Phosphorylation of the α subunit of eukaryotic initiation factor 2 is required for activation of NF-κB in response to diverse cellular stresses

Hao Yuan Jiang, Sheree A. Wek, Barbara C. McGrath, Donalyn Scheuner, Randal J. Kaufman, Douglas R. Cavener, Ronald C. Wek

Research output: Contribution to journalArticle

308 Scopus citations

Abstract

Nuclear factor κB (NF-κB) serves to coordinate the transcription of genes in response to diverse environmental stresses. In this report we show that phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2) is fundamental to the process by which many stress signals activate NF-κB. Phosphorylation of this translation factor is carried out by a family of protein kinases that each respond to distinct stress conditions. During impaired protein folding and assembly in the endoplasmic reticulum (ER), phosphorylation of eIF2α by PEK (Perk or EIF2AK3) is essential for induction of NF-κB transcriptional activity. The mechanism by which NF-κB is activated during ER stress entails the release, but not the degradation, of the inhibitory protein IκB. During amino acid deprivation, phosphorylation of eIF2α by GCN2 (EIF2AK4) signals the activation of NF-κB. Furthermore, inhibition of general translation or transcription by cycloheximide and actinomycin D, respectively, elicits the eIF2α phosphorylation required for induction of NF-κB. Together, these studies suggest that eIF2α kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIFα phosphorylation is central to activation of the NF-κB. The absence of NF-κB-mediated transcription and its antiapoptotic function provides an explanation for why eIF2α kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease.

Original languageEnglish (US)
Pages (from-to)5651-5663
Number of pages13
JournalMolecular and cellular biology
Volume23
Issue number16
DOIs
StatePublished - Aug 2003

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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