Wek

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

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-κB (nuclear factor-κB) family. However, the mechanisms by which UV irradiation activates NF-κB are not well understood. In eukaryotes, a variety of environmental stresses are recognized and remediated by a family of protein kinases that phosphorylate the α subunit of eIF2 (eukaryotic initiation factor-2). In the present study we show that NF-κB in MEF (murine embryo fibroblast) cells is activated by UV-C and UV-B irradiation through a mechanism requiring eIF2α phosphorylation. The primary eIF2α kinase in response to UV is GCN2 (general control non-derepressible-2), with PEK/PERK (pancreatic eIF2α kinase/RNA- dependent-protein-kinase-like endoplasmic-reticulum kinase) carrying out a secondary function. Our studies indicate that lowered protein synthesis accompanying eIF2α phosphorylation, combined with eIF2α kinase-independent turnover of Iκ Bα (inhibitor of κ Bα), reduces the levels of Iκ Bα in response to UV irradiation. Release of NF-κB from the inhibitory Iκ Bα would facilitate NF-κB 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-κB. These results demonstrate that GCN2 is central to recognition of UV stress, and that eIF2α phosphorylation provides resistance to apoptosis in response to this environmental insult.

Original languageEnglish (US)
Pages (from-to)371-380
Number of pages10
JournalBiochemical Journal
Volume385
Issue number2
DOIs
StatePublished - Jan 15 2005

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Keywords

  • Eukaryotic initiation factor-2 (eIF2)
  • General control non-derepressible-2 (GCN2)
  • Nuclear factor κB (NF-κB)
  • Stress response
  • Translational Control
  • UV irradiation

ASJC Scopus subject areas

  • Biochemistry

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