Cellular and Molecular Life Sciences

, Volume 70, Issue 19, pp 3493–3511 | Cite as

The eIF2α kinases: their structures and functions

  • Neysan Donnelly
  • Adrienne M. Gorman
  • Sanjeev Gupta
  • Afshin Samali
Review

Abstract

Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2α on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell’s armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2α is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2α kinases in their kinase domains, underlying their common role in phosphorylating eIF2α, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2α kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2α kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed.

Keywords

eIF2α kinases Cell stress PKR-like ER kinase (PERK) Protein kinase double-stranded RNA-dependent (PKR) General control non-derepressible-2 (GCN2) Heme-regulated inhibitor (HRI) Activating transcription factor 4 (ATF4) 

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Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Neysan Donnelly
    • 1
    • 2
    • 4
  • Adrienne M. Gorman
    • 1
    • 2
  • Sanjeev Gupta
    • 1
    • 3
  • Afshin Samali
    • 1
    • 2
  1. 1.Apoptosis Research CenterNational University of IrelandGalwayIreland
  2. 2.School of Natural SciencesNational University of IrelandGalwayIreland
  3. 3.School of MedicineNational University of IrelandGalwayIreland
  4. 4.Department of Molecular Cell BiologyMax Planck Institute of BiochemistryMunichGermany

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